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play a pivotal role in COPD pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">3</span></a> Oxidants activate the transcription of the pro-inflammatory factor NF-kB in macrophages and bronchial and alveolar epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a> This leads to the recruitment and activation of other inflammatory cells such as neutrophils&#44; which can also induce the additional release of reactive oxygen intermediates and proteases<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">5</span></a> involved in emphysematous destruction&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">6</span></a> In addition to this&#44; it has also been reported that COPD patients have diminished antioxidant defences&#44; which can enhance this oxidative stress-driven inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">7</span></a> Specifically&#44; it has been shown that the levels of Nuclear factor erythroid-2-related factor-2 &#40;Nrf2&#41;&#44; the master transcription factor involved in the antioxidant defence&#44; and its stabilizer DJ1&#44; are reduced in lungs of COPD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The activity of antioxidant enzymes is crucial against the action of free radicals&#44; either by stabilizing or deactivating them before they damage cellular components&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> Among them&#44; extracellular superoxide dismutase &#40;EC-SOD&#44; EC 1&#46;15&#46;1&#46;1&#41; is a main oxidant scavenger in extracellular space&#44; including lung interstitium&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">9</span></a> Thus&#44; high levels of EC-SOD can be found in lung extracellular matrix&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">10</span></a> where it binds with heparin sulphate proteoglycan and fibulin-5&#44; an integrin-binding matricellular protein involved in elastogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">11&#44;12</span></a> There&#44; EC-SOD catalyzes the reduction of superoxide radical to hydrogen peroxide&#44; a less reactive molecule&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> Moreover&#44; several preclinical studies have also shown that EC-SOD can effectively inhibit lung inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">14&#44;15</span></a> In this regard&#44; it has been suggested that the anti-inflammatory activity of EC-SOD could be achieved either by reducing the release of pro-inflammatory cytokines from phagocytes or by inhibiting the production of extracellular matrix fragments that act as chemoattractants for inflammatory cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">14&#44;16</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">As the only antioxidant scavenging superoxide in the pulmonary extracellular compartment&#44; EC-SOD is thought to play a relevant role in COPD&#46; Hence&#44; it has been shown that smokers carrying the EC-SOD polymorphism R213G have a reduced risk of developing COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">17&#44;18</span></a> Moreover&#44; it has been reported that COPD patients have higher levels of EC-SOD in induced sputum but not in BALF as compared to control non-smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> Regarding EC-SOD levels in lung tissue of COPD patients&#44; data available are scarce and contradictory&#46; Whereas one study found decreased expression of EC-SOD in lung vessels and bronchioles of COPD patients&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> another reported no differences among subjects with COPD and controls&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of the present study is to analyze the antioxidant expression in COPD lungs not only by determining levels of EC-SOD&#44; 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Spain&#41;&#46; The Hospital&#39;s ethics committee approved the study and written informed consent was obtained from all subjects&#46; Pulmonary function was assessed through spirometry according to ERS recommendations<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a> using standard equipment &#40;Masterlab&#59; Jaeger&#44; W&#252;rzburg&#44; Germany&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Subjects were divided into COPD &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41; and non-COPD patients &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41;&#46; All of them were free of acute lung infections in the last three weeks and none had received chemotherapy before surgery&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Tissue processing</span><p id="par0040" class="elsevierStylePara elsevierViewall">The excised lungs or lobes were inflated immediately after surgery at 30<span class="elsevierStyleHsp" style=""></span>cm of water pressure for 1<span class="elsevierStyleHsp" style=""></span>h with 4&#37; &#40;w&#47;v&#41; formaldehyde in 0&#46;1<span class="elsevierStyleHsp" style=""></span>M phosphate-buffered saline solution &#40;pH 7&#46;4&#41;&#46; In patients with lung cancer&#44; tissue samples were taken from the non-malignant lung tissue as demonstrated by pathologist examination&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Samples to be analyzed by light microscopy were then immersed in fixative for 24<span class="elsevierStyleHsp" style=""></span>h&#46; After that&#44; 2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>0&#46;3<span class="elsevierStyleHsp" style=""></span>cm randomly selected tissue blocks were excised&#44; embedded in paraffin&#44; cut into 4-&#956;m sections and mounted on positive charged slides Starfrost Plus &#40;Menzel-Gl&#228;ser&#44; Braunschweig&#44; Germany&#41;&#46; Four consecutive serial sections from a representative block from each patient were selected for histologic&#44; histochemical and immunohistochemical analyses&#46; Every first section was stained with haematoxylin and eosin &#40;H&#38;E&#41; to reveal lung histology&#46; The second and third sections were reserved for immunolocalization of EC-SOD and fibulin-5&#46; The last section in each set was stained with Verhoeff&#39;s haematoxylin to detect pulmonary elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">On another front&#44; after initial fixation&#44; samples to be studied by transmission electron microscopy were cut into 1&#8211;2-mm thick pieces and fixed in 1&#37; &#40;w&#47;v&#41; paraformaldehyde&#44; 0&#46;1&#37; &#40;v&#47;v&#41; glutaraldehyde in 0&#46;1<span class="elsevierStyleHsp" style=""></span>M phosphate-buffered saline &#40;PBS&#41; solution for 2<span class="elsevierStyleHsp" style=""></span>h at room temperature&#46; After that&#44; a post-fixation with 1&#37; &#40;w&#47;v&#41; osmium tetroxide in cacodylate buffer was performed for 1<span class="elsevierStyleHsp" style=""></span>h&#46; Embedding was performed in Lowycril K4M resin according to standard procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Immunohistochemistry</span><p id="par0055" class="elsevierStylePara elsevierViewall">Samples to be analyzed by light microscopy were deparaffinised and processed at 121<span class="elsevierStyleHsp" style=""></span>&#176;C in a 2100 Antigen Retriever &#40;PickCell Laboratories&#44; Leiden&#44; Netherland&#41; in Tris&#8211;HCl 10<span class="elsevierStyleHsp" style=""></span>mM-EDTA 0&#46;5<span class="elsevierStyleHsp" style=""></span>mM pH 9&#46;0 buffer for EC-SOD slides and in Citrate 10<span class="elsevierStyleHsp" style=""></span>mM pH 6&#46;0 for fibulin-5 slides&#46; After antigen unmasking&#44; sections were washed three times in PBS and submerged in 3&#37; hydrogen peroxide&#44; 10&#37; methanol in PBS for 15<span class="elsevierStyleHsp" style=""></span>min&#46; After washing three times with PBS&#44; nonspecific binding was suppressed by incubation with blocking solution&#46; Following that&#44; samples were incubated at 4<span class="elsevierStyleHsp" style=""></span>&#176;C overnight with polyclonal anti-EC-SOD antibody &#40;1&#58;500&#44; Abnova&#44; Taipei&#44; China&#41; monoclonal anti-fibulin 5 antibody &#40;1&#58;750&#44; Abcam&#44; Cambridge&#44; UK&#41;&#44; rabbit polyclonal anti-4-HNE antibody &#40;1&#58;300&#59; Calbiochem&#44; San Diego&#44; CA&#44; USA&#41;&#44; rabbit polyclonal anti-MDA antibody &#40;1&#58;400&#59; Abcam Ltd&#46;&#44; Cambridge&#44; UK&#41; or with rabbit polyclonal anti-NT antibody &#40;1&#58;90&#59; Upstate Biotechnology&#44; Inc&#46;&#44; Lake Placid&#44; NY&#44; USA&#41; in blocking solution&#46; Negative controls were obtained by incubating a slide with rabbit IgG &#40;1&#58;500&#44; ab37415&#44; Abcam&#44; Cambridge&#44; UK&#41; or mouse IgG &#40;1&#58;200&#44; ab37355&#44; Abcam&#41;&#46; On the following day&#44; sections were washed in PBS and incubated with biotinylated anti-Rabbit or ant-Mouse IgG antibody &#40;Vector Laboratories&#59; Burlingame&#44; CA&#41; for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature&#46; Immunostaining was performed using the avidin&#8211;biotin complex &#40;ABC&#41; immunoperoxidase method &#40;Vectastain Elite ABC kit&#59; Vector Laboratories&#44; Burlingame&#44; CA&#44; USA&#41; with a 3&#44;3&#8242;-diaminobenzidine tetrahydrochloride &#40;DAB&#41; reaction&#46; Finally&#44; the slides were counterstained in haematoxylin&#44; dehydrated&#44; and mounted&#46; For analysis of immunostained lung tissue&#44; two independent observers &#40;JGV and JO&#41; assessed the intensity and extent of immunoreactivity of EC-SOD in a double-blind fashion through a semi quantitative score &#40;0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no staining&#59; 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>weak&#47;intermediate staining&#59; 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>strong staining&#41;&#46; At least twelve fields of each sample were randomly and systematically sampled to assess EC-SOD and fibulin-5 staining in alveolar interstitium&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Samples to be analyzed by transmission electron microscopy &#40;TEM&#41; were hydrated in a PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M glycine 0&#46;1<span class="elsevierStyleHsp" style=""></span>M solution and non-specific binding was suppressed by incubation in 2&#37; ovalbumin in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M&#46; After that&#44; samples were incubated with the primary antibody &#40;anti-EC-SOD&#44; 1&#58;150&#44; Abnova&#44; Taipei&#44; China&#41; in blocking solution for2<span class="elsevierStyleHsp" style=""></span>h&#46; Then&#44; samples were washed three times in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M glycine 0&#46;1<span class="elsevierStyleHsp" style=""></span>M solution and incubated with Goat Anti-Rabbit IgG with 10<span class="elsevierStyleHsp" style=""></span>nm Gold preadsorbed &#40;1&#58;10&#44; ab27234&#44; Abcam&#41; for1<span class="elsevierStyleHsp" style=""></span>h&#46; Finally&#44; samples were washed in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M and jet-washed in 10<span class="elsevierStyleHsp" style=""></span>ml of milli-Q water prior to counterstaining and mounting&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Quantitative real-time PCR</span><p id="par0065" class="elsevierStylePara elsevierViewall">Isolation of total RNA from tissue samples was performed using the AllPrep DNA&#47;RNA Mini Kit &#40;QIAGEN&#44; Hilden&#44; Germany&#41;&#46; After reverse transcription of mRNA into complementary DNA &#40;cDNA&#41;&#44; qRT-PCR was performed using primer and probe sets for <span class="elsevierStyleItalic">ECSOD</span> and fibulin-5 from TaqMan Gene Expression Assays purchased from Applied Biosystems &#40;Foster City&#44; CA&#44; USA&#41;&#46; Data from qRT-PCR reactions was analyzed by the comparative Ct &#40;2-&#916;&#916;Ct&#41; quantification method&#46; Relative expression levels of <span class="elsevierStyleItalic">ECSOD</span> and <span class="elsevierStyleItalic">fibulin-5</span> genes were determined using <span class="elsevierStyleItalic">18S</span> mRNA as an endogenous control&#46; Three independent experiments were performed and results were expressed as the normalized mean of the relative quantification &#40;RQ&#41; of the tested transcripts&#46; Non-template controls exhibited no signal&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The descriptive statistical analysis included mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM or SD for each parameter and patient group&#46; Data were compared between the two groups using the Chi-square and Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-tests&#46; The significance level was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; All analyses were performed using Statgraphics Centurion XV &#40;StatPoint&#44; Inc&#46;&#44; Warrenton&#44; VA&#44; USA&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Demographic and clinical findings</span><p id="par0075" class="elsevierStylePara elsevierViewall">The two clinical groups were similar regarding age and body-mass index&#44; with a predominance of males and tobacco smoking in the COPD group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; As expected&#44; the mMRC dyspnoea score&#44; the number of previous exacerbations in the last year and the use of inhaled corticosteroids were higher in COPD patients&#46; In this group&#44; the microscopic &#40;LM&#41; and macroscopic emphysema &#40;MED&#41; degree was increased and the spirometry variables were reduced compared with non-COPD patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Histology and histochemistry</span><p id="par0080" class="elsevierStylePara elsevierViewall">In order to determine whether the architecture of elastic fibres in alveolar walls was different among COPD patients and controls&#44; we used Verhoeff&#39;s staining&#44; a method that allows highlighting elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">As expected&#44; sections from COPD patients exhibited an altered elastin network when compared to control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Thus&#44; there were anomalous accumulations of elastic fibres in periemphysematous alveolar walls of COPD patients&#44; suggesting a tissue collapse in periemphysematous areas &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#44; D and F&#41;&#46; By contrast&#44; control samples did not show these histological alterations &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#44; C and E&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">When the tips of alveolar walls were observed under TEM&#44; COPD patients showed vacuolar changes in the amorphous component of elastic fibres&#44; resulting in a pierced pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>H&#41;&#46; These alterations were absent in control samples &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>G&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Immunohistochemistry</span><p id="par0095" class="elsevierStylePara elsevierViewall">Light microscopy study showed that EC-SOD was immunolocalised in airway and parenchymal epithelial cells &#40;primarily in the apical area&#41;&#44; as well as in alveolar macrophages and endothelial cells&#46; EC-SOD was also present in the perimeter of elastic fibres of pulmonary vessels and alveolar walls&#44; whereas collagen showed a weaker or no staining&#46; Interestingly&#44; EC-SOD immunostaining was higher in airway and vascular walls of control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and C&#41; when compared to COPD patients &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B and D&#41;&#46; Regarding fibulin-5&#44; it was also observed mainly in airway and vascular walls&#44; as well as in alveolar interstitium of lung samples &#40;Fig&#46; S1&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Moreover&#44; immunolocalization of EC-SOD and fibulin-5 allowed us to study the interstitial expression of these proteins&#46; Alveolar&#44; bronchiolar and arteriolar walls of patients with COPD showed a reduced expression of EC-SOD and fibulin-5 when compared to control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; The additional immunohistochemical analysis by TEM confirmed the reduced expression of EC-SOD in interstitium of COPD patients&#44; and revealed that EC-SOD was tightly associated with fibrillary components in the unaffected elastic fibres &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; Moreover&#44; in altered fibres&#44; the decrease in EC-SOD labelling was associated with the loss of the fibrillary component and the partial degradation of elastin&#44; which produced the pierced pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Furthermore&#44; when the expression of EC-SOD and fibulin-5 in alveolar&#44; bronchiolar and arteriolar walls of COPD patients and control samples was compared through a semi-quantitative score&#44; we found that COPD patients have a significant reduced expression of both EC-SOD and fibulin-5 &#40;0&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64 and 0&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; respectively&#41; compared to control subjects &#40;1&#46;39<span class="elsevierStyleHsp" style=""></span>&#177; 0&#46;63 and 1&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;52&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; Additionally&#44; levels of EC-SOD and fibulin-5 were analyzed in patients without COPD by comparing smokers &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; and non-smokers &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; and males &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41; versus females &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#46; Immunoscore values for EC-SOD in alveolar&#44; arteriolar and bronchiolar wall were 1&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23&#44; 1&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;21 and 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12 in non-smokers and 1&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13 and 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in smokers without COPD &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;63&#44; 0&#46;12 and 0&#46;89 respectively&#41;&#46; The immunoscore for fibulin-5 in these compartments were 1&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18&#44; 1&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 and 1&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17 in non-smokers and 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17&#44; 1&#46;60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18 and 1&#46;66<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13 in smokers without COPD &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;96&#44; 0&#46;81 and 0&#46;51 respectively&#41;&#46; Thus&#44; no significant differences were observed in the expression of the antioxidant markers when comparing smokers and non-smokers&#46; Immunoscore values for EC-SOD in alveolar&#44; arteriolar and bronchiolar wall were 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20 and 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in non-COPD females and 1&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;15 and 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12 in non-COPD males &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;37&#44; 0&#46;23 and 0&#46;89&#44; respectively&#46; Values for fibulin-5 in the same compartments were 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13&#44; 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17 and 1&#46;80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in non-COPD females and 1&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;21&#44; 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;14 and 1&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18 in non-COPD males &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;54&#44; 0&#46;92 and 0&#46;25&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding oxidative stress markers&#44; malondialdehyde was the most reliable to distinguish COPD patients&#46; Indeed&#44; the adducts of this lipid peroxidation product were mainly immunolocalised in the connectives tissues&#44; such as adventitia layers&#44; alveolar walls&#44; arterioles and the parenchymal interstitium surrounding emphysematous areas of COPD patients&#44; showing significant differences with non COPD samples &#40;Fig&#46; S2&#41;&#46; Although 4-hydroxynonenal adducts were detected in all patients&#44; they showed a significant increase in COPD groups &#40;Fig&#46; S3&#41;&#44; while the 3-nitrotyrosine biomarker was primarily located in the tissues close to the respiratory tract and alveolar spaces of smokers &#40;Figure S3&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Quantitative real-time PCR</span><p id="par0115" class="elsevierStylePara elsevierViewall">Quantitative PCR analyses showed that both mRNA levels of <span class="elsevierStyleItalic">EC-SOD</span> and <span class="elsevierStyleItalic">fibulin-5</span> were lower in COPD patients than in controls &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; though these differences did not reach statistical significance &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">It is widely acknowledged that an imbalance between free radicals and antioxidant defences plays a main role in COPD pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> However&#44; the <span class="elsevierStyleItalic">in situ</span> expression of oxidative stress in lungs of COPD patients remains poorly understood&#46; The present study shows for the first time an association between a reduced expression of EC-SOD&#44; the main antioxidant in the lung interstitium&#44; its binding protein fibulin-5 and parenchymal alterations in alveolar walls of COPD patients&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Recent studies assessing the pathological remodelling of elastic fibres in emphysematous lung have shown contradictory conclusions&#44; since while some of them showed a reduction in the volume fraction of elastic fibres&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">25</span></a> others found an increase<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a> or even no changes&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">27</span></a> Our histochemical analysis by light microscopy revealed matrix alterations coinciding with emphysema in COPD patients&#46; Damage consisted in frayed elastic fibres clumped into dense masses lying within remnants of collapsing alveolar walls&#44; coinciding with pathologic changes described by Robert Wright almost sixty years ago<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">28</span></a> When interstitium of collapsing walls were further analyzed through TEM&#44; we observed a loss of fibrillary component&#44; mainly in the core of the elastic fibres&#44; together with the presence of vacuoles affecting the amorphous component&#46; A similar pierced pattern has been described in previous TEM studies in humans and murine models of emphysema&#44;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">29&#8211;31</span></a> and underpins the importance of structural abnormalities of elastic fibres in areas of emphysematous destruction&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Our results showed that lungs from COPD patients exhibit lower expression of EC-SOD in alveolar walls likely leading to an impaired antioxidant defence in these patients&#46; Indeed&#44; cigarette smoke and other air pollutants contain high levels of oxidants and other molecules capable of inducing the formation of free radicals in pulmonary cells and a chronic inflammatory response in COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">32&#8211;34</span></a> Both oxidative stress and inflammation act in concert to foster the emphysematous destruction of alveolar walls and to affect the repair and maintenance of parenchymal structure&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">35</span></a> Among the rich network of enzymatic antioxidants that lungs possess to protect themselves from oxidative burden&#44; EC-SOD plays a primordial role in the extracellular space&#44; both by scavenging superoxide radicals and by inhibiting the inflammatory response&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">13&#8211;15</span></a> Importantly&#44; EC-SOD activity in the lung has been extensively studied in the <span class="elsevierStyleItalic">SOD3</span> mice model&#46; Gongora and colleagues showed that loss of EC-SOD leads to severe lung damage in mice&#44; while treatment with EC-SOD mimetic MnTBAP reduces lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">36</span></a> Using the same animal model&#44; Yao and colleagues demonstrated that EC-SOD attenuates fragmentation of elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> Since extracellular matrix components such as elastin&#44; heparin sulphate and hyaluronan are known to trigger lung inflammation&#44; the authors concluded that EC-SOD protects lungs from emphysema by decreasing the inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> Hence&#44; our results support the hypothesis that a reduced antioxidant defence caused by diminished levels of EC-SOD is detrimental for COPD patients by increasing the progression of emphysema&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; only two previous papers studied pulmonary EC-SOD expression in patients with COPD&#46; Thus&#44; whereas Harju and co-workers reported no differences in EC-SOD immunoreactivity among non-smokers&#44; smokers without COPD and COPD patients&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a> a more recent study found a significant decrease of EC-SOD immunoreactivity around vessels and bronchioles of COPD patients compared to controls&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> Our results demonstrate a reduced expression of EC-SOD in vascular and airway walls in COPD and TEM analysis confirmed the decreased expression of interstitial EC-SOD observed by light microscopy in COPD patients&#46; The mentioned discrepancy of results among the three studies may be due to differences in the characteristics of COPD patients &#40;mild to moderate in the study by Harju et al&#46; and moderate to severe in our study and the one by Regan et al&#46;&#41; and the different compartments analyzed&#46; Thus the expression of EC-SOD in sputum or bronchoalveolar lavage does not need to mirror its in situ expression in the lung interstitium&#44; where it exerts its protective effect&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A relevant finding in our study is that immunoreactivity of fibulin-5 was significantly lower in alveolar walls&#44; airway and vascular walls of COPD patients than in control subjects&#46; Fibulin-5 and fibulin-4 are the most critical molecules for aiding assembly of elastic fibres&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">11&#44;12</span></a> although fibulin-5 exhibits higher binding affinity to tropoelastin and is expressed at much higher levels than fibulin-4 in lung&#44; aorta and skin&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">38</span></a> In a experimental model&#44; fibulin-5-null mouse developed emphysema and disruption of elastic fibres thus suggesting the critical role of fibulin-5 in the maintenance of the lung architecture&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">39&#44;40</span></a> Furthermore&#44; a decrease of fibulin-5 may likely impair its binding to EC-SOD<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> and affect negatively the protection against oxidative stress of the elastin matrix&#46; This lack would favour elastin degradation by extracellular elastase activity thus accelerating the evolution to emphysema in COPD patients&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In spite of our immunohistochemical analyses revealing reduced presence of EC-SOD and fibulin-5 in alveolar walls of COPD patients&#44; the difference between pulmonary mRNA levels of these proteins in COPD patients and controls was not statistically significant&#46; This discrepancy regarding gene expression is not surprising&#44; since mRNA expression is not necessarily related to tissue protein levels&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a> Whole tissue samples for PCR analysis contain not only different lung compartments&#44; but also circulating blood and secretions&#46; On the contrary&#44; immunohistochemistry in lung slices allows for detecting the markers in specific tissue localizations&#44; such as alveolar walls&#46; Indeed&#44; in a previous study the levels of EC-SOD were high in sputum of COPD patients&#44; but not in blood or BALF&#44; whereas EC-SOD tissue immunoreactivity was lower in COPD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Our results suggest that patients with COPD have a reduced antioxidant activity in their lungs which make them more vulnerable to the disease&#46; This finding supports the hypothesis that antioxidant therapy might be useful for these patients&#46; However&#44; further studies must be conducted in the clinical setting to address this probability&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In summary&#44; our results show that EC-SOD and fibulin-5 expression are reduced in alveolar walls of patients with COPD&#44; which also show alterations in elastic fibres&#46; This reduction supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">This study was funded by the Spanish Health Research Fund-Instituto de Salud Carlos III &#40;FIS 04&#47;0635&#41; and the Sociedad Espa&#241;ola de Pneumologia &#40;SEPAR 165&#124;2012&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Demographic and clinical findings"
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              "titulo" => "Immunohistochemistry"
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              "titulo" => "Quantitative real-time PCR"
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    "fechaRecibido" => "2020-11-30"
    "fechaAceptado" => "2020-12-22"
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            0 => "COPD"
            1 => "EC-SOD"
            2 => "Electron microscopy"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to analyze the expression of the main oxidant scavenger superoxide dismutase &#40;EC-SOD&#41;&#44; its main binding protein Fibulin-5 and several oxidative and nitrosative-derived products in the lung of COPD patients and controls&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Lung tissue samples from 19 COPD patients and 20 control subjects were analyzed&#46; The architecture of elastic fibres was assessed by light and electron microscope histochemical techniques&#44; and levels of EC-SOD and fibulin-5 were analyzed by immunohistochemistry and RT-PCR&#46; The impact of oxidative stress on the extracellular matrix was estimated by immunolocalization of 4-hydroxynonenal &#40;4-HNE&#41;&#44; malondialdehyde &#40;MDA&#41; and 3-nitrotyrosine &#40;3-NYT&#41; adducts&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Alveolar walls of COPD patients exhibited abnormal accumulations of collapsing elastic fibres&#44; showing a pierced pattern in the amorphous component&#46; The semiquantitative analysis revealed that COPD patients have a significantly reduced expression of both EC-SOD and fibulin-5 &#40;0&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64 and 0&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; respectively&#41; in alveolar&#44; bronchiolar and arteriolar walls compared to control subjects &#40;1&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;63 and 1&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;52&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; No significant changes in mRNA levels of these proteins were observed between groups&#46; Among the oxidation markers&#44; malondialdehyde was the best in distinguishing COPD patients&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">COPD patients show a reduced expression of EC-SOD and fibulin-5 in the lung interstitium&#46; Paralleling the reduction of EC-SOD levels&#44; the decrease of fibulin-5 expression in COPD lungs supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Localization of elastic fibres in lung samples from COPD patients and control subjects&#46; Verhoeff&#39;s staining of elastic fibres in alveolar ducts of a healthy control &#40;A&#41; and a COPD patient &#40;B&#41;&#44; with arrows indicating accumulation of elastic fibres in collapsing walls of emphysematous areas &#40;bars<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#46; Detail of a tip of an alveolar wall of a control subject &#40;C&#41;&#44; showing the normal distribution of elastic fibres&#44; while the alveolar walls of the emphysematous &#40;D&#41; areas appear collapsed in COPD patients &#40;bars<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#46; Micrography of normal lung parenchyma of a control subject &#40;E&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; and emphysematous parenchyma of COPD patient &#40;F&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#44; showing prominent elastic accumulations&#46; &#40;G&#41; Electron microscopy of a tip of a normal alveolar wall &#40;bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; &#40;H&#41; Electron microscopy of a collapsing alveolar wall&#44; showing vacuoles and a pierced pattern in the amorphous component &#40;bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Immunolocalization of EC-SOD and fibulin-5 in alveolar walls of COPD patients and control subjects&#46; Alveolar walls of control subjects showed increased presence of EC-SOD &#40;A&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; and fibulin-5 &#40;E&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; as compared to those of COPD patients &#40;B&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;m&#44; and F&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>&#956;m&#44; respectively&#41;&#46; &#40;C&#41; and &#40;D&#41; Electron microscopy of immunolocalised EC-SOD in elastic fibres from alveolar walls of a control subject &#40;C&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>nm&#41; and a COPD patient &#40;D&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; Colloidal gold labelling indicating EC-SOD immunolocalization was mostly absent in the fibrillary component alveolar elastic fibres of COPD samples&#46; Dashed lines indicate loss of fibrillary component&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Semiquantitative score of the expression of EC-SOD and Fibulin-5 in the lung parenchyma&#46; Semiquantitative score showed a significant reduction of EC-SOD and fibulin-5 in the connective tissues of the lung parenchyma from COPD patients when compared to control subjects &#40;estimated mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">SD&#58; Standard Deviation&#59; BMI&#58; Body Mass Index&#59; mMRC&#58; Modified Medical Research Council Dyspnoea Scale&#59; ICS&#58; Inhaled Corticosteroids&#59; MED&#58; Macroscopic Emphysema Degree&#59; LM&#58; Mean Airspace Chord length&#46;</p>"
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&#46; male vs&#46; Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;21 &#40;4&#46;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;17 &#40;3&#46;81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1774&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smokers &#40;<span class="elsevierStyleItalic">n</span>&#44; Pack-years &#40;SD&#41;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44; 28&#46;84 &#40;33&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#44; 58&#46;05 &#40;23&#46;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0044&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dyspnoea score &#40;mMRC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;19 &#40;10&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#47;20 &#40;55&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any exacerbations in the last year&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;19 &#40;15&#46;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;20 &#40;70&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients treated with ICS&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;19 &#40;10&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;20 &#40;70&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Patients with oxygen&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;19 &#40;0&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;20 &#40;30&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">FEV<span class="elsevierStyleInf">1</span> postbronchodilator &#40;&#37;pred&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#46;92 &#40;18&#46;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">38&#46;36 &#40;21&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">FEV<span class="elsevierStyleInf">1</span>&#47;FVC postbronchodilator &#40;&#37;pred&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#46;26 &#40;7&#46;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">44&#46;58 &#40;13&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">MED &#37; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5&#46;92 &#40;8&#46;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">50&#46;0 &#40;27&#46;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LM &#40;mm&#41; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">220&#46;74 &#40;81&#46;57&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">489&#46;54 &#40;317&#46;92&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;0017&nbsp;\t\t\t\t\t\t\n
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                          "colaboracion" => "Global&#44; regional&#44; and national age-sex specific all-cause and cause-specific mortality for 240 causes of death&#44; 1990-2013&#58; a systematic analysis for the Global Burden of Disease Study 2013"
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                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(14)61682-2"
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                        "tituloSerie" => "Lancet &#40;London England&#41;"
                        "fecha" => "2015"
                        "volumen" => "385"
                        "paginaInicial" => "117"
                        "paginaFinal" => "171"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25530442"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
              ]
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            1 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical Practice Guideline for the Diagnosis and Treatment of Patients with Chronic Obstructive Pulmonary disease &#40;COPD&#41; &#8211; the Spanish COPD Guideline &#40;GesEPOC&#41; 2017 Version"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "Working group of the GesEPOC"
                          "etal" => false
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2017"
                        "volumen" => "53"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "2"
                        "paginaFinal" => "64"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary and systemic oxidant&#47;antioxidant imbalance in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46; MacNee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1513/pats.200411-056SF"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Am Thorac Soc"
                        "fecha" => "2005"
                        "volumen" => "2"
                        "paginaInicial" => "50"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16113469"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "LPS stimulation of IL-8 release is inhibited by thiol antioxidant at the transcriptional level in THP-1 macrophage cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "F&#46;P&#46;M&#46; Antonicelli"
                            1 => "N&#46; Hirani"
                            2 => "E&#46; Drost"
                            3 => "I&#46; Rahman"
                            4 => "K&#46; Donaldson"
                            5 => "W&#46; MacNee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "161"
                        "paginaInicial" => "1319"
                        "paginaFinal" => "1327"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current perspectives of oxidative stress and its measurement in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;L&#46; Lin"
                            1 => "P&#46;S&#46; Thomas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/15412555.2010.496818"
                      "Revista" => array:6 [
                        "tituloSerie" => "COPD"
                        "fecha" => "2010"
                        "volumen" => "7"
                        "paginaInicial" => "291"
                        "paginaFinal" => "306"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20673039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enhanced neutrophil response in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Noguera"
                            1 => "S&#46; Batle"
                            2 => "C&#46; Miralles"
                            3 => "J&#46; Iglesias"
                            4 => "X&#46; Busquets"
                            5 => "W&#46; MacNee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thorax.56.6.432"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorax"
                        "fecha" => "2001"
                        "volumen" => "56"
                        "paginaInicial" => "432"
                        "paginaFinal" => "437"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11359957"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator DJ-1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Malhotra"
                            1 => "R&#46; Thimmulappa"
                            2 => "A&#46; Navas-Acien"
                            3 => "A&#46; Sandford"
                            4 => "M&#46; Elliott"
                            5 => "A&#46; Singh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200803-380OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2008"
                        "volumen" => "178"
                        "paginaInicial" => "592"
                        "paginaFinal" => "604"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18556627"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antioxidant enzymes and their implications in pathophysiologic processes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;M&#46; Mates"
                            1 => "F&#46; Sanchez-Jimenez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2741/mates"
                      "Revista" => array:6 [
                        "tituloSerie" => "Front Biosci"
                        "fecha" => "1999"
                        "volumen" => "4"
                        "paginaInicial" => "D339"
                        "paginaFinal" => "D345"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10077544"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extracellular superoxide dismutase &#40;EC-SOD&#41; as a protective factor for risk of chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;P&#46; Bowler"
                            1 => "J&#46; Hokanson"
                            2 => "M&#46; Taylor"
                            3 => "S&#46; Levy"
                            4 => "E&#46;M&#46; Canaham"
                            5 => "E&#46; Regan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir Rev"
                        "fecha" => "2006"
                        "volumen" => "15"
                        "paginaInicial" => "200"
                        "paginaFinal" => "201"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extracellular superoxide dismutase in vessels and airways of humans and baboons"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "T&#46;D&#46; Oury"
                            1 => "B&#46;J&#46; Day"
                            2 => "J&#46;D&#46; Crapo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0891-5849(95)02222-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Free Rad Biol Med"
                        "fecha" => "1996"
                        "volumen" => "20"
                        "paginaInicial" => "957"
                        "paginaFinal" => "965"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8743981"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibulin-5 is a novel binding protein for extracellular superoxide dismutase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;D&#46; Nguyen"
                            1 => "S&#46; Itoh"
                            2 => "V&#46; Jeney"
                            3 => "H&#46; Yanagisawa"
                            4 => "M&#46; Fujimoto"
                            5 => "M&#46; Ushio-Fukai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.RES.0000149568.85071.FB"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2004"
                        "volumen" => "95"
                        "paginaInicial" => "1067"
                        "paginaFinal" => "1074"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15528465"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0265"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibulin-5&#44; an integrin-binding matricellular protein&#58; its function in development and disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Yanagisawa"
                            1 => "M&#46;K&#46; Schluterman"
                            2 => "R&#46;A&#46; Brekken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12079-009-0065-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cell Commun Signal"
                        "fecha" => "2009"
                        "volumen" => "3"
                        "paginaInicial" => "337"
                        "paginaFinal" => "347"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19798595"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Superoxide dismutase&#46; An enzymic function for erythrocuprein &#40;hemocuprein&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;M&#46; McCord"
                            1 => "I&#46; Fridovich"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "1969"
                        "volumen" => "244"
                        "paginaInicial" => "6049"
                        "paginaFinal" => "6055"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5389100"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0275"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extracellular superoxide dismutase attenuates lipopolysaccharide-induced neutrophilic inflammation"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;P&#46; Bowler"
                            1 => "M&#46; Nicks"
                            2 => "K&#46; Tran"
                            3 => "G&#46; Tanner"
                            4 => "L&#46;Y&#46; Chang"
                            5 => "S&#46;K&#46; Young"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.2004-0057OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2004"
                        "volumen" => "31"
                        "paginaInicial" => "432"
                        "paginaFinal" => "439"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15256385"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Tan"
                            1 => "J&#46;S&#46; Lee"
                            2 => "M&#46;L&#46; Manni"
                            3 => "C&#46;L&#46; Fattman"
                            4 => "J&#46;M&#46; Tobolewski"
                            5 => "M&#46; Zheng"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.2005-0212OC"
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                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2006"
                        "volumen" => "34"
                        "paginaInicial" => "226"
                        "paginaFinal" => "232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16224105"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0285"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extracellular superoxide dismutase in pulmonary fibrosis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "F&#46; Gao"
                            1 => "V&#46;L&#46; Kinnula"
                            2 => "M&#46; Myllarniemi"
                            3 => "T&#46;D&#46; Oury"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Antiox Redox Signal"
                        "fecha" => "2008"
                        "volumen" => "10"
                        "paginaInicial" => "343"
                        "paginaFinal" => "354"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0290"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46; Juul"
                            1 => "A&#46; Tybjaerg-Hansen"
                            2 => "S&#46; Marklund"
                            3 => "P&#46; Lange"
                            4 => "B&#46;G&#46; Nordestgaard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200509-1387OC"
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                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2006"
                        "volumen" => "173"
                        "paginaInicial" => "858"
                        "paginaFinal" => "864"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16399992"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function"
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                            0 => "R&#46;P&#46; Young"
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                            3 => "C&#46; Eddy"
                            4 => "L&#46; Wu"
                            5 => "G&#46;D&#46; Gamble"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thx.2005.048512"
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                        "tituloSerie" => "Thorax"
                        "fecha" => "2006"
                        "volumen" => "61"
                        "paginaInicial" => "394"
                        "paginaFinal" => "399"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16467073"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smoking and COPD increase sputum levels of extracellular superoxide dismutase"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;A&#46; Regan"
                            1 => "W&#46; Mazur"
                            2 => "E&#46; Meoni"
                            3 => "T&#46; Toljamo"
                            4 => "J&#46; Millar"
                            5 => "K&#46; Vuopala"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.freeradbiomed.2011.05.008"
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                        "tituloSerie" => "Free Radic Biol Med"
                        "fecha" => "2011"
                        "volumen" => "51"
                        "paginaInicial" => "726"
                        "paginaFinal" => "732"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21621610"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0305"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Manganese superoxide dismutase is increased in the airways of smokers&#8217; lungs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Harju"
                            1 => "R&#46; Kaarteenaho-Wiik"
                            2 => "R&#46; Sirvio"
                            3 => "P&#46; Paakko"
                            4 => "J&#46;D&#46; Crapo"
                            5 => "T&#46;D&#46; Oury"
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                    0 => array:2 [
                      "doi" => "10.1183/09031936.04.00121203"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2004"
                        "volumen" => "24"
                        "paginaInicial" => "765"
                        "paginaFinal" => "771"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15516670"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            20 => array:3 [
              "identificador" => "bib0310"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "General considerations for lung function testing"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;R&#46; Miller"
                            1 => "R&#46; Crapo"
                            2 => "J&#46; Hankinson"
                            3 => "V&#46; Brusasco"
                            4 => "F&#46; Burgos"
                            5 => "R&#46; Casaburi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.05.00034505"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2005"
                        "volumen" => "26"
                        "paginaInicial" => "153"
                        "paginaFinal" => "161"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15994402"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "22"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A modified Verhoeff&#39;s elastin histochemical stain to enable pulmonary arterial hypertension model characterization"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;R&#46; Percival"
                            1 => "Z&#46;A&#46; Radi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4081/ejh.2016.2588"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur J Histochem"
                        "fecha" => "2016"
                        "volumen" => "60"
                        "paginaInicial" => "2588"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26972717"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rapid embedding of tissues in Lowicryl K4M for immunoelectron microscopy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46;G&#46; Altman"
                            1 => "B&#46;G&#46; Schneider"
                            2 => "D&#46;S&#46; Papermaster"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/32.11.6436366"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Histochem Cytochem"
                        "fecha" => "1984"
                        "volumen" => "32"
                        "paginaInicial" => "1217"
                        "paginaFinal" => "1223"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6436366"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Involvement of oxidative stress in COPD"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46; Marginean"
                            1 => "M&#46;S&#46; Popescu"
                            2 => "M&#46; Vladaia"
                            3 => "D&#46; Tudorascu"
                            4 => "D&#46;C&#46; Pirvu"
                            5 => "F&#46; Petrescu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.12865/CHSJ.44.01.08"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Health Sci J"
                        "fecha" => "2018"
                        "volumen" => "44"
                        "paginaInicial" => "48"
                        "paginaFinal" => "55"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30622755"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            24 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Changes in elastic fibres in the small airways and alveoli in COPD"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "P&#46;N&#46; Black"
                            1 => "P&#46;S&#46; Ching"
                            2 => "B&#46; Beaumont"
                            3 => "S&#46; Ranasinghe"
                            4 => "G&#46; Taylor"
                            5 => "M&#46;J&#46; Merrilees"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.00017207"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2008"
                        "volumen" => "31"
                        "paginaInicial" => "998"
                        "paginaFinal" => "1004"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18216063"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0335"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cellular and connective tissue changes in alveolar septal walls in emphysema"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "G&#46; Vlahovic"
                            1 => "M&#46;L&#46; Russell"
                            2 => "R&#46;R&#46; Mercer"
                            3 => "J&#46;D&#46; Crapo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1999"
                        "volumen" => "160"
                        "paginaInicial" => "2086"
                        "paginaFinal" => "2092"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quantitative assessment of elastic fibers in chronic obstructive pulmonary disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46; Rufino"
                            1 => "K&#46; Madi"
                            2 => "H&#46;S&#46; Souza"
                            3 => "C&#46;H&#46; Costa"
                            4 => "E&#46;H&#46; Saito"
                            5 => "J&#46;R&#46; Silva"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1590/s1806-37132007000500004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Bras Pneumol"
                        "fecha" => "2007"
                        "volumen" => "33"
                        "paginaInicial" => "502"
                        "paginaFinal" => "509"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18026647"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0345"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elastic tissue of normal and emphysematous lungs&#46; A tridimensional histologic study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;R&#46; Wright"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Pathol"
                        "fecha" => "1961"
                        "volumen" => "39"
                        "paginaInicial" => "355"
                        "paginaFinal" => "367"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13786819"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Morphogenesis of abnormal elastic fibers in lungs of patients with panacinar and centriacinar emphysema"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Y&#46; Fukuda"
                            1 => "Y&#46; Masuda"
                            2 => "M&#46; Ishizaki"
                            3 => "Y&#46; Masugi"
                            4 => "V&#46;J&#46; Ferrans"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0046-8177(89)90152-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Pathol"
                        "fecha" => "1989"
                        "volumen" => "20"
                        "paginaInicial" => "652"
                        "paginaFinal" => "659"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2661409"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Three-dimensional architecture of elastin and collagen fiber networks in the human and rat lung"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Toshima"
                            1 => "Y&#46; Ohtani"
                            2 => "O&#46; Ohtani"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1679/aohc.67.31"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Histol Cytol"
                        "fecha" => "2004"
                        "volumen" => "67"
                        "paginaInicial" => "31"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15125021"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elastin and collagen remodeling in emphysema&#46; A scanning electron microscopy study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46;A&#46; Finlay"
                            1 => "M&#46;D&#46; O&#8217;Donnell"
                            2 => "C&#46;M&#46; O&#8217;Connor"
                            3 => "J&#46;P&#46; Hayes"
                            4 => "M&#46;X&#46; FitzGerald"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Pathol"
                        "fecha" => "1996"
                        "volumen" => "149"
                        "paginaInicial" => "1405"
                        "paginaFinal" => "1415"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8863687"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0365"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of oxidative stress in chronic obstructive pulmonary disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;P&#46; Bowler"
                            1 => "P&#46;J&#46; Barnes"
                            2 => "J&#46;D&#46; Crapo"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1081/copd-200027031"
                      "Revista" => array:6 [
                        "tituloSerie" => "COPD"
                        "fecha" => "2004"
                        "volumen" => "1"
                        "paginaInicial" => "255"
                        "paginaFinal" => "277"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17136992"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            32 => array:3 [
              "identificador" => "bib0370"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers"
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "B&#46;W&#46; Willemse"
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                            2 => "B&#46; Rutgers"
                            3 => "I&#46;G&#46; Lesman-Leegte"
                            4 => "D&#46;S&#46; Postma"
                            5 => "W&#46; Timens"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.05.00108904"
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                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2005"
                        "volumen" => "26"
                        "paginaInicial" => "835"
                        "paginaFinal" => "845"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16264044"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Persistence of oxidant and protease burden in the airways after smoking cessation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "N&#46; Louhelainen"
                            1 => "P&#46; Rytila"
                            2 => "T&#46; Haahtela"
                            3 => "V&#46;L&#46; Kinnula"
                            4 => "R&#46; Djukanovic"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2466-9-25"
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                        "tituloSerie" => "BMC Pulm Med"
                        "fecha" => "2009"
                        "volumen" => "9"
                        "paginaInicial" => "25"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19473482"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0380"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of elastases in the pathogenesis of chronic obstructive pulmonary disease&#58; implications for treatment"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "U&#46; Demkow"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/2047-783x-15-s2-27"
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                        "tituloSerie" => "Eur J Med Res"
                        "fecha" => "2010"
                        "volumen" => "15"
                        "numero" => "Suppl&#46; 2"
                        "paginaInicial" => "27"
                        "paginaFinal" => "35"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21147616"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0385"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air&#58; a potential mechanism underlying adult respiratory distress syndrome"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "H&#46;E&#46; Lob"
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                            3 => "T&#46;J&#46; Guzik"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2353/ajpath.2008.080119"
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                        "tituloSerie" => "Am J Pathol"
                        "fecha" => "2008"
                        "volumen" => "173"
                        "paginaInicial" => "915"
                        "paginaFinal" => "926"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18787098"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0390"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "G&#46; Arunachalam"
                            2 => "J&#46;W&#46; Hwang"
                            3 => "S&#46; Chung"
                            4 => "I&#46;K&#46; Sundar"
                            5 => "V&#46;L&#46; Kinnula"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.1007625107"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci USA"
                        "fecha" => "2010"
                        "volumen" => "107"
                        "paginaInicial" => "15571"
                        "paginaFinal" => "15576"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20713693"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
            ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Fibulin-4 and fibulin-5 in elastogenesis and beyond&#58; Insights from mouse and human studies"
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Vol. 58. Issue 6.
Pages 482-489 (June 2022)
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Vol. 58. Issue 6.
Pages 482-489 (June 2022)
Original Article
Decreased Expression of EC-SOD and Fibulin-5 in Alveolar Walls of Lungs From COPD Patients
José García-Valeroa,1, Jordi Olloquequib,1, Esther Rodríguezc, Mireia Martín-Satuéd,e, Laura Texidód, Jaume Ferrerc,
Corresponding author
jjferrer@vhebron.net

Corresponding author.
a Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
b Laboratory of Cellular and Molecular Pathology, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
c Department of Pneumology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
d Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain
e Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain

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Original Article
Decreased Expression of EC-SOD and Fibulin-5 in Alveolar Walls of Lungs From COPD Patients
José García-Valeroa,1, Jordi Olloquequib,1, Esther Rodríguezc, Mireia Martín-Satuéd,e, Laura Texidód, Jaume Ferrerc,
Corresponding author
jjferrer@vhebron.net

Corresponding author.
a Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
b Laboratory of Cellular and Molecular Pathology, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
c Department of Pneumology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
d Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain
e Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; is a global health problem&#44; which has been projected to produce 4&#46;7 million deaths worldwide in 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> Prolonged exposure to tobacco smoking and less frequently to other particles and gases produce a chronic inflammatory pattern leading to different pulmonary histopathological features&#44; the two most predominant being small airways narrowing and emphysematous parenchymal destruction&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Oxidative stress&#44; which is defined as an imbalance between oxidizing molecules and antioxidant defences&#44; play a pivotal role in COPD pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">3</span></a> Oxidants activate the transcription of the pro-inflammatory factor NF-kB in macrophages and bronchial and alveolar epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a> This leads to the recruitment and activation of other inflammatory cells such as neutrophils&#44; which can also induce the additional release of reactive oxygen intermediates and proteases<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">5</span></a> involved in emphysematous destruction&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">6</span></a> In addition to this&#44; it has also been reported that COPD patients have diminished antioxidant defences&#44; which can enhance this oxidative stress-driven inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">7</span></a> Specifically&#44; it has been shown that the levels of Nuclear factor erythroid-2-related factor-2 &#40;Nrf2&#41;&#44; the master transcription factor involved in the antioxidant defence&#44; and its stabilizer DJ1&#44; are reduced in lungs of COPD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The activity of antioxidant enzymes is crucial against the action of free radicals&#44; either by stabilizing or deactivating them before they damage cellular components&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> Among them&#44; extracellular superoxide dismutase &#40;EC-SOD&#44; EC 1&#46;15&#46;1&#46;1&#41; is a main oxidant scavenger in extracellular space&#44; including lung interstitium&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">9</span></a> Thus&#44; high levels of EC-SOD can be found in lung extracellular matrix&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">10</span></a> where it binds with heparin sulphate proteoglycan and fibulin-5&#44; an integrin-binding matricellular protein involved in elastogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">11&#44;12</span></a> There&#44; EC-SOD catalyzes the reduction of superoxide radical to hydrogen peroxide&#44; a less reactive molecule&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> Moreover&#44; several preclinical studies have also shown that EC-SOD can effectively inhibit lung inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">14&#44;15</span></a> In this regard&#44; it has been suggested that the anti-inflammatory activity of EC-SOD could be achieved either by reducing the release of pro-inflammatory cytokines from phagocytes or by inhibiting the production of extracellular matrix fragments that act as chemoattractants for inflammatory cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">14&#44;16</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">As the only antioxidant scavenging superoxide in the pulmonary extracellular compartment&#44; EC-SOD is thought to play a relevant role in COPD&#46; Hence&#44; it has been shown that smokers carrying the EC-SOD polymorphism R213G have a reduced risk of developing COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">17&#44;18</span></a> Moreover&#44; it has been reported that COPD patients have higher levels of EC-SOD in induced sputum but not in BALF as compared to control non-smokers&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> Regarding EC-SOD levels in lung tissue of COPD patients&#44; data available are scarce and contradictory&#46; Whereas one study found decreased expression of EC-SOD in lung vessels and bronchioles of COPD patients&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> another reported no differences among subjects with COPD and controls&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of the present study is to analyze the antioxidant expression in COPD lungs not only by determining levels of EC-SOD&#44; but also those of its binding protein fibulin-5&#46; Expression of these two molecules was analyzed through immunohistochemistry and RT-PCR in lung tissue from COPD patients and control subjects&#46; The localization of EC-SOD in emphysematous walls was also assessed at an ultrastructural level&#46; Lung expression of 4-hidroxynonennal &#40;4-HNE&#41;&#44; malondialdehyde &#40;MDA&#41; and 3-nitrotyrosine &#40;3-NTS&#41; was also analyzed by immunochemistry&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Subjects</span><p id="par0030" class="elsevierStylePara elsevierViewall">The study included thirty-nine patients who underwent lung resection for non-obstructive peripheral lung tumours or were subjected to double lung transplantation for very severe COPD at Vall d&#8217;Hebron University Hospital &#40;Barcelona&#44; Spain&#41;&#46; The Hospital&#39;s ethics committee approved the study and written informed consent was obtained from all subjects&#46; Pulmonary function was assessed through spirometry according to ERS recommendations<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a> using standard equipment &#40;Masterlab&#59; Jaeger&#44; W&#252;rzburg&#44; Germany&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Subjects were divided into COPD &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41; and non-COPD patients &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41;&#46; All of them were free of acute lung infections in the last three weeks and none had received chemotherapy before surgery&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Tissue processing</span><p id="par0040" class="elsevierStylePara elsevierViewall">The excised lungs or lobes were inflated immediately after surgery at 30<span class="elsevierStyleHsp" style=""></span>cm of water pressure for 1<span class="elsevierStyleHsp" style=""></span>h with 4&#37; &#40;w&#47;v&#41; formaldehyde in 0&#46;1<span class="elsevierStyleHsp" style=""></span>M phosphate-buffered saline solution &#40;pH 7&#46;4&#41;&#46; In patients with lung cancer&#44; tissue samples were taken from the non-malignant lung tissue as demonstrated by pathologist examination&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Samples to be analyzed by light microscopy were then immersed in fixative for 24<span class="elsevierStyleHsp" style=""></span>h&#46; After that&#44; 2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>0&#46;3<span class="elsevierStyleHsp" style=""></span>cm randomly selected tissue blocks were excised&#44; embedded in paraffin&#44; cut into 4-&#956;m sections and mounted on positive charged slides Starfrost Plus &#40;Menzel-Gl&#228;ser&#44; Braunschweig&#44; Germany&#41;&#46; Four consecutive serial sections from a representative block from each patient were selected for histologic&#44; histochemical and immunohistochemical analyses&#46; Every first section was stained with haematoxylin and eosin &#40;H&#38;E&#41; to reveal lung histology&#46; The second and third sections were reserved for immunolocalization of EC-SOD and fibulin-5&#46; The last section in each set was stained with Verhoeff&#39;s haematoxylin to detect pulmonary elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">On another front&#44; after initial fixation&#44; samples to be studied by transmission electron microscopy were cut into 1&#8211;2-mm thick pieces and fixed in 1&#37; &#40;w&#47;v&#41; paraformaldehyde&#44; 0&#46;1&#37; &#40;v&#47;v&#41; glutaraldehyde in 0&#46;1<span class="elsevierStyleHsp" style=""></span>M phosphate-buffered saline &#40;PBS&#41; solution for 2<span class="elsevierStyleHsp" style=""></span>h at room temperature&#46; After that&#44; a post-fixation with 1&#37; &#40;w&#47;v&#41; osmium tetroxide in cacodylate buffer was performed for 1<span class="elsevierStyleHsp" style=""></span>h&#46; Embedding was performed in Lowycril K4M resin according to standard procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Immunohistochemistry</span><p id="par0055" class="elsevierStylePara elsevierViewall">Samples to be analyzed by light microscopy were deparaffinised and processed at 121<span class="elsevierStyleHsp" style=""></span>&#176;C in a 2100 Antigen Retriever &#40;PickCell Laboratories&#44; Leiden&#44; Netherland&#41; in Tris&#8211;HCl 10<span class="elsevierStyleHsp" style=""></span>mM-EDTA 0&#46;5<span class="elsevierStyleHsp" style=""></span>mM pH 9&#46;0 buffer for EC-SOD slides and in Citrate 10<span class="elsevierStyleHsp" style=""></span>mM pH 6&#46;0 for fibulin-5 slides&#46; After antigen unmasking&#44; sections were washed three times in PBS and submerged in 3&#37; hydrogen peroxide&#44; 10&#37; methanol in PBS for 15<span class="elsevierStyleHsp" style=""></span>min&#46; After washing three times with PBS&#44; nonspecific binding was suppressed by incubation with blocking solution&#46; Following that&#44; samples were incubated at 4<span class="elsevierStyleHsp" style=""></span>&#176;C overnight with polyclonal anti-EC-SOD antibody &#40;1&#58;500&#44; Abnova&#44; Taipei&#44; China&#41; monoclonal anti-fibulin 5 antibody &#40;1&#58;750&#44; Abcam&#44; Cambridge&#44; UK&#41;&#44; rabbit polyclonal anti-4-HNE antibody &#40;1&#58;300&#59; Calbiochem&#44; San Diego&#44; CA&#44; USA&#41;&#44; rabbit polyclonal anti-MDA antibody &#40;1&#58;400&#59; Abcam Ltd&#46;&#44; Cambridge&#44; UK&#41; or with rabbit polyclonal anti-NT antibody &#40;1&#58;90&#59; Upstate Biotechnology&#44; Inc&#46;&#44; Lake Placid&#44; NY&#44; USA&#41; in blocking solution&#46; Negative controls were obtained by incubating a slide with rabbit IgG &#40;1&#58;500&#44; ab37415&#44; Abcam&#44; Cambridge&#44; UK&#41; or mouse IgG &#40;1&#58;200&#44; ab37355&#44; Abcam&#41;&#46; On the following day&#44; sections were washed in PBS and incubated with biotinylated anti-Rabbit or ant-Mouse IgG antibody &#40;Vector Laboratories&#59; Burlingame&#44; CA&#41; for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature&#46; Immunostaining was performed using the avidin&#8211;biotin complex &#40;ABC&#41; immunoperoxidase method &#40;Vectastain Elite ABC kit&#59; Vector Laboratories&#44; Burlingame&#44; CA&#44; USA&#41; with a 3&#44;3&#8242;-diaminobenzidine tetrahydrochloride &#40;DAB&#41; reaction&#46; Finally&#44; the slides were counterstained in haematoxylin&#44; dehydrated&#44; and mounted&#46; For analysis of immunostained lung tissue&#44; two independent observers &#40;JGV and JO&#41; assessed the intensity and extent of immunoreactivity of EC-SOD in a double-blind fashion through a semi quantitative score &#40;0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no staining&#59; 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>weak&#47;intermediate staining&#59; 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>strong staining&#41;&#46; At least twelve fields of each sample were randomly and systematically sampled to assess EC-SOD and fibulin-5 staining in alveolar interstitium&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Samples to be analyzed by transmission electron microscopy &#40;TEM&#41; were hydrated in a PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M glycine 0&#46;1<span class="elsevierStyleHsp" style=""></span>M solution and non-specific binding was suppressed by incubation in 2&#37; ovalbumin in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M&#46; After that&#44; samples were incubated with the primary antibody &#40;anti-EC-SOD&#44; 1&#58;150&#44; Abnova&#44; Taipei&#44; China&#41; in blocking solution for2<span class="elsevierStyleHsp" style=""></span>h&#46; Then&#44; samples were washed three times in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M glycine 0&#46;1<span class="elsevierStyleHsp" style=""></span>M solution and incubated with Goat Anti-Rabbit IgG with 10<span class="elsevierStyleHsp" style=""></span>nm Gold preadsorbed &#40;1&#58;10&#44; ab27234&#44; Abcam&#41; for1<span class="elsevierStyleHsp" style=""></span>h&#46; Finally&#44; samples were washed in PBS 0&#46;1<span class="elsevierStyleHsp" style=""></span>M and jet-washed in 10<span class="elsevierStyleHsp" style=""></span>ml of milli-Q water prior to counterstaining and mounting&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Quantitative real-time PCR</span><p id="par0065" class="elsevierStylePara elsevierViewall">Isolation of total RNA from tissue samples was performed using the AllPrep DNA&#47;RNA Mini Kit &#40;QIAGEN&#44; Hilden&#44; Germany&#41;&#46; After reverse transcription of mRNA into complementary DNA &#40;cDNA&#41;&#44; qRT-PCR was performed using primer and probe sets for <span class="elsevierStyleItalic">ECSOD</span> and fibulin-5 from TaqMan Gene Expression Assays purchased from Applied Biosystems &#40;Foster City&#44; CA&#44; USA&#41;&#46; Data from qRT-PCR reactions was analyzed by the comparative Ct &#40;2-&#916;&#916;Ct&#41; quantification method&#46; Relative expression levels of <span class="elsevierStyleItalic">ECSOD</span> and <span class="elsevierStyleItalic">fibulin-5</span> genes were determined using <span class="elsevierStyleItalic">18S</span> mRNA as an endogenous control&#46; Three independent experiments were performed and results were expressed as the normalized mean of the relative quantification &#40;RQ&#41; of the tested transcripts&#46; Non-template controls exhibited no signal&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The descriptive statistical analysis included mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM or SD for each parameter and patient group&#46; Data were compared between the two groups using the Chi-square and Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-tests&#46; The significance level was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; All analyses were performed using Statgraphics Centurion XV &#40;StatPoint&#44; Inc&#46;&#44; Warrenton&#44; VA&#44; USA&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Demographic and clinical findings</span><p id="par0075" class="elsevierStylePara elsevierViewall">The two clinical groups were similar regarding age and body-mass index&#44; with a predominance of males and tobacco smoking in the COPD group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; As expected&#44; the mMRC dyspnoea score&#44; the number of previous exacerbations in the last year and the use of inhaled corticosteroids were higher in COPD patients&#46; In this group&#44; the microscopic &#40;LM&#41; and macroscopic emphysema &#40;MED&#41; degree was increased and the spirometry variables were reduced compared with non-COPD patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Histology and histochemistry</span><p id="par0080" class="elsevierStylePara elsevierViewall">In order to determine whether the architecture of elastic fibres in alveolar walls was different among COPD patients and controls&#44; we used Verhoeff&#39;s staining&#44; a method that allows highlighting elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">As expected&#44; sections from COPD patients exhibited an altered elastin network when compared to control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Thus&#44; there were anomalous accumulations of elastic fibres in periemphysematous alveolar walls of COPD patients&#44; suggesting a tissue collapse in periemphysematous areas &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#44; D and F&#41;&#46; By contrast&#44; control samples did not show these histological alterations &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#44; C and E&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">When the tips of alveolar walls were observed under TEM&#44; COPD patients showed vacuolar changes in the amorphous component of elastic fibres&#44; resulting in a pierced pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>H&#41;&#46; These alterations were absent in control samples &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>G&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Immunohistochemistry</span><p id="par0095" class="elsevierStylePara elsevierViewall">Light microscopy study showed that EC-SOD was immunolocalised in airway and parenchymal epithelial cells &#40;primarily in the apical area&#41;&#44; as well as in alveolar macrophages and endothelial cells&#46; EC-SOD was also present in the perimeter of elastic fibres of pulmonary vessels and alveolar walls&#44; whereas collagen showed a weaker or no staining&#46; Interestingly&#44; EC-SOD immunostaining was higher in airway and vascular walls of control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and C&#41; when compared to COPD patients &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B and D&#41;&#46; Regarding fibulin-5&#44; it was also observed mainly in airway and vascular walls&#44; as well as in alveolar interstitium of lung samples &#40;Fig&#46; S1&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Moreover&#44; immunolocalization of EC-SOD and fibulin-5 allowed us to study the interstitial expression of these proteins&#46; Alveolar&#44; bronchiolar and arteriolar walls of patients with COPD showed a reduced expression of EC-SOD and fibulin-5 when compared to control subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; The additional immunohistochemical analysis by TEM confirmed the reduced expression of EC-SOD in interstitium of COPD patients&#44; and revealed that EC-SOD was tightly associated with fibrillary components in the unaffected elastic fibres &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; Moreover&#44; in altered fibres&#44; the decrease in EC-SOD labelling was associated with the loss of the fibrillary component and the partial degradation of elastin&#44; which produced the pierced pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Furthermore&#44; when the expression of EC-SOD and fibulin-5 in alveolar&#44; bronchiolar and arteriolar walls of COPD patients and control samples was compared through a semi-quantitative score&#44; we found that COPD patients have a significant reduced expression of both EC-SOD and fibulin-5 &#40;0&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64 and 0&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; respectively&#41; compared to control subjects &#40;1&#46;39<span class="elsevierStyleHsp" style=""></span>&#177; 0&#46;63 and 1&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;52&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Fig&#46; S1</a>&#41;&#46; Additionally&#44; levels of EC-SOD and fibulin-5 were analyzed in patients without COPD by comparing smokers &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; and non-smokers &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; and males &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41; versus females &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#46; Immunoscore values for EC-SOD in alveolar&#44; arteriolar and bronchiolar wall were 1&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23&#44; 1&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;21 and 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12 in non-smokers and 1&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13 and 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in smokers without COPD &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;63&#44; 0&#46;12 and 0&#46;89 respectively&#41;&#46; The immunoscore for fibulin-5 in these compartments were 1&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18&#44; 1&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 and 1&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17 in non-smokers and 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17&#44; 1&#46;60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18 and 1&#46;66<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13 in smokers without COPD &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;96&#44; 0&#46;81 and 0&#46;51 respectively&#41;&#46; Thus&#44; no significant differences were observed in the expression of the antioxidant markers when comparing smokers and non-smokers&#46; Immunoscore values for EC-SOD in alveolar&#44; arteriolar and bronchiolar wall were 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20 and 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in non-COPD females and 1&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&#44; 1&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;15 and 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12 in non-COPD males &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;37&#44; 0&#46;23 and 0&#46;89&#44; respectively&#46; Values for fibulin-5 in the same compartments were 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13&#44; 1&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;17 and 1&#46;80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;11 in non-COPD females and 1&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;21&#44; 1&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;14 and 1&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18 in non-COPD males &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;54&#44; 0&#46;92 and 0&#46;25&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding oxidative stress markers&#44; malondialdehyde was the most reliable to distinguish COPD patients&#46; Indeed&#44; the adducts of this lipid peroxidation product were mainly immunolocalised in the connectives tissues&#44; such as adventitia layers&#44; alveolar walls&#44; arterioles and the parenchymal interstitium surrounding emphysematous areas of COPD patients&#44; showing significant differences with non COPD samples &#40;Fig&#46; S2&#41;&#46; Although 4-hydroxynonenal adducts were detected in all patients&#44; they showed a significant increase in COPD groups &#40;Fig&#46; S3&#41;&#44; while the 3-nitrotyrosine biomarker was primarily located in the tissues close to the respiratory tract and alveolar spaces of smokers &#40;Figure S3&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Quantitative real-time PCR</span><p id="par0115" class="elsevierStylePara elsevierViewall">Quantitative PCR analyses showed that both mRNA levels of <span class="elsevierStyleItalic">EC-SOD</span> and <span class="elsevierStyleItalic">fibulin-5</span> were lower in COPD patients than in controls &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; though these differences did not reach statistical significance &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">It is widely acknowledged that an imbalance between free radicals and antioxidant defences plays a main role in COPD pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> However&#44; the <span class="elsevierStyleItalic">in situ</span> expression of oxidative stress in lungs of COPD patients remains poorly understood&#46; The present study shows for the first time an association between a reduced expression of EC-SOD&#44; the main antioxidant in the lung interstitium&#44; its binding protein fibulin-5 and parenchymal alterations in alveolar walls of COPD patients&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Recent studies assessing the pathological remodelling of elastic fibres in emphysematous lung have shown contradictory conclusions&#44; since while some of them showed a reduction in the volume fraction of elastic fibres&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">25</span></a> others found an increase<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a> or even no changes&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">27</span></a> Our histochemical analysis by light microscopy revealed matrix alterations coinciding with emphysema in COPD patients&#46; Damage consisted in frayed elastic fibres clumped into dense masses lying within remnants of collapsing alveolar walls&#44; coinciding with pathologic changes described by Robert Wright almost sixty years ago<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">28</span></a> When interstitium of collapsing walls were further analyzed through TEM&#44; we observed a loss of fibrillary component&#44; mainly in the core of the elastic fibres&#44; together with the presence of vacuoles affecting the amorphous component&#46; A similar pierced pattern has been described in previous TEM studies in humans and murine models of emphysema&#44;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">29&#8211;31</span></a> and underpins the importance of structural abnormalities of elastic fibres in areas of emphysematous destruction&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Our results showed that lungs from COPD patients exhibit lower expression of EC-SOD in alveolar walls likely leading to an impaired antioxidant defence in these patients&#46; Indeed&#44; cigarette smoke and other air pollutants contain high levels of oxidants and other molecules capable of inducing the formation of free radicals in pulmonary cells and a chronic inflammatory response in COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">32&#8211;34</span></a> Both oxidative stress and inflammation act in concert to foster the emphysematous destruction of alveolar walls and to affect the repair and maintenance of parenchymal structure&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">35</span></a> Among the rich network of enzymatic antioxidants that lungs possess to protect themselves from oxidative burden&#44; EC-SOD plays a primordial role in the extracellular space&#44; both by scavenging superoxide radicals and by inhibiting the inflammatory response&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">13&#8211;15</span></a> Importantly&#44; EC-SOD activity in the lung has been extensively studied in the <span class="elsevierStyleItalic">SOD3</span> mice model&#46; Gongora and colleagues showed that loss of EC-SOD leads to severe lung damage in mice&#44; while treatment with EC-SOD mimetic MnTBAP reduces lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">36</span></a> Using the same animal model&#44; Yao and colleagues demonstrated that EC-SOD attenuates fragmentation of elastic fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> Since extracellular matrix components such as elastin&#44; heparin sulphate and hyaluronan are known to trigger lung inflammation&#44; the authors concluded that EC-SOD protects lungs from emphysema by decreasing the inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> Hence&#44; our results support the hypothesis that a reduced antioxidant defence caused by diminished levels of EC-SOD is detrimental for COPD patients by increasing the progression of emphysema&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; only two previous papers studied pulmonary EC-SOD expression in patients with COPD&#46; Thus&#44; whereas Harju and co-workers reported no differences in EC-SOD immunoreactivity among non-smokers&#44; smokers without COPD and COPD patients&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a> a more recent study found a significant decrease of EC-SOD immunoreactivity around vessels and bronchioles of COPD patients compared to controls&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> Our results demonstrate a reduced expression of EC-SOD in vascular and airway walls in COPD and TEM analysis confirmed the decreased expression of interstitial EC-SOD observed by light microscopy in COPD patients&#46; The mentioned discrepancy of results among the three studies may be due to differences in the characteristics of COPD patients &#40;mild to moderate in the study by Harju et al&#46; and moderate to severe in our study and the one by Regan et al&#46;&#41; and the different compartments analyzed&#46; Thus the expression of EC-SOD in sputum or bronchoalveolar lavage does not need to mirror its in situ expression in the lung interstitium&#44; where it exerts its protective effect&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A relevant finding in our study is that immunoreactivity of fibulin-5 was significantly lower in alveolar walls&#44; airway and vascular walls of COPD patients than in control subjects&#46; Fibulin-5 and fibulin-4 are the most critical molecules for aiding assembly of elastic fibres&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">11&#44;12</span></a> although fibulin-5 exhibits higher binding affinity to tropoelastin and is expressed at much higher levels than fibulin-4 in lung&#44; aorta and skin&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">38</span></a> In a experimental model&#44; fibulin-5-null mouse developed emphysema and disruption of elastic fibres thus suggesting the critical role of fibulin-5 in the maintenance of the lung architecture&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">39&#44;40</span></a> Furthermore&#44; a decrease of fibulin-5 may likely impair its binding to EC-SOD<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> and affect negatively the protection against oxidative stress of the elastin matrix&#46; This lack would favour elastin degradation by extracellular elastase activity thus accelerating the evolution to emphysema in COPD patients&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In spite of our immunohistochemical analyses revealing reduced presence of EC-SOD and fibulin-5 in alveolar walls of COPD patients&#44; the difference between pulmonary mRNA levels of these proteins in COPD patients and controls was not statistically significant&#46; This discrepancy regarding gene expression is not surprising&#44; since mRNA expression is not necessarily related to tissue protein levels&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a> Whole tissue samples for PCR analysis contain not only different lung compartments&#44; but also circulating blood and secretions&#46; On the contrary&#44; immunohistochemistry in lung slices allows for detecting the markers in specific tissue localizations&#44; such as alveolar walls&#46; Indeed&#44; in a previous study the levels of EC-SOD were high in sputum of COPD patients&#44; but not in blood or BALF&#44; whereas EC-SOD tissue immunoreactivity was lower in COPD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Our results suggest that patients with COPD have a reduced antioxidant activity in their lungs which make them more vulnerable to the disease&#46; This finding supports the hypothesis that antioxidant therapy might be useful for these patients&#46; However&#44; further studies must be conducted in the clinical setting to address this probability&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In summary&#44; our results show that EC-SOD and fibulin-5 expression are reduced in alveolar walls of patients with COPD&#44; which also show alterations in elastic fibres&#46; This reduction supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">This study was funded by the Spanish Health Research Fund-Instituto de Salud Carlos III &#40;FIS 04&#47;0635&#41; and the Sociedad Espa&#241;ola de Pneumologia &#40;SEPAR 165&#124;2012&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Demographic and clinical findings"
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              "titulo" => "Histology and histochemistry"
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              "titulo" => "Immunohistochemistry"
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    "fechaRecibido" => "2020-11-30"
    "fechaAceptado" => "2020-12-22"
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            1 => "EC-SOD"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to analyze the expression of the main oxidant scavenger superoxide dismutase &#40;EC-SOD&#41;&#44; its main binding protein Fibulin-5 and several oxidative and nitrosative-derived products in the lung of COPD patients and controls&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Lung tissue samples from 19 COPD patients and 20 control subjects were analyzed&#46; The architecture of elastic fibres was assessed by light and electron microscope histochemical techniques&#44; and levels of EC-SOD and fibulin-5 were analyzed by immunohistochemistry and RT-PCR&#46; The impact of oxidative stress on the extracellular matrix was estimated by immunolocalization of 4-hydroxynonenal &#40;4-HNE&#41;&#44; malondialdehyde &#40;MDA&#41; and 3-nitrotyrosine &#40;3-NYT&#41; adducts&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Alveolar walls of COPD patients exhibited abnormal accumulations of collapsing elastic fibres&#44; showing a pierced pattern in the amorphous component&#46; The semiquantitative analysis revealed that COPD patients have a significantly reduced expression of both EC-SOD and fibulin-5 &#40;0&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64 and 0&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; respectively&#41; in alveolar&#44; bronchiolar and arteriolar walls compared to control subjects &#40;1&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;63 and 1&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;52&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; No significant changes in mRNA levels of these proteins were observed between groups&#46; Among the oxidation markers&#44; malondialdehyde was the best in distinguishing COPD patients&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">COPD patients show a reduced expression of EC-SOD and fibulin-5 in the lung interstitium&#46; Paralleling the reduction of EC-SOD levels&#44; the decrease of fibulin-5 expression in COPD lungs supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Localization of elastic fibres in lung samples from COPD patients and control subjects&#46; Verhoeff&#39;s staining of elastic fibres in alveolar ducts of a healthy control &#40;A&#41; and a COPD patient &#40;B&#41;&#44; with arrows indicating accumulation of elastic fibres in collapsing walls of emphysematous areas &#40;bars<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#46; Detail of a tip of an alveolar wall of a control subject &#40;C&#41;&#44; showing the normal distribution of elastic fibres&#44; while the alveolar walls of the emphysematous &#40;D&#41; areas appear collapsed in COPD patients &#40;bars<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#46; Micrography of normal lung parenchyma of a control subject &#40;E&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; and emphysematous parenchyma of COPD patient &#40;F&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#44; showing prominent elastic accumulations&#46; &#40;G&#41; Electron microscopy of a tip of a normal alveolar wall &#40;bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; &#40;H&#41; Electron microscopy of a collapsing alveolar wall&#44; showing vacuoles and a pierced pattern in the amorphous component &#40;bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Immunolocalization of EC-SOD and fibulin-5 in alveolar walls of COPD patients and control subjects&#46; Alveolar walls of control subjects showed increased presence of EC-SOD &#40;A&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; and fibulin-5 &#40;E&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; as compared to those of COPD patients &#40;B&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;m&#44; and F&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>&#956;m&#44; respectively&#41;&#46; &#40;C&#41; and &#40;D&#41; Electron microscopy of immunolocalised EC-SOD in elastic fibres from alveolar walls of a control subject &#40;C&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>nm&#41; and a COPD patient &#40;D&#44; bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; Colloidal gold labelling indicating EC-SOD immunolocalization was mostly absent in the fibrillary component alveolar elastic fibres of COPD samples&#46; Dashed lines indicate loss of fibrillary component&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Semiquantitative score of the expression of EC-SOD and Fibulin-5 in the lung parenchyma&#46; Semiquantitative score showed a significant reduction of EC-SOD and fibulin-5 in the connective tissues of the lung parenchyma from COPD patients when compared to control subjects &#40;estimated mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#41;&#46;</p>"
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        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">SD&#58; Standard Deviation&#59; BMI&#58; Body Mass Index&#59; mMRC&#58; Modified Medical Research Council Dyspnoea Scale&#59; ICS&#58; Inhaled Corticosteroids&#59; MED&#58; Macroscopic Emphysema Degree&#59; LM&#58; Mean Airspace Chord length&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-COPD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COPD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-For trend&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#46;26 &#40;12&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#46;00 &#40;9&#46;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8219&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&#46; male vs&#46; Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;21 &#40;4&#46;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;17 &#40;3&#46;81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1774&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smokers &#40;<span class="elsevierStyleItalic">n</span>&#44; Pack-years &#40;SD&#41;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44; 28&#46;84 &#40;33&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#44; 58&#46;05 &#40;23&#46;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0044&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dyspnoea score &#40;mMRC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;19 &#40;10&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#47;20 &#40;55&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any exacerbations in the last year&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;19 &#40;15&#46;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;20 &#40;70&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients treated with ICS&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;19 &#40;10&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;20 &#40;70&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with oxygen&#46; <span class="elsevierStyleItalic">n</span>&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;19 &#40;0&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;20 &#40;30&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FEV<span class="elsevierStyleInf">1</span> postbronchodilator &#40;&#37;pred&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#46;92 &#40;18&#46;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&#46;36 &#40;21&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FEV<span class="elsevierStyleInf">1</span>&#47;FVC postbronchodilator &#40;&#37;pred&#41;&#46; &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#46;26 &#40;7&#46;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#46;58 &#40;13&