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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Lung transplantation is an established lifesaving therapy for an increasing number of patients suffering from irreversible end-stage pulmonary diseases&#46; Although early outcomes &#40;hospital mortality and one-year survival rates&#41; have dramatically improved over recent years&#44; long-term survival rates are still far from those achieved with other solid organs&#46; In the last decade&#44; the 5-year survival rate has remained 50&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> which contrasts with survival rates above 70&#37; for heart&#44; kidney&#44; liver or pancreas recipients&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Chronic lung allograft dysfunction &#40;CLAD&#41; as a whole&#44; and bronchiolitis obliterans syndrome &#40;BOS&#41; as a specific phenotype&#44; is the main cause of death after the first year post-lung transplant<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> and represents the Achilles&#8217; heel of this therapeutic option&#46; Half of our patients will develop BOS by 5 years and more than 70&#37; by 10 years after transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a> Its pathological expression is termed bronchiolitis obliterans &#40;BO&#41; and&#44; essentially&#44; consists of a fibrotic process affecting the small airway&#46; In the early phases a lymphocytic infiltrate is observed in the submucosa and epithelium&#44; which is called lymphocytic bronchiolitis&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">3</span></a> Later&#44; necrotic changes and ulceration occur in the epithelium and trigger a chronic inflammatory reaction&#44; which results in fibroblastic migration into the airway lumen&#46; The subsequent fibroproliferative process leads to small airway partial or total obstruction&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">4</span></a> The etiology of this process is still unknown&#46; Although likely multifactorial&#44; there is increasing evidence that innate and acquired immunological factors play a crucial role in its course&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Stem cells have shown a consistent ability to modulate the inflammatory response and enhance the healing process of many disorders in different target tissues&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">7&#8211;9</span></a> Besides&#44; the lack of Major Histocompatibility Complex &#40;MHC&#41; class I and II expressions on these cells prevents immunological rejection&#46; Furthermore&#44; it has been described that mesenchymal stem cells applied both locally and systemically may slow the development of bronchiolitis obliterans in other animal models because of this immunomodulatory ability&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this paper&#44; we aim to assess the impact of allogeneic adult bone marrow-derived mesenchymal stem cells &#40;BMSC&#41; in an experimental rat model of BO using different routes of administration&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This is an experimental randomized study&#46; The experimentation committee of Hospital Universitario Puerta de Hierro-Majadahonda&#44; Spain&#44; approved all phases of the project&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Animal model of BO</span><p id="par0030" class="elsevierStylePara elsevierViewall">We used heterotopic tracheal transplantation in rats as a model of BO&#44; in accordance with our previous publication&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">11</span></a> Briefly&#44; a 2&#8211;3 cartilage ring segment of trachea &#40;allograft&#41; from a female Lewis rat donor was grafted into the recipient left lung parenchyma&#44; a female Wistar rat&#46; All rats were euthanized on day 21 and allografts processed for histological analysis&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Bone marrow-derived mesenchymal stem cell &#40;BMSC&#41; isolation and characterization</span><p id="par0035" class="elsevierStylePara elsevierViewall">BMSC isolation from male rats and phenotypic characterization were performed as described in previous publications from the Neuroscience Research Unit at our Hospital&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">12</span></a> BMSC were retrieved from tibia and femur of male rats by washing both epiphysis and diaphysis with alfa-minimun essential medium &#40;alfa-MEM&#41;&#46; Bone marrow was collected and dissociated by mechanical methods&#46; The obtained homogeneous sample was then filtered and incubated at 37<span class="elsevierStyleHsp" style=""></span>&#176;C in 5&#37; CO<span class="elsevierStyleInf">2</span> for 5 weeks&#46; For characterization of the BMSC phenotype&#44; we used flow cytometry analysis &#40;Cytometer Cytomics FC500 MPL &#8211; Beckman Coulter&#44; Inc&#46;&#44; Brea&#44; CA&#44; USA&#44; and CFC 500MXP software&#44; version 2&#46;2 &#8211; Beckman Coulter Inc&#46;&#44; Miami&#44; FL&#44; USA&#41;&#46; The following cell-surface markers were characterized CD11b&#44; CD29&#44; CD31&#44; CD45 and CD90&#44; with a suitable fluorochrome-conjugated isotype control &#40;all antibodies were from AbD Serotec &#8211; Oxford&#44; United Kingdom&#44; all specific to rats&#41;&#46; Only cells under 5 weeks in culture and with phenotypic characteristics for MSC published by International Society of Cellular Therapy &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; expression of CD29 and CD90 &#91;95&#37; positive&#93; and absence of expression of CD11b&#44; CD45 or CD31 &#91;&#60;5&#37; positive&#93;&#41; were used &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Control and experimental groups&#44; and BMSC application</span><p id="par0040" class="elsevierStylePara elsevierViewall">Once the tracheal segments were grafted in the recipients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#41;&#44; they were divided into a Control Group &#40;CG&#41;&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#44; and 3 experimental groups &#40;15 rats each&#41; depending on the day on which the BMSC were transplanted&#58; group 0 recipients &#40;G0&#41; received BMSC the same day of tracheal segment grafting&#59; group 7 &#40;G7&#41; received BMSC on day 7&#59; and group 14 &#40;G14&#41; received BMSC on day 14&#46; Each experimental group was divided into subgroups &#40;5 animals each&#41; depending on the route used for BMSC application&#58; endotracheal &#40;ET&#41;&#44; intravenous &#40;IV&#41; or lung injection &#40;LI&#41;&#46; In order to preferentially direct the BMSCs toward the left lung&#44; which contained the tracheal graft&#44; rats were placed in left lateral decubitus for ET administration&#46; BMSCs were then injected through the endotracheal tube&#46; For IV injection we used a jugular access with neck dissection as it has previously been showed that revascularization of the tracheal graft is derived from the pulmonary circulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">11&#44;14</span></a> Finally&#44; for LI transplantation&#44; we reopened the thoracotomy and injected BMSC in the tissue around the allograft&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Different BMSC doses were administered depending on the selected route&#44; ensuring the maximal concentration of cells without causing vascular or airway clots&#46; Through the ET route&#44; 7<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> cells suspended in 500<span class="elsevierStyleHsp" style=""></span>&#956;l of autologous plasma were transplanted &#40;concentration of 14<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;ml&#41;&#59; LI route&#44; 15<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> cells suspended in 250<span class="elsevierStyleHsp" style=""></span>&#956;l of autologous plasma &#40;concentration 60<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;ml&#41;&#59; and EV route&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> cells suspended in 300<span class="elsevierStyleHsp" style=""></span>&#956;l of autologous plasma &#40;concentration of 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;ml&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">All allografts were retrieved after 21 days&#44; as described before&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Histology&#44; BMSC detection and immunohistochemical staining</span><p id="par0055" class="elsevierStylePara elsevierViewall">After 21 days of tracheal segment grafting&#44; all individuals were euthanized by transcardiac injection of potassium &#40;1<span class="elsevierStyleHsp" style=""></span>ml&#41; after inhaled anesthesia with 8&#37; sevoflurane&#46; The tracheal allograft and a portion of surrounding lung parenchyma were recovered and processed for paraffin sectioning &#40;2&#46;5&#8211;4<span class="elsevierStyleHsp" style=""></span>&#956;m&#41;&#46; At least 2 sections were used for Hematoxylin&#8211;Eosin &#40;H&#8211;E&#41; and trichromic staining and another 2 for BMSC detection&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Fluorescent <span class="elsevierStyleItalic">in situ</span> hybridization &#40;FISH&#41; technique was performed for BMSC detection<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">12</span></a> by using specific biotinylated DNA that links the murine Sry gene sequence in the Y-chromosomes &#40;sex determining region&#41;&#46; The only cells showing Y-chromosomes are BMSC obtained from male donor rats&#46; The biotinylated DNA probe was visualized by immunofluorescence using a primary antibody-IgG monoclonal mouse anti-biotin &#40;1&#58;100&#44; Jackson&#41;&#44; and a secondary antibody-rhodamine IgG-conjugated anti-mouse &#40;1&#58;200&#44; Jackson&#41;&#46; Both negative and positive controls were performed&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Immunohistochemical &#40;IHQ&#41; staining was done for both proliferative cell and pneumocyte II biomarkers &#40;Ki-67 and pulmonary surfactant protein B&#44; respectively&#41;&#46; Ki-67 proliferation markers were determined in the same manner as previously reported&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">12</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">IHQ for protein B detection was performed in specific samples&#44; as described in the results&#46; These selected samples were incubated overnight with biotin-conjugated anti-mouse immunoglobulin Ig&#40;G&#41; anti-protein B &#40;dilution 1&#58;500&#44; ab40876 Abcam&#44; Cambridge&#44; UK&#41;&#46; After washing&#44; they were incubated with a secondary anti-mouse biotin-conjugated Ig&#40;G&#41; antibody &#40;1&#58;200&#44; Jackson Immuno Research Laboratories&#44; Inc&#46;&#44; West Grove&#44; PA&#44; USA&#41;&#46; All sections were washed with PBS&#44; incubated with avidin&#8211;biotin&#8211;horseradish peroxidase complex &#40;Vector Inc&#46;&#41;&#44; and 3&#44;3&#8242;-Diaminobenzidine was used as chromogen&#46; Negative and positive controls were performed&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Variables</span><p id="par0075" class="elsevierStylePara elsevierViewall">Different histological variables were studied&#44; such as fibrosis &#40;grade 0 &#8211; no fibrosis&#44; grade 1 &#8211; mild fibrosis&#44; grade 2 &#8211; severe fibrosis&#41;&#44; inflammation &#40;grade 0 &#8211; nil&#59; grade 1 &#8211; moderate&#44; inflammatory cell local accumulations&#59; grade 2 &#8211; severe&#44; diffuse inflammatory infiltrates&#41;&#44; neovascularization &#40;grade 0 &#8211; nil or slight presence of visible vessels and endothelium&#59; grade 1 &#8211; moderate presence&#59; grade 2 &#8211; more significant presence&#41;&#44; and edema &#40;grade 0 &#8211; nil or slight&#59; grade 1 &#8211; patchy distribution&#59; grade 2 &#8211; diffuse distribution&#41;&#46; Finally&#44; we looked for the presence of BMSC in the samples&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">This is a prospective&#44; randomized&#44; experimental study&#46; The pathologist was blinded regarding the application or not of BMSC in the analyzed samples&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Qualitative variables were analyzed using corrected <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> and Fisher tests&#46; Data analysis was carried out using SPSS software v14&#46;0 &#40;IBM SPSS Statistics&#44; Armonk&#44; NY&#44; USA&#41;&#46; A <span class="elsevierStyleItalic">p</span> value of &#60;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Control group is representative of the typical BO lesion</span><p id="par0090" class="elsevierStylePara elsevierViewall">As stated in Material and Methods&#44; we used a heterotopic rat transplantation animal model for reproducing the BO lesion&#46; After 21 days&#44; allografts were retrieved and analyzed &#40;H&#8211;E staining&#41;&#46; All 5 animals in the control group demonstrated absence of epithelium and dense collagen tissue with no inflammatory infiltrate occupying the lumen of the allograft &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; These findings are consistent with previously published histological patterns using this model&#44;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">11&#44;14</span></a> such as loss of epithelium and base membrane&#44; and fibrous obliteration of the lumen&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Administration of BMSCs and modification of the histological course in the allografts</span><p id="par0095" class="elsevierStylePara elsevierViewall">Histological qualitative analysis showed numerous large neovessels in a very loose fibrous tissue matrix with no inflammatory infiltrate &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Trichromic staining showed collagen deposition in both cartilaginous and membranous walls of the allograft&#44; and a loose collagenous net inside the lumen&#46; These findings were found in all groups&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; we present the most remarkable aspects of the histological analysis&#46; In comparison to CG&#44; in which no inflammation at all was found&#44; G0 and G14 animals showed significantly more inflammatory response &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#44; respectively&#41;&#44; regardless the route of BMSC administration&#46; With regard to the presence of edema&#44; we observed that G0 and G14 rats had significantly more than CG &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;023 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#44; respectively&#41;&#44; also regardless the route of BMSC application&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">None of the animals across all 3 experimental groups showed restitution of the epithelium&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Fibroproliferative response</span><p id="par0110" class="elsevierStylePara elsevierViewall">A reparative effect that leads to fibrocollagenous tissue formation is expected within the allograft lumen in this specific animal model of BO&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">11&#44;14</span></a> This sort of fibroblastic response is also initiated whenever the lung tissue experiences an injury after transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">15</span></a> Therefore&#44; with the purpose of describing the different fibroproliferative responses between experimental groups G0&#44; G7 and G14 and CG&#44; histological qualitative analysis was performed in all samples&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Either grade 1 or 2 fibrosis was found in most of the animals in G0 and G14&#46; On the other hand&#44; significantly less fibrosis was detected in G7 in comparison to CG &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41;&#46; A more detailed analysis considering the routes of administration of BMSC showed&#44; essentially&#44; that those animals who received BMSC through endotracheal route &#40;G7&#95;ET&#41; did not develop any grade of fibrosis whatsoever &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Alveolar-like tissue patches were detected across all BMSC transplanted groups</span><p id="par0120" class="elsevierStylePara elsevierViewall">Administration of BMSC has previously demonstrated the ability to enhance lung regeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">16</span></a> In the present study&#44; patches of epithelial tissue with histological architecture similar to alveoli were observed within the allograft lumen &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; This alveolar-like tissue was homogeneously distributed across all three experimental groups &#40;53&#46;4&#37;&#44; 46&#46;7&#37; and 40&#37; in G0&#44; G7 and G14&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; We then performed an IHQ test after FISH in those samples with alveolar-like tissue patches&#46; These cells demonstrated positivity for CrY and pulmonary surfactant-associated protein B proving that these BMSCs had developed surfactant-producing properties&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">For further characterization&#44; IHQ test after FISH was performed in those samples with alveolar-like tissue patches to clarify whether these cells were producing typical pneumocyte-type II markers &#40;in particular&#44; pulmonary surfactant-associated protein B&#41;&#46; The majority of the analyzed samples showed both FISH and IHQ positiveness in the same section &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In other words&#44; CrY&#43; cells &#40;BMSC&#41; were expressing pulmonary surfactant-associated protein B &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">BMSC detection and location</span><p id="par0130" class="elsevierStylePara elsevierViewall">CrY&#43; cells &#40;BMSC&#41; were detected in all three experimental groups &#40;G0&#44; G7&#44; G14&#41;&#44; irrespective of the transplantation route &#40;ET&#44; EV&#44; LP&#41;&#46; Also&#44; we randomly investigated the expression of Ki67 in all groups&#44; finding expression in all groups&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">From a morphological standpoint&#44; BMSC were observed as a part of cartilage&#44; connective tissue and endothelium of neovessels &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0140" class="elsevierStylePara elsevierViewall">BOS hampers the long-term survival of lung transplant recipients&#46; Regardless of the immunosuppressive regimen&#44; only one-third of our patients will remain free from BOS 10 years after transplantation&#46; Therefore&#44; it is of paramount importance to find therapeutic strategies that prevent or attenuate the incidence of this condition&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Histopathologically&#44; end-stage BOS consists of an excessive fibroproliferative thickening of the bronchiolar walls in response to epithelial injury&#46; In the initial stages&#44; lymphocytic infiltrates invade the epithelium and submucosal layer and the epithelium loses its architectural consistency&#46; As the disease progresses&#44; the bronchiolar lumen is progressively replaced by granulation tissue containing fibroblasts and myofibroblasts&#44; and finally forms a fibrotic scar&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">3</span></a> Although this process was initially thought to be a direct result of T-cell mediated injury of graft structures&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">17</span></a> there is now evidence to support that antibody-mediated rejection &#40;circulating antibodies to donor HLA molecules&#41;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">18&#44;19</span></a> and autoimmune responses to airway components &#40;collagen V&#44; K&#945;-1 tubulin&#41; are also associated&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Heterotopic tracheal transplantation into the lung parenchyma has been successfully used to reproduce the histologic changes of BO lesion and investigate angiogenesis and fibroproliferative tissue remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">14</span></a> However&#44; some limitations have been described with regard to this animal model&#44; such as the lack of connection of the graft to the airway or vessels&#44; as well as the fact that BO occurs in the small airways in the clinical setting&#46; Despite these limitations&#44; we were able to reproduce the typical histological changes of BO lesions&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Our results show that BMSC are able to impact the histologic course of BOS at any time point and through any route of administration&#44; moving from a pattern of dense fibrous scar tissue to another kind of histologic presentation&#44; with various degrees of inflammation&#44; edema and neovascularization&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The most impressive reductions in fibrosis were seen when BMSC were applied at day 7&#46; In particular&#44; the rats receiving BMSC <span class="elsevierStyleItalic">via</span> the endotracheal route at day 7 showed no fibrosis and no inflammation at all&#44; suggesting that early endobronchial therapy should be the preferred choice&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Concerning the dosage of BMSC&#44; the literature is unclear on its importance&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">10&#44;12</span></a> The most effective concentration has not yet been established and warrants further research&#46; Therefore&#44; we planned to use the maximum tolerated concentration depending on the route of administration&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">It has been described&#44; both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; that mesenchymal stem cells &#40;MSC&#41; have immunomodulatory properties that promote or prevent innate and acquired inflammatory response&#44; depending on the local environment&#46; They can inhibit the proliferation and function of T-Lymphocytes&#44; natural killer &#40;NK&#41; cells and dendritic cells &#40;DC&#41;&#46; MSC are able to prompt T cell expansion toward a regulatory phenotype &#40;Treg&#41; by the production of prostaglandin E2 &#40;PGE2&#41; and transforming growth factor &#946;-1 &#40;TGF&#946;-1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">22</span></a> Similarly&#44; MSC can shift the macrophage population toward a predominantly immunosuppressive M2 phenotype by secretion of IL-10&#44; IL-2 and IL-13&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">23&#44;24</span></a> The effect of MSC in B cells is controversial&#59; some studies have shown inhibited proliferation&#44; differentiation and immunoglobulin production&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">25&#8211;27</span></a> whereas other groups have reported stimulatory effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">28&#44;29</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The differentiation of BMSCs is strongly influenced by T cell activation and the type and concentrations of cytokines in the local environment at the time of the exposure&#44; which explains the different properties they can show in different scenarios&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">30</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">This special feature of MSC supports our observation that the administration of these cells at the appropriate moment is critical to get the desired effect&#46; The most impressive results were seen at day 7&#44; when histopathological changes were at early stages in our model&#44; with some degree of inflammatory activity&#46; Prior to this &#40;T0&#41;&#44; there was no damage to restore and&#44; later on &#40;T14&#41;&#44; established fibrotic changes exceeded their ability to completely reverse the process&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">When tissue is damaged&#44; circulating MSC are attracted to the site&#44; and&#44; as they have multipotent differentiation potential&#44; they can differentiate into mature functional cells replacing damaged ones&#46; Nonetheless&#44; this is arguably a minor event&#44; as MSC mainly exert their reparative effects by stimulating <span class="elsevierStyleItalic">in situ</span> progenitor cells&#44; endothelial cells and fibroblasts to repair the injury through immunoregulation and growth factor secretion &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; paracrine mechanism&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">One of the most interesting findings in our experiment is the BMSC-mediated response to injury&#44; developing an alveolar-like tissue and mimicking what is supposed to be a normal tissue in that environment&#46; Moreover&#44; those cells involved in this peculiar tissue showed BMSC markers and produced surfactant protein B&#44; a specific biomarker of alveolar epithelial cells&#46; Although it is impossible to proof whether this alveolar-like tissue is functional or not&#44; this finding not only shows BMSC inclination to repair and restore normal tissue&#44; but also it might be proof of their transdifferentiation ability&#44;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">31&#8211;33</span></a> leading to mature cells of different lineages&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Another example of this is the finding of BMSC &#40;CrY&#43;&#41; taking part of the walls of neovessels&#44; which are morphologically identical to endothelial cells &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Previous heterotopic tracheal transplant models have shown the capacity of stem cells to attenuate histopathological changes of BO after either topical or systemic administration&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">34&#8211;36</span></a> In this study&#44; we have found that BMSC are able to nest and survive&#44; detect an injury scenario&#44; modify the histopathological course of BO lesions&#44; and repair the structure&#46; Moreover&#44; although intravenous and locally injected BMSC have an impact in the BO lesions&#44; the most remarkable effects are seen after endotracheal instillation of BMSC&#46; This finding might mean that the endoscopic administration of BMSC should be considered for further experimental or clinical projects&#44; while potential systemic collateral effects in other organs are minimized&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Given the fact that lung injury and repair is a complex process in a model of BOS&#44; it is difficult to attribute our experimental results to one or another mechanism led by BMSC&#46; It is clear that both paracrine&#44; as the main mechanism&#44; and differentiation&#44; as a minor one&#44; have a role in the modification of the histological course of BOS&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Although we have been able to find statistically significant results with very small sample sizes&#44; using a control group and masking techniques&#44; we must be cautious and await the results of this type of therapy in other models before generalizing our findings&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">In the clinical scenario&#44; there have been two phase I studies so far&#46; Chambers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">37</span></a> infused 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> BMSC from an unrelated donor to 10 patients with BOS <span class="elsevierStyleItalic">via</span> a peripheral vein twice a week for two weeks&#44; without any procedure related toxicity&#46; Similarly&#44; Keller et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">38</span></a> infused 1&#8211;4 million of allogeneic mesenchymal stem cells into nine patients with moderate BOS without any negative impact in measured clinical&#44; functional or laboratory variables&#44; opening the door for the use of these cells in the setting of established BOS&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions</span><p id="par0220" class="elsevierStylePara elsevierViewall">Bone marrow-derived mesenchymal stem cells modify the histopathological development of BO in this heterotopic tracheal transplantation animal model of BO&#46; Moreover&#44; they are able to express alveolar cell markers&#44; such us pulmonary surfactant protein B&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Endotracheal administration of BMSCs might be considered an effective way of preventing BO development in this animal model&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Funding</span><p id="par0230" class="elsevierStylePara elsevierViewall">This project has been granted by <span class="elsevierStyleGrantSponsor" id="gs1">Fundaci&#243;n Mutua Madrile&#241;a</span> &#40;identification number&#58; PR87532011&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Authorship</span><p id="par0235" class="elsevierStylePara elsevierViewall">David Gomez-de-Antonio&#58; design&#44; animal surgeries&#44; interpretation of results&#44; manuscript&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Jose Luis Campo-Ca&#241;averal de la Cruz&#58; design&#44; experimental surgeries&#44; interpretation of results&#44; manuscript&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Mercedes Zurita&#58; FISH and IHQ techniques&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Mart&#237;n Santos&#58; experimental surgeries anesthesia&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Carmen Gonz&#225;lez Lois&#58; pathological analysis of the samples&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Andr&#233;s Varela&#58; manuscript edition&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Jes&#250;s Vaquero&#58; manuscript edition&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interests</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Keywords"
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        3 => array:2 [
          "identificador" => "xpalclavsec1212864"
          "titulo" => "Abbreviations"
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        4 => array:3 [
          "identificador" => "xres1314076"
          "titulo" => "Resumen"
          "secciones" => array:4 [
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              "titulo" => "Introducci&#243;n"
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              "titulo" => "Material y m&#233;todos"
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          "titulo" => "Materials and methods"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Animal model of BO"
            ]
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              "identificador" => "sec0020"
              "titulo" => "Bone marrow-derived mesenchymal stem cell &#40;BMSC&#41; isolation and characterization"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Control and experimental groups&#44; and BMSC application"
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              "titulo" => "Histology&#44; BMSC detection and immunohistochemical staining"
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              "titulo" => "Variables"
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          "titulo" => "Results"
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              "identificador" => "sec0050"
              "titulo" => "Control group is representative of the typical BO lesion"
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            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Administration of BMSCs and modification of the histological course in the allografts"
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              "identificador" => "sec0060"
              "titulo" => "Fibroproliferative response"
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              "identificador" => "sec0065"
              "titulo" => "Alveolar-like tissue patches were detected across all BMSC transplanted groups"
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              "identificador" => "sec0070"
              "titulo" => "BMSC detection and location"
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          "titulo" => "Discussion"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2019-03-20"
    "fechaAceptado" => "2019-05-23"
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          "clase" => "keyword"
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            0 => "Mesenchymal stem cells"
            1 => "Lung transplantation"
            2 => "Bronchiolitis obliterans"
            3 => "Animal model"
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        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1212864"
          "palabras" => array:2 [
            0 => "BMSC"
            1 => "BO"
          ]
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          "palabras" => array:4 [
            0 => "C&#233;lulas madre mesenquimales"
            1 => "Trasplante pulmonar"
            2 => "Bronquiolitis obliterante"
            3 => "Modelo animal"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Bronchiolitis obliterans &#40;BO&#41; is the most common expression of chronic allograft dysfunction in lung transplantation&#46; Moreover&#44; BO represents the major cause of death in the long-term after this procedure&#46; On the other hand&#44; mesenchymal stem cells have been tested in animal models of BO aiming to interfere in its development&#46; The aim of this experimental study is to explore the role of bone-marrow derived stem cells &#40;BMSCs&#41; as a preventive intervention of BO occurrence&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This an experimental randomized study&#46; A bronchiolitis obliterans animal model in rats was reproduced&#58; heterotopical tracheal transplant model in lung parenchyma&#46; Five of these animals were used as control group&#46; After setting up the model&#44; individuals were divided in 3 groups of treatment &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41;&#44; in which BMSCs were administered in 3 different time points after the tracheal transplant &#40;tracheal transplantation and BMSCs administration occurred the same day&#44; group G0&#59; after 7 days&#44; group G7&#59; after 14 days&#44; group G14&#46; In addition&#44; within each group&#44; BMSCs were administered through 3 different routes&#58; endotracheally&#44; endovascular and topically in the lung parenchyma&#41;&#46; Animals were sacrificed at 21 days&#46; Histology&#44; fluorescence <span class="elsevierStyleItalic">in situ</span> hybridization and immunohistochemistry techniques were performed for identifying stem cells&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Compared to control group&#44; animals receiving BMSCs showed large neovessels in a loose fibrous matrix&#46; Group G7 showed less fibrosis &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41; and edema &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41;&#46; Moreover&#44; G7 animals receiving stem cells endotracheally showed no fibrosis &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41;&#46; Alveolar-like patches of tissue were observed among all groups &#40;53&#46;4&#37;&#44; 46&#46;7&#37; and 40&#37; in G0&#44; G7 and G14 respectively&#41;&#44; consisting of cells expressing both stem and alveolar cells biomarkers&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">BMSCs modify the course of bronchiolitis obliterans and differentiate into alveolar cells&#46; Endotracheal administration of BMSCs 7 days after the heterotopical tracheal transplant might be considered an effective way to prevent BO in this animal model&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
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            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Materials and methods"
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          2 => array:2 [
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            "titulo" => "Results"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La bronquiolitis obliterante &#40;OB&#41; es la forma m&#225;s frecuente de disfunci&#243;n cr&#243;nica del injerto en el trasplante pulmonar&#46; Asimismo&#44; representa la principal causa de mortalidad a largo plazo tras este procedimiento&#46; Por otro lado&#44; las c&#233;lulas madre mesenquimales se han utilizado en diferentes modelos animales de BO&#44; con el prop&#243;sito de interferir en el desarrollo de dicha disfunci&#243;n&#46; El objetivo de este estudio experimental es explorar el papel del trasplante de c&#233;lulas madre mesenquimales derivadas de la m&#233;dula &#243;sea &#40;BMSC&#44; por sus siglas en ingl&#233;s&#41; como tratamiento preventivo de la BO&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Material y m&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio experimental y aleatorizado en el que se emple&#243; un modelo de BO en ratas basado en el trasplante traqueal heterot&#243;pico en par&#233;nquima pulmonar&#46; Los animales se dividieron en los siguientes grupos&#58; grupo control &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; y 3 grupos de tratamiento &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41; en los que las c&#233;lulas madre mesenquimales derivadas de m&#233;dula &#243;sea se administraron a distintos tiempos tras el trasplante traqueal heterot&#243;pico &#40;el mismo d&#237;a &#91;grupo G0&#93;&#59; a 7 d&#237;as &#91;grupo G7&#93;&#44; y a 14 d&#237;as &#91;grupo G14&#93;&#41;&#46; Adem&#225;s&#44; dentro de cada grupo&#44; las c&#233;lulas se trasplantaron mediante 3 v&#237;as diferentes&#58; endotraqueal&#44; endovascular y t&#243;picamente en el par&#233;nquima pulmonar&#46; Todos los animales se sacrificaron a los 21 d&#237;as tras el trasplante traqueal&#46; Las c&#233;lulas madre se identificaron mediante t&#233;cnicas histol&#243;gicas utilizando hibridaci&#243;n fluorescente <span class="elsevierStyleItalic">in situ</span> &#40;FISH&#41; e inmunohistoqu&#237;mica&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Comparado con el grupo control&#44; los animales que recibieron las BMSC mostraron neovasos de gran tama&#241;o en una matriz muy laxa de tejido fibroso&#46; En el grupo G7 se observ&#243; menor grado de fibrosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;033&#41; y edema &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;028&#41;&#46; Adem&#225;s&#44; ninguno de los animales del grupo G7 que recibieron las c&#233;lulas madre por v&#237;a endotraqueal desarroll&#243; alg&#250;n grado de fibrosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;008&#41;&#46; En todos los grupos se observaron parches de tejido con caracter&#237;sticas histol&#243;gicas similares al tejido alveolar &#40;53&#44;4&#44; 46&#44;7&#37; y 40&#37; in G0&#44; G7 y G14&#44; respectivamente&#41; con expresi&#243;n de marcadores tanto alveolares como de c&#233;lulas madre&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Las c&#233;lulas madre mesenquimales derivadas de la m&#233;dula &#243;sea modifican el curso histopatol&#243;gico de la BO y son capaces de diferenciarse a c&#233;lulas de tipo alveolar&#46; La administraci&#243;n endotraqueal de estas c&#233;lulas a los 7 d&#237;as del trasplante traqueal heterot&#243;pico podr&#237;a considerarse una v&#237;a efectiva para prevenir el desarrollo de BO en este modelo animal&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Characterization of BMSC&#44; by flow cytometry&#46; Rat BMSC were labeled with CD29&#44; CD31&#44; CD34&#44; CD44&#44; CD45 and CD90 antibodies and analyzed by flow cytometry&#46; BMSC were positive for CD29&#44; CD44 and CD90 and negative for CD31&#44; CD34 and CD45&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Histological findings in groups than received BMSC&#46; These findings consist in a large number of neovessels in a very loose collagen bed &#40;25&#215;&#44; H&#8211;E&#41;&#46; The arrow is pointing to a one of the neovessels&#46; &#40;B&#41; Next section of the same histologic sample showing the loose collagen tissue &#40;green color&#41; with trichrome staining &#40;25&#215;&#41;&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Alveolar-like tissue described in the lumen of the tracheal segment in BMSC groups &#40;25&#215;&#44; H&#8211;E&#41;&#46; As it can be seen in the amplification in the right corner&#44; the tissue is mimicking the alveolar structure&#46;</p>"
        ]
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        "etiqueta" => "Fig&#46; 5"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Consecutive sections of the previously described alveolar-like tissue in which we performed both FISH and IHQ &#40;using antibodies against protein B of pulmonary surfactant&#41; for characterization of the present cells&#46; Under the fluorescence microscope &#40;40&#215;&#41;&#44; red color indicates Sry region &#40;CrY&#41;&#44; nuclei can be seen in blue&#44; and green represents protein B expression&#46; As it can be observed&#44; BMSCs are present in the alveolar-like tissue and they are producing protein B of pulmonary surfactant&#46; Cells without Sry region marked with red&#44; might be either BMSC or other cells whose differentiation might have been induced by BMSC&#46;</p>"
        ]
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        "identificador" => "fig0030"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">BMSC differentiated in an endothelial cell&#46; White arrow is pointing to Sry region of CrY&#44; which is marked in red in the FISH technique&#46; Phenotypically&#44; this BMSC &#40;white arrow&#41; is similar to an endothelial cell and is taking part of the structure of the vessel wall&#46; The blue color is the nucleus&#44; and green is connective tissue&#46;</p>"
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">G0&#58; animals receiving BMSC the same day of tracheal grafting&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">G7&#58; animals receiving BMSC 7 days after tracheal grafting&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">G14&#58; animals receiving BMSC 14 days after tracheal grafting&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables&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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \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">G7&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">G14&nbsp;\t\t\t\t\t\t\n
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                  \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">Control Group-CG&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Fibrosis</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">No&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">1 &#40;6&#46;7&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;66&#46;6&#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="char" valign="\n
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                  \t\t\t\t">0&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&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
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                  \t\t\t\t">Yes &#40;1&#44; 2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">14 &#40;93&#46;3&#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="char" valign="\n
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                  \t\t\t\t">5 &#40;33&#46;4&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&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">15 &#40;100&#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="char" valign="\n
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                  \t\t\t\t">5 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">Inflammation</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  " align="char" valign="\n
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                  \t\t\t\t">9 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;6&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">15 &#40;100&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&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\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">14 &#40;93&#46;4&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&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">7 &#40;46&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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