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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LUBAC is necessary for NF-&#954;B dependent inflammation</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Seasonal influenza A viral infection affects a significant proportion of the population worldwide&#44; with an estimated 500&#44;000 people succumbing to IAV-related complications each year&#46; While most patients infected with influenza A virus &#40;IAV&#41; recover without major sequelae&#44; severe viral pneumonia is one of the most common causes of acute respiratory distress syndrome &#40;ARDS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;4</span></a> Clinically&#44; ARDS presents with bilateral pulmonary infiltrates&#44; hypoxemia&#44; pulmonary edema and widespread lung inflammation that lead to high mortality rates due respiratory and to multiple organ failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#8211;6</span></a> ARDS patients can be sub-grouped based on the severity of the inflammatory response&#44; where patients with hyper-inflammation have worse clinical outcomes&#44; spending more days on mechanical ventilation&#44; experiencing increased incidence of organ failure and a higher mortality rate compared to hypo-inflammatory ARDS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Impairment of gas exchange in IAV-induced ARDS&#44; in large part&#44; is due to damage to the respiratory epithelial barrier and edema accumulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#8211;8</span></a> During IAV infection&#44; an exaggerated inflammatory response&#44; known as &#8220;cytokine storm&#8221;&#44; can occur leading to the development of hyper-inflammatory ARDS&#44; increasing IAV-induced morbidity and mortality &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Post-mortem studies of lungs from IAV-infected patients show extensive diffuse alveolar damage characterized by edema&#44; cellular infiltration&#44; thickening of alveolar walls&#44; and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Interestingly&#44; a study of critically ill patients showed no differences in pulmonary viral load between those who died and those who recovered&#44; while mortality directly correlated with exuberant inflammation&#44; further supporting a maladaptive host response as the major driver of IAV-induced lung injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;14</span></a> Similar observations are being reported in patients with severe coronavirus disease &#40;COVID-19&#41;&#44; where severe lung damage is associated with increased pro-inflammatory cytokines and respiratory failure from ARDS is the leading cause of mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> With no virus-specific treatment options currently validated&#44; therapies which target the inflammatory response are currently being considered for patients with severe COVID-19&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> However&#44; as it has been reported for severe IAV infections&#44; current anti-inflammatory drugs have pleiotropic effects and may lack the specificity needed to carefully calibrate the host response&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Respiratory epithelial cells&#44; as primary targets for IAV infection and replication&#44; initiate inflammatory signaling&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#8211;22</span></a> In response to respiratory epithelial derived cytokines&#44; innate immune cells&#44; such as neutrophils&#44; monocyte-derived inflammatory macrophages&#44; and natural killer &#40;NK&#41; cells are recruited to the airspace&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Together with tissue resident alveolar macrophages&#44; recruited innate immune cells are critical for control of viral replication through both lysis and clearance of virus-infected cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;26</span></a> However&#44; in addition to controlling viral spread&#44; innate immune cells contribute to the overproduction of pro-inflammatory cytokines that enhance IAV-induced lung injury &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The pulmonary immune response must be carefully balanced&#44; simultaneously promoting viral clearance and limiting excessive inflammation to maintain proper lung function&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Findings from animal models of IAV infection have shown that modulation of the host immune response is associated with reduced lung injury and improved survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;14&#44;27&#44;28</span></a> Blockade of specific immune cell subsets has been shown to improve outcomes in mouse models of severe IAV infection&#46; For example&#44; genetic deletion of the chemokine receptor CCR2 inhibited the recruitment of monocyte-derived inflammatory macrophages during IAV infection and resulted in reduced lung injury with improved survival&#46; However&#44; loss of this myeloid cell population resulted in a delay in viral clearance&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> Moreover&#44; adoptive transfer of NK cells from IAV-infected lungs&#44; as compared to NK cell from na&#239;ve lungs&#44; resulted in increased mortality of influenza-infected mice&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> suggesting that inflammation-dependent activation&#44; rather than recruitment&#44; drives the observed pathology&#46; Taken together data from these animal models suggest that the determinant of influenza severity be orchestrated by respiratory epithelial cells&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">LUBAC regulates the amplitude of the lung epithelial driven responses during IAV infection</span><p id="par0020" class="elsevierStylePara elsevierViewall">The linear ubiquitin assembly complex &#40;LUBAC&#41; is a multi-protein E3 ubiquitin ligase complex composed of two stabilizing proteins&#44; the Heme-Oxidized Iron responsive element binding protein 2 ubiquitin Ligase-1L &#40;HOIL-1L&#41; and Shank-Associated RH domain-Interacting Protein &#40;SHARPIN&#41;&#44; and a catalytic component&#44; HOIL-1-Interacting Protein &#40;HOIP&#41;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;34</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The proteins within the heteromeric complex contain multiple domains for interactions within the complex&#44; ubiquitin binding&#44; as well as catalytic activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;36</span></a> LUBAC is an essential regulator of NF-&#954;B activation and has been shown to act as a molecular rheostat&#44; regulating the amplitude of the epithelial-driven inflammatory response dung IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The respiratory epithelium actively participates in the first line of defense against pathogens by orchestrating host innate immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;37&#8211;39</span></a> As IAV replicates within the respiratory epithelium cells&#44; the cytosolic pattern recognition receptor &#40;PRR&#41;&#44; RIG-I&#44; is activated and initiates formation of a signaling platform to which LUBAC is recruited&#46; LUBAC covalently attaches Met-1 linked linear ubiquitin chains to the NF-&#954;B essential modulator &#40;NEMO&#41;&#44; a component of the inhibitor of NF-&#954;B &#40;I&#954;B&#41; kinase &#40;IKK&#41; complex along with IKK&#945; and IKK&#946;&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Due to the high affinity of NEMO&#39;s ubiquitin binding domain for linear chains&#44; linear ubiquitination of NEMO facilitates the recruitment of additional IKK complexes&#44; which results in the efficient trans-autophosphorylation and activation of proximal IKK&#946; followed by the phosphorylation and degradation of I&#954;B&#945; and robust NF-kB activation &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35&#44;40&#44;42&#44;43</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Recent reports show that destabilization of respiratory epithelial LUBAC&#44; <span class="elsevierStyleItalic">via</span> loss of the non-catalytic component HOIL-1L&#44; dampens the host response during severe influenza and promotes survival with reduced lung injury as well as reduced viral titers&#46; However&#44; when LUBAC activity is abolished through deletion of HOIP&#44; the alveolar epithelia driven inflammatory response is inhibited and mortality is increased&#46; These findings highlight the fine line between an excessive and an inadequate immune response and suggest that therapeutic modulation of LUBAC activity may be crucial&#44; as it functions as a rheostat regulating the amplitude of the host response to IAV infection&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacological immunomodulation during IAV infection</span><p id="par0040" class="elsevierStylePara elsevierViewall">Current anti-influenza strategies are limited to yearly vaccination or administration of antiviral drugs&#44; however&#44; short therapeutic windows&#44; viral mutation&#44; and resistance to current therapies limit their effectiveness&#46; Despite available vaccination and anti-viral drugs&#44; the most recent pandemic in 2009 resulted in an estimated 151&#44;700&#8211;575&#44;400 deaths in its first year of circulation worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> The pandemic strain contained a novel assortment of viral genes not previously identified in animal or human populations&#46; From its first detection in April 2009&#44; it was only 3 months until resistance to anti-viral drugs was reported&#44; and it took an additional 3 months before the first vaccine offering protection from the pandemic strain was administered&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> In addition to emerging pandemic strains&#44; between 291&#44;000 and 646&#44;000 people worldwide die from seasonal influenza-related respiratory illnesses each year&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Novel mutations and reassortments of the virus will inevitably lead to the next IAV pandemic&#59; therefore&#44; the use and development of therapeutics that target conserved host pathways&#44; rather than the virus itself&#44; hold promise to curtail the impact of viral infection&#46; Moreover&#44; a heterogeneous response to IAV with the same virulence exists within the population&#44; suggesting that host factors play a crucial role regulating the host response and determining the severity of lung injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;47</span></a> Additionally&#44; experimental evidence from human studies and animal models of severe IAV show that viral titers do not always correlate with severity of disease&#44; but rather ARDS induced &#8220;cytokine storm&#8221; is the major driver of morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;28&#44;38&#44;48</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Severe IAV infection is associated with inflammatory cytokines in humans and mice&#46; Due to their pleiotropic and redundant effects&#44; targeting of individual cytokines may not be a suitable approach to reduce pathology during IAV infection&#46; Instead&#44; dampening of the immune response may be more effective&#44; as was the case with LUBAC destabilization noted above&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> FDA-approved anti-inflammatory drugs&#44; including corticosteroids and statins&#44; have been proposed for the treatment of &#8220;cytokine storm&#8221; associated with severe IAV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Moreover&#44; current data regarding their efficacy is limited to mouse models and retrospective patient observations&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> Corticosteroids have been shown to be effective in limiting the inflammation in some lung pathologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#8211;51</span></a> However&#44; observational studies of the impact of corticosteroid treatment of IAV-infected patients suggest against their use&#59; with administration associated with higher incidence of hospital-acquired pneumonia&#44; longer duration of mechanical ventilation&#44; and increased mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Similarly&#44; clinical evidence does not support corticosteroid treatment for COVID-19 lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Statins are another class of drugs recognized for their ability to dampen inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> While experimental evidence from mouse models using statins during IAV infection have been inconclusive regarding their benefit&#44;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;53&#44;54</span></a> retrospective analysis of patient data suggests an association between statin treatment and lower IAV mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> These examples highlight the need for new avenues of drug discovery and validations&#44; as no currently available immune modulators have convincingly demonstrated their ability to improve outcomes during influenza infection&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">LUBAC represents a potential new target for limiting the pathological inflammation that occurs during IAV infection&#46; Several chemical inhibitors as well as peptides that bind HOIP have been used to inhibit LUBAC activity in cell culture<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#8211;59</span></a> and <span class="elsevierStyleItalic">in vitro</span> assays<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a> and support the specific targetablility of LUBAC &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Currently&#44; LUBAC inhibitors fall into two categories&#58; those that target the catalytic activity of HOIP &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span> BAY117082&#44; Gliotoxin&#44; HOIPIN&#41; or those that disrupt the interaction between LUBAC components to destabilize the complex &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span> stapled peptides&#41;&#46; BAY117082&#44; a small molecule commonly used as an inhibitor of NF-&#954;B activation&#46; It has been observed that treatment of RAW 264&#46;7 macrophages with BAY117082 prevented IL-1 stimulated formation of linear ubiquitin chains&#46; Further investigation revealed that BAY117082 irreversibly inhibits LUBAC through a chemical reaction with cysteine residues in the active site of HOIP&#44; the catalytic unit of LUBAC&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> While BAY117082 represents a potent inhibitor of LUBAC activity&#44; it targets multiple components of the ubiquitin system&#44; including inhibition of E2 ubiquitin conjugating enzymes&#44; and possible proteasome inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> As such&#44; use of BAY117082 is not suitable for the study of LUBAC-dependent physiological functions or therapeutic targeting of LUBAC activity in disease&#46; Gliotoxin&#44; a fungal metabolite&#44; was identified in a high-throughput screening for LUBAC inhibitors using a time-resolved FRET-based screening system&#46; While gliotoxin is known to have multiple cellular targets&#44; it is able to inhibit LUBAC activity and downstream activation of NF-&#954;B at 10x lower concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Gliotoxin&#39;s strong&#44; irreversible binding to the catalytic site of HOIP makes it a selective inhibitor of LUBAC activity&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Interestingly&#44; the potency of gliotoxin has been shown to vary between cell types&#44; with myeloid and lymphoid cells being more sensitive to gliotoxin-mediated NF-&#954;B inhibition than epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> However&#44; this irreversible inhibition may quench the inflammatory response and increase susceptibility to secondary infections&#46; HOIPINs are synthetic small molecules that reversibly inhibit LUBAC though targeting of HOIP activity&#44; displaying both LUBAC specificity as well as low cytotoxicity&#46; Several derivatives have been made with varying degrees of efficacy &#40;HOIPIN-1-8&#41;&#44; with HOIPIN-8 showing significantly enhanced ability to prevent LUBAC-mediated NF-&#954;B activation in response to TNF-&#945; without cytotoxicity compared to the other derivatives <span class="elsevierStyleItalic">in vitro</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Conversely&#44; stapled &#945;-helical peptides developed based on specific LUBAC structures disrupt interactions necessary for stable complex formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;63</span></a> Stapled peptides are a class of synthetic macrocycles where the secondary &#945;-helix structure is stabilized by the introduction of a hydrophobic bridge or &#8220;staple&#8221; that rigidifies specific areas to inhibit protein&#58;protein interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Stapled peptides based on the HOIP ubiquitin binding domain have been shown to successfully inhibit LUBAC activity <span class="elsevierStyleItalic">in vitro</span> by disrupting its interaction with HOIL-1L and destabilizing the overall complex&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;63</span></a> While several inhibitors of LUBAC have been developed and shown promise <span class="elsevierStyleItalic">in vitro</span>&#44; no data is available detailing their efficacy <span class="elsevierStyleItalic">in vivo</span>&#46; Further investigation in to these compounds which target LUBAC stability to modulate the degree of LUBAC activity is warranted as they may be therapeutically beneficial for the treatment of hyper-inflammatory response during viral infection&#44; where a graded host response is necessary&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusions</span><p id="par0055" class="elsevierStylePara elsevierViewall">Within the past 150 years&#44; IAV has been the causative agent of at least five pandemics &#40;1889&#44; 1918&#44; 1957&#44; 1968&#44; 2009&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;64</span></a> In addition to IAV&#44; novel viral threats&#44; such as the coronavirus outbreaks of 2003&#44; 2015 and 2019&#44; quickly spread worldwide before virus-specific vaccines or pharmacological options could be developed&#46; Thus&#44; therapies that target conserved host pathways may provide a novel universal treatment strategies&#44; regardless of viral sequence&#46; Findings from animal models of IAV infection have shown that inhibition of the exuberant host immune response is associated with reduced lung injury and improved survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;14&#44;27&#44;28</span></a> However&#44; current FDA-approved anti-inflammatory drugs&#44; such as corticosteroids and statins&#44; have failed to show benefit during severe IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> Beyond viral infections&#44; the amplitude of the inflammatory response has been shown to be a critical determinant in outcome during bacterial sepsis in community acquired pneumonia&#44; a common complication post IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;65</span></a> Analysis of a cohort of patients showed that reductions in the inflammatory response during bacterial pnumonia&#44; both due to host inability to mount a response or the administration of anti-inflammatory steroids&#44; lead to increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;65</span></a> These clinical observations highlight the need to balance the inflammatory response during viral infection&#44; not only to improve lung injury during the primary viral infection&#44; but also to prevent poor outcomes to secondary infections&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In addition to the seasonal threat of influenza&#44; we must also be cautious in the regulation of inflammation in treatment of the ongoing CoVID-19 pandemic&#46; While a subgroup of patients with severe COVID-19 develop &#8216;cytokine storm&#8217;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;18</span></a> it must be remembered that current anti-inflammatory drugs have pleiotropic effects and lack the specificity needed to carefully calibrate the host response&#46; As such&#44; newly developed pharmacologics such as those that target LUBAC&#44; a molecular rheostat of inflammatory signaling&#44; have the potential to fine tune inflammation and moderate the host response&#46; Further investigation of compounds which modulate LUBAC activity is warranted&#44; as they may be therapeutically beneficial for the treatment of hyper-inflammatory response during viral infections&#44; where a milder host response should improve outcomes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have declared that no conflict of interest exists&#46;</p></span></span>"
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          "identificador" => "xres1386462"
          "titulo" => "Abstract"
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          "titulo" => "Keywords"
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          "identificador" => "xres1386461"
          "titulo" => "Resumen"
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            0 => array:1 [
              "identificador" => "abst0010"
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          "titulo" => "Palabras clave"
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        4 => array:3 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "LUBAC regulates the amplitude of the lung epithelial driven responses during IAV infection"
            ]
            1 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Pharmacological immunomodulation during IAV infection"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Conclusions"
        ]
        6 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conflict of interest"
        ]
        7 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2020-03-05"
    "fechaAceptado" => "2020-04-15"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:3 [
            0 => "Inflammation"
            1 => "Influenza virus"
            2 => "Acute lung injury"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1272231"
          "palabras" => array:3 [
            0 => "Inflamaci&#243;n"
            1 => "Virus Influenza"
            2 => "Lesi&#243;n pulmonar aguda"
          ]
        ]
      ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure&#46; While the majority of those exposed have minor symptoms and recover with little morbidity&#44; an estimated 500&#44;000 people succumb to IAV-related complications each year worldwide&#46; In these severe cases&#44; an exaggerated inflammatory response&#44; known as &#8220;cytokine storm&#8221;&#44; occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome &#40;ARDS&#41;&#46; Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response&#44; where the host response must balance viral clearance with exuberant inflammation&#46; Current pharmacological modulators of inflammation&#44; including corticosteroids and statins&#44; have not been successful in improving outcomes during influenza virus infection&#46; We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex &#40;LUBAC&#41; activity and that dampening of LUBAC activity is protective during severe influenza virus infection&#46; Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection&#44; as it functions as a molecular rheostat of the host response&#46; Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury&#44; data on current anti-inflammatory strategies&#44; and potential new avenues to target viral inflammation and improve outcomes&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por el virus de la gripe se caracteriza por s&#237;ntomas que van desde la congesti&#243;n leve y los dolores corporales hasta el edema pulmonar grave y la insuficiencia respiratoria&#46; Aunque que la mayor&#237;a de las personas expuestas presentan s&#237;ntomas leves y se recuperan con poca morbilidad&#44; se estima que cada a&#241;o 500&#46;000 personas en todo el mundo fallecen por las complicaciones relacionadas con esta infecci&#243;n&#46; En estos casos graves&#44; se produce una respuesta inflamatoria exagerada&#44; conocida como &#171;tormenta de citocinas&#187;&#44; que causa da&#241;os en la barrera epitelial respiratoria y el desarrollo del s&#237;ndrome de distr&#233;s respiratorio agudo&#46; Los datos de estudios retrospectivos en humanos&#44; as&#237; como de modelos animales experimentales de infecci&#243;n por el virus de la gripe&#44; resaltan la delgada l&#237;nea que existe entre una respuesta inmunitaria excesiva y una inadecuada&#44; cuando la respuesta del hu&#233;sped debe mantener el equilibrio entre el aclaramiento viral y la inflamaci&#243;n exagerada&#46; Los moduladores farmacol&#243;gicos de la inflamaci&#243;n actuales&#44; incluidos los corticoides y las estatinas&#44; no han tenido &#233;xito a la hora de mejorar los resultados de la infecci&#243;n por el virus de la gripe&#46; Hemos publicado que la amplitud de la respuesta inflamatoria est&#225; regulada por la actividad del complejo de ensamblaje de cadenas lineales de ubiquitina &#40;LUBAC&#44; por sus siglas en ingl&#233;s&#41; y que la atenuaci&#243;n de la actividad de LUBAC protege durante la infecci&#243;n grave por este virus&#46; La modulaci&#243;n terap&#233;utica de la actividad de LUBAC puede ser crucial para mejorar los resultados&#44; ya que funciona como un re&#243;stato molecular de la respuesta del hu&#233;sped&#46; Aqu&#237; revisamos la evidencia al respecto de la modulaci&#243;n de la inflamaci&#243;n para mejorar el da&#241;o pulmonar inducido por la infecci&#243;n por el virus de la gripe&#44; los datos sobre las estrategias antiinflamatorias actuales y las posibles nuevas v&#237;as para tratar la inflamaci&#243;n viral y mejorar los resultados&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This work has been supported in part by HL-48129&#44; HL71643 and HL-76139&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the balance that must exist to fine tune the pulmonary inflammatory response to viral infection to promote pathogen clearance and prevent immunopathology&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Schematic model of IAV-induced ARDS &#40;Left&#41; The healthy alveolus is free of fluid with tight junctions between alveolar type 1 &#40;AT1&#41; and type 2 &#40;AT2&#41; epithelial cells&#46; Tissue resident alveolar macrophages &#40;AM&#41; facilitate lung homeostasis through clearance of cellular and environmental debris&#46; &#40;Right&#41; Upon inhalation&#44; IAV targets alveolar epithelial cells &#40;AEC&#41; for infection and replication&#46; IAV infection induces epithelial cytokine production that recruits immune cells to the airspace&#46; Recruited immune cells &#40;RIC&#41; contribute to hyper-inflammatory environment and which further contributes to cytokine storm and tissue damage &#40;dashed outline&#41;&#46; Barrier disruption due to the denuded epithelium allows extravasation of proteinaceous edema fluid into the airspace that disrupts gas exchange and causes ARDS&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LUBAC is necessary for NF-&#954;B dependent inflammation</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the small molecule inhibitors &#40;BAY117082&#44; Gliotoxin&#44; HOIPIN1-8&#41; that target the catalytic domain of HOIP and the stapled &#945;-helical peptides which disrupt the interaction between LUBAC components to destabilize the complex&#46;</p>"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology of ARDS and ALI"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Blank"
                            1 => "L&#46;M&#46; Napolitano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ccc.2011.05.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Clin&#46;"
                        "fecha" => "2011"
                        "volumen" => "27"
                        "paginaInicial" => "439"
                        "paginaFinal" => "458"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21742210"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            1 => array:3 [
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              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nonventilatory strategies for patients with life-threatening 2009 H1N1 influenza and severe respiratory failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "L&#46;M&#46; Napolitano"
                            1 => "P&#46;K&#46; Park"
                            2 => "K&#46; Raghavendran"
                            3 => "R&#46;H&#46; Bartlett"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e3181cc5373"
                      "Revista" => array:7 [
                        "tituloSerie" => "Crit Care Med&#46;"
                        "fecha" => "2010"
                        "volumen" => "38"
                        "numero" => "4 Suppl"
                        "paginaInicial" => "e74"
                        "paginaFinal" => "e90"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20035216"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Complications of seasonal and pandemic influenza"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;B&#46; Rothberg"
                            1 => "S&#46;D&#46; Haessler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e3181c92eeb"
                      "Revista" => array:7 [
                        "tituloSerie" => "Crit Care Med&#46;"
                        "fecha" => "2010"
                        "volumen" => "38"
                        "numero" => "4 Suppl"
                        "paginaInicial" => "e91"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19935413"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
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Review
Targeting the Linear Ubiquitin Assembly Complex to Modulate the Host Response and Improve Influenza A Virus Induced Lung Injury
Tratamiento dirigido al complejo de ensamblaje de cadenas lineales de ubiquitina para modular la respuesta del huésped y mejorar el daño pulmonar inducido por el virus de la gripe A
Patricia L. Brazee, Jacob I. Sznajder
Corresponding author
j-sznajder@northwestern.edu

Corresponding author.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, United States
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LUBAC is necessary for NF-&#954;B dependent inflammation</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Seasonal influenza A viral infection affects a significant proportion of the population worldwide&#44; with an estimated 500&#44;000 people succumbing to IAV-related complications each year&#46; While most patients infected with influenza A virus &#40;IAV&#41; recover without major sequelae&#44; severe viral pneumonia is one of the most common causes of acute respiratory distress syndrome &#40;ARDS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;4</span></a> Clinically&#44; ARDS presents with bilateral pulmonary infiltrates&#44; hypoxemia&#44; pulmonary edema and widespread lung inflammation that lead to high mortality rates due respiratory and to multiple organ failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#8211;6</span></a> ARDS patients can be sub-grouped based on the severity of the inflammatory response&#44; where patients with hyper-inflammation have worse clinical outcomes&#44; spending more days on mechanical ventilation&#44; experiencing increased incidence of organ failure and a higher mortality rate compared to hypo-inflammatory ARDS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Impairment of gas exchange in IAV-induced ARDS&#44; in large part&#44; is due to damage to the respiratory epithelial barrier and edema accumulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#8211;8</span></a> During IAV infection&#44; an exaggerated inflammatory response&#44; known as &#8220;cytokine storm&#8221;&#44; can occur leading to the development of hyper-inflammatory ARDS&#44; increasing IAV-induced morbidity and mortality &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Post-mortem studies of lungs from IAV-infected patients show extensive diffuse alveolar damage characterized by edema&#44; cellular infiltration&#44; thickening of alveolar walls&#44; and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Interestingly&#44; a study of critically ill patients showed no differences in pulmonary viral load between those who died and those who recovered&#44; while mortality directly correlated with exuberant inflammation&#44; further supporting a maladaptive host response as the major driver of IAV-induced lung injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;14</span></a> Similar observations are being reported in patients with severe coronavirus disease &#40;COVID-19&#41;&#44; where severe lung damage is associated with increased pro-inflammatory cytokines and respiratory failure from ARDS is the leading cause of mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> With no virus-specific treatment options currently validated&#44; therapies which target the inflammatory response are currently being considered for patients with severe COVID-19&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> However&#44; as it has been reported for severe IAV infections&#44; current anti-inflammatory drugs have pleiotropic effects and may lack the specificity needed to carefully calibrate the host response&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Respiratory epithelial cells&#44; as primary targets for IAV infection and replication&#44; initiate inflammatory signaling&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#8211;22</span></a> In response to respiratory epithelial derived cytokines&#44; innate immune cells&#44; such as neutrophils&#44; monocyte-derived inflammatory macrophages&#44; and natural killer &#40;NK&#41; cells are recruited to the airspace&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Together with tissue resident alveolar macrophages&#44; recruited innate immune cells are critical for control of viral replication through both lysis and clearance of virus-infected cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;26</span></a> However&#44; in addition to controlling viral spread&#44; innate immune cells contribute to the overproduction of pro-inflammatory cytokines that enhance IAV-induced lung injury &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The pulmonary immune response must be carefully balanced&#44; simultaneously promoting viral clearance and limiting excessive inflammation to maintain proper lung function&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Findings from animal models of IAV infection have shown that modulation of the host immune response is associated with reduced lung injury and improved survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;14&#44;27&#44;28</span></a> Blockade of specific immune cell subsets has been shown to improve outcomes in mouse models of severe IAV infection&#46; For example&#44; genetic deletion of the chemokine receptor CCR2 inhibited the recruitment of monocyte-derived inflammatory macrophages during IAV infection and resulted in reduced lung injury with improved survival&#46; However&#44; loss of this myeloid cell population resulted in a delay in viral clearance&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> Moreover&#44; adoptive transfer of NK cells from IAV-infected lungs&#44; as compared to NK cell from na&#239;ve lungs&#44; resulted in increased mortality of influenza-infected mice&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> suggesting that inflammation-dependent activation&#44; rather than recruitment&#44; drives the observed pathology&#46; Taken together data from these animal models suggest that the determinant of influenza severity be orchestrated by respiratory epithelial cells&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">LUBAC regulates the amplitude of the lung epithelial driven responses during IAV infection</span><p id="par0020" class="elsevierStylePara elsevierViewall">The linear ubiquitin assembly complex &#40;LUBAC&#41; is a multi-protein E3 ubiquitin ligase complex composed of two stabilizing proteins&#44; the Heme-Oxidized Iron responsive element binding protein 2 ubiquitin Ligase-1L &#40;HOIL-1L&#41; and Shank-Associated RH domain-Interacting Protein &#40;SHARPIN&#41;&#44; and a catalytic component&#44; HOIL-1-Interacting Protein &#40;HOIP&#41;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;34</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The proteins within the heteromeric complex contain multiple domains for interactions within the complex&#44; ubiquitin binding&#44; as well as catalytic activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;36</span></a> LUBAC is an essential regulator of NF-&#954;B activation and has been shown to act as a molecular rheostat&#44; regulating the amplitude of the epithelial-driven inflammatory response dung IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The respiratory epithelium actively participates in the first line of defense against pathogens by orchestrating host innate immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;37&#8211;39</span></a> As IAV replicates within the respiratory epithelium cells&#44; the cytosolic pattern recognition receptor &#40;PRR&#41;&#44; RIG-I&#44; is activated and initiates formation of a signaling platform to which LUBAC is recruited&#46; LUBAC covalently attaches Met-1 linked linear ubiquitin chains to the NF-&#954;B essential modulator &#40;NEMO&#41;&#44; a component of the inhibitor of NF-&#954;B &#40;I&#954;B&#41; kinase &#40;IKK&#41; complex along with IKK&#945; and IKK&#946;&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Due to the high affinity of NEMO&#39;s ubiquitin binding domain for linear chains&#44; linear ubiquitination of NEMO facilitates the recruitment of additional IKK complexes&#44; which results in the efficient trans-autophosphorylation and activation of proximal IKK&#946; followed by the phosphorylation and degradation of I&#954;B&#945; and robust NF-kB activation &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35&#44;40&#44;42&#44;43</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Recent reports show that destabilization of respiratory epithelial LUBAC&#44; <span class="elsevierStyleItalic">via</span> loss of the non-catalytic component HOIL-1L&#44; dampens the host response during severe influenza and promotes survival with reduced lung injury as well as reduced viral titers&#46; However&#44; when LUBAC activity is abolished through deletion of HOIP&#44; the alveolar epithelia driven inflammatory response is inhibited and mortality is increased&#46; These findings highlight the fine line between an excessive and an inadequate immune response and suggest that therapeutic modulation of LUBAC activity may be crucial&#44; as it functions as a rheostat regulating the amplitude of the host response to IAV infection&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacological immunomodulation during IAV infection</span><p id="par0040" class="elsevierStylePara elsevierViewall">Current anti-influenza strategies are limited to yearly vaccination or administration of antiviral drugs&#44; however&#44; short therapeutic windows&#44; viral mutation&#44; and resistance to current therapies limit their effectiveness&#46; Despite available vaccination and anti-viral drugs&#44; the most recent pandemic in 2009 resulted in an estimated 151&#44;700&#8211;575&#44;400 deaths in its first year of circulation worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> The pandemic strain contained a novel assortment of viral genes not previously identified in animal or human populations&#46; From its first detection in April 2009&#44; it was only 3 months until resistance to anti-viral drugs was reported&#44; and it took an additional 3 months before the first vaccine offering protection from the pandemic strain was administered&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> In addition to emerging pandemic strains&#44; between 291&#44;000 and 646&#44;000 people worldwide die from seasonal influenza-related respiratory illnesses each year&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Novel mutations and reassortments of the virus will inevitably lead to the next IAV pandemic&#59; therefore&#44; the use and development of therapeutics that target conserved host pathways&#44; rather than the virus itself&#44; hold promise to curtail the impact of viral infection&#46; Moreover&#44; a heterogeneous response to IAV with the same virulence exists within the population&#44; suggesting that host factors play a crucial role regulating the host response and determining the severity of lung injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;47</span></a> Additionally&#44; experimental evidence from human studies and animal models of severe IAV show that viral titers do not always correlate with severity of disease&#44; but rather ARDS induced &#8220;cytokine storm&#8221; is the major driver of morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;28&#44;38&#44;48</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Severe IAV infection is associated with inflammatory cytokines in humans and mice&#46; Due to their pleiotropic and redundant effects&#44; targeting of individual cytokines may not be a suitable approach to reduce pathology during IAV infection&#46; Instead&#44; dampening of the immune response may be more effective&#44; as was the case with LUBAC destabilization noted above&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> FDA-approved anti-inflammatory drugs&#44; including corticosteroids and statins&#44; have been proposed for the treatment of &#8220;cytokine storm&#8221; associated with severe IAV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Moreover&#44; current data regarding their efficacy is limited to mouse models and retrospective patient observations&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> Corticosteroids have been shown to be effective in limiting the inflammation in some lung pathologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#8211;51</span></a> However&#44; observational studies of the impact of corticosteroid treatment of IAV-infected patients suggest against their use&#59; with administration associated with higher incidence of hospital-acquired pneumonia&#44; longer duration of mechanical ventilation&#44; and increased mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Similarly&#44; clinical evidence does not support corticosteroid treatment for COVID-19 lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Statins are another class of drugs recognized for their ability to dampen inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> While experimental evidence from mouse models using statins during IAV infection have been inconclusive regarding their benefit&#44;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;53&#44;54</span></a> retrospective analysis of patient data suggests an association between statin treatment and lower IAV mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> These examples highlight the need for new avenues of drug discovery and validations&#44; as no currently available immune modulators have convincingly demonstrated their ability to improve outcomes during influenza infection&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">LUBAC represents a potential new target for limiting the pathological inflammation that occurs during IAV infection&#46; Several chemical inhibitors as well as peptides that bind HOIP have been used to inhibit LUBAC activity in cell culture<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#8211;59</span></a> and <span class="elsevierStyleItalic">in vitro</span> assays<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a> and support the specific targetablility of LUBAC &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Currently&#44; LUBAC inhibitors fall into two categories&#58; those that target the catalytic activity of HOIP &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span> BAY117082&#44; Gliotoxin&#44; HOIPIN&#41; or those that disrupt the interaction between LUBAC components to destabilize the complex &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span> stapled peptides&#41;&#46; BAY117082&#44; a small molecule commonly used as an inhibitor of NF-&#954;B activation&#46; It has been observed that treatment of RAW 264&#46;7 macrophages with BAY117082 prevented IL-1 stimulated formation of linear ubiquitin chains&#46; Further investigation revealed that BAY117082 irreversibly inhibits LUBAC through a chemical reaction with cysteine residues in the active site of HOIP&#44; the catalytic unit of LUBAC&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> While BAY117082 represents a potent inhibitor of LUBAC activity&#44; it targets multiple components of the ubiquitin system&#44; including inhibition of E2 ubiquitin conjugating enzymes&#44; and possible proteasome inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> As such&#44; use of BAY117082 is not suitable for the study of LUBAC-dependent physiological functions or therapeutic targeting of LUBAC activity in disease&#46; Gliotoxin&#44; a fungal metabolite&#44; was identified in a high-throughput screening for LUBAC inhibitors using a time-resolved FRET-based screening system&#46; While gliotoxin is known to have multiple cellular targets&#44; it is able to inhibit LUBAC activity and downstream activation of NF-&#954;B at 10x lower concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Gliotoxin&#39;s strong&#44; irreversible binding to the catalytic site of HOIP makes it a selective inhibitor of LUBAC activity&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Interestingly&#44; the potency of gliotoxin has been shown to vary between cell types&#44; with myeloid and lymphoid cells being more sensitive to gliotoxin-mediated NF-&#954;B inhibition than epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> However&#44; this irreversible inhibition may quench the inflammatory response and increase susceptibility to secondary infections&#46; HOIPINs are synthetic small molecules that reversibly inhibit LUBAC though targeting of HOIP activity&#44; displaying both LUBAC specificity as well as low cytotoxicity&#46; Several derivatives have been made with varying degrees of efficacy &#40;HOIPIN-1-8&#41;&#44; with HOIPIN-8 showing significantly enhanced ability to prevent LUBAC-mediated NF-&#954;B activation in response to TNF-&#945; without cytotoxicity compared to the other derivatives <span class="elsevierStyleItalic">in vitro</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Conversely&#44; stapled &#945;-helical peptides developed based on specific LUBAC structures disrupt interactions necessary for stable complex formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;63</span></a> Stapled peptides are a class of synthetic macrocycles where the secondary &#945;-helix structure is stabilized by the introduction of a hydrophobic bridge or &#8220;staple&#8221; that rigidifies specific areas to inhibit protein&#58;protein interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Stapled peptides based on the HOIP ubiquitin binding domain have been shown to successfully inhibit LUBAC activity <span class="elsevierStyleItalic">in vitro</span> by disrupting its interaction with HOIL-1L and destabilizing the overall complex&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;63</span></a> While several inhibitors of LUBAC have been developed and shown promise <span class="elsevierStyleItalic">in vitro</span>&#44; no data is available detailing their efficacy <span class="elsevierStyleItalic">in vivo</span>&#46; Further investigation in to these compounds which target LUBAC stability to modulate the degree of LUBAC activity is warranted as they may be therapeutically beneficial for the treatment of hyper-inflammatory response during viral infection&#44; where a graded host response is necessary&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusions</span><p id="par0055" class="elsevierStylePara elsevierViewall">Within the past 150 years&#44; IAV has been the causative agent of at least five pandemics &#40;1889&#44; 1918&#44; 1957&#44; 1968&#44; 2009&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;64</span></a> In addition to IAV&#44; novel viral threats&#44; such as the coronavirus outbreaks of 2003&#44; 2015 and 2019&#44; quickly spread worldwide before virus-specific vaccines or pharmacological options could be developed&#46; Thus&#44; therapies that target conserved host pathways may provide a novel universal treatment strategies&#44; regardless of viral sequence&#46; Findings from animal models of IAV infection have shown that inhibition of the exuberant host immune response is associated with reduced lung injury and improved survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;14&#44;27&#44;28</span></a> However&#44; current FDA-approved anti-inflammatory drugs&#44; such as corticosteroids and statins&#44; have failed to show benefit during severe IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> Beyond viral infections&#44; the amplitude of the inflammatory response has been shown to be a critical determinant in outcome during bacterial sepsis in community acquired pneumonia&#44; a common complication post IAV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;65</span></a> Analysis of a cohort of patients showed that reductions in the inflammatory response during bacterial pnumonia&#44; both due to host inability to mount a response or the administration of anti-inflammatory steroids&#44; lead to increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;65</span></a> These clinical observations highlight the need to balance the inflammatory response during viral infection&#44; not only to improve lung injury during the primary viral infection&#44; but also to prevent poor outcomes to secondary infections&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In addition to the seasonal threat of influenza&#44; we must also be cautious in the regulation of inflammation in treatment of the ongoing CoVID-19 pandemic&#46; While a subgroup of patients with severe COVID-19 develop &#8216;cytokine storm&#8217;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;18</span></a> it must be remembered that current anti-inflammatory drugs have pleiotropic effects and lack the specificity needed to carefully calibrate the host response&#46; As such&#44; newly developed pharmacologics such as those that target LUBAC&#44; a molecular rheostat of inflammatory signaling&#44; have the potential to fine tune inflammation and moderate the host response&#46; Further investigation of compounds which modulate LUBAC activity is warranted&#44; as they may be therapeutically beneficial for the treatment of hyper-inflammatory response during viral infections&#44; where a milder host response should improve outcomes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have declared that no conflict of interest exists&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure&#46; While the majority of those exposed have minor symptoms and recover with little morbidity&#44; an estimated 500&#44;000 people succumb to IAV-related complications each year worldwide&#46; In these severe cases&#44; an exaggerated inflammatory response&#44; known as &#8220;cytokine storm&#8221;&#44; occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome &#40;ARDS&#41;&#46; Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response&#44; where the host response must balance viral clearance with exuberant inflammation&#46; Current pharmacological modulators of inflammation&#44; including corticosteroids and statins&#44; have not been successful in improving outcomes during influenza virus infection&#46; We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex &#40;LUBAC&#41; activity and that dampening of LUBAC activity is protective during severe influenza virus infection&#46; Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection&#44; as it functions as a molecular rheostat of the host response&#46; Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury&#44; data on current anti-inflammatory strategies&#44; and potential new avenues to target viral inflammation and improve outcomes&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por el virus de la gripe se caracteriza por s&#237;ntomas que van desde la congesti&#243;n leve y los dolores corporales hasta el edema pulmonar grave y la insuficiencia respiratoria&#46; Aunque que la mayor&#237;a de las personas expuestas presentan s&#237;ntomas leves y se recuperan con poca morbilidad&#44; se estima que cada a&#241;o 500&#46;000 personas en todo el mundo fallecen por las complicaciones relacionadas con esta infecci&#243;n&#46; En estos casos graves&#44; se produce una respuesta inflamatoria exagerada&#44; conocida como &#171;tormenta de citocinas&#187;&#44; que causa da&#241;os en la barrera epitelial respiratoria y el desarrollo del s&#237;ndrome de distr&#233;s respiratorio agudo&#46; Los datos de estudios retrospectivos en humanos&#44; as&#237; como de modelos animales experimentales de infecci&#243;n por el virus de la gripe&#44; resaltan la delgada l&#237;nea que existe entre una respuesta inmunitaria excesiva y una inadecuada&#44; cuando la respuesta del hu&#233;sped debe mantener el equilibrio entre el aclaramiento viral y la inflamaci&#243;n exagerada&#46; Los moduladores farmacol&#243;gicos de la inflamaci&#243;n actuales&#44; incluidos los corticoides y las estatinas&#44; no han tenido &#233;xito a la hora de mejorar los resultados de la infecci&#243;n por el virus de la gripe&#46; Hemos publicado que la amplitud de la respuesta inflamatoria est&#225; regulada por la actividad del complejo de ensamblaje de cadenas lineales de ubiquitina &#40;LUBAC&#44; por sus siglas en ingl&#233;s&#41; y que la atenuaci&#243;n de la actividad de LUBAC protege durante la infecci&#243;n grave por este virus&#46; La modulaci&#243;n terap&#233;utica de la actividad de LUBAC puede ser crucial para mejorar los resultados&#44; ya que funciona como un re&#243;stato molecular de la respuesta del hu&#233;sped&#46; Aqu&#237; revisamos la evidencia al respecto de la modulaci&#243;n de la inflamaci&#243;n para mejorar el da&#241;o pulmonar inducido por la infecci&#243;n por el virus de la gripe&#44; los datos sobre las estrategias antiinflamatorias actuales y las posibles nuevas v&#237;as para tratar la inflamaci&#243;n viral y mejorar los resultados&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This work has been supported in part by HL-48129&#44; HL71643 and HL-76139&#46;</p>"
      ]
    ]
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      0 => array:7 [
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        "etiqueta" => "Fig&#46; 1"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the balance that must exist to fine tune the pulmonary inflammatory response to viral infection to promote pathogen clearance and prevent immunopathology&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Schematic model of IAV-induced ARDS &#40;Left&#41; The healthy alveolus is free of fluid with tight junctions between alveolar type 1 &#40;AT1&#41; and type 2 &#40;AT2&#41; epithelial cells&#46; Tissue resident alveolar macrophages &#40;AM&#41; facilitate lung homeostasis through clearance of cellular and environmental debris&#46; &#40;Right&#41; Upon inhalation&#44; IAV targets alveolar epithelial cells &#40;AEC&#41; for infection and replication&#46; IAV infection induces epithelial cytokine production that recruits immune cells to the airspace&#46; Recruited immune cells &#40;RIC&#41; contribute to hyper-inflammatory environment and which further contributes to cytokine storm and tissue damage &#40;dashed outline&#41;&#46; Barrier disruption due to the denuded epithelium allows extravasation of proteinaceous edema fluid into the airspace that disrupts gas exchange and causes ARDS&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LUBAC is necessary for NF-&#954;B dependent inflammation</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">LUBAC covalently attaches linear ubiquitin chains to NEMO&#44; which facilitates the recruitment of additional IKK complexes&#46; Stably docked IKK complexes result in the efficient transautophosphorylation and activation of proximal IKK&#945;&#47;&#946;&#44; followed by the phosphorylation and degradation of I&#954;B&#945;&#46; NF-&#954;B translocates to the nucleus to stimulate transcription of inflammatory genes&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1186
            "Ancho" => 1508
            "Tamanyo" => 117626
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the small molecule inhibitors &#40;BAY117082&#44; Gliotoxin&#44; HOIPIN1-8&#41; that target the catalytic domain of HOIP and the stapled &#945;-helical peptides which disrupt the interaction between LUBAC components to destabilize the complex&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
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      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:65 [
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                          "etal" => false
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                            1 => "S&#46;D&#46; Haessler"
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                      "doi" => "10.1097/CCM.0b013e3181c92eeb"
                      "Revista" => array:7 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46;R&#46; Short"
                            1 => "E&#46; Kroeze"
                            2 => "R&#46;A&#46;M&#46; Fouchier"
                            3 => "T&#46; Kuiken"
                          ]
                        ]
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                  ]
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                    0 => array:2 [
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                        "tituloSerie" => "Lancet Infect Dis&#46;"
                        "fecha" => "2014"
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                        "paginaInicial" => "57"
                        "paginaFinal" => "69"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24239327"
                            "web" => "Medline"
                          ]
                        ]
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              "identificador" => "bib0025"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An official American Thoracic Society workshop report&#58; features and measurements of experimental acute lung injury in animals"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Matute-Bello"
                            1 => "G&#46; Downey"
                            2 => "B&#46;B&#46; Moore"
                            3 => "S&#46;D&#46; Groshong"
                            4 => "M&#46;A&#46; Matthay"
                            5 => "A&#46;S&#46; Slutsky"
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                        ]
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                        "tituloSerie" => "Am J Respir Cell Mol Biol&#46;"
                        "fecha" => "2011"
                        "volumen" => "44"
                        "paginaInicial" => "725"
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                          0 => array:2 [
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                        ]
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                      "titulo" => "Mortality Trends of Acute Respiratory Distress Syndrome in the United States from 1999 to 2013"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "S&#46;E&#46; Cochi"
                            1 => "J&#46;A&#46; Kempker"
                            2 => "S&#46; Annangi"
                            3 => "M&#46;R&#46; Kramer"
                            4 => "G&#46;S&#46; Martin"
                          ]
                        ]
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                  ]
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                        "fecha" => "2016"
                        "volumen" => "13"
                        "paginaInicial" => "1742"
                        "paginaFinal" => "1751"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27403914"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subphenotypes in acute respiratory distress syndrome&#58; latent class analysis of data from two randomised controlled trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;S&#46; Calfee"
                            1 => "K&#46; Delucchi"
                            2 => "P&#46;E&#46; Parsons"
                            3 => "B&#46;T&#46; Thompson"
                            4 => "L&#46;B&#46; Ware"
                            5 => "M&#46;A&#46; Matthay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(14)70097-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Respir Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "2"
                        "paginaInicial" => "611"
                        "paginaFinal" => "620"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24853585"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46; Vadasz"
                            1 => "J&#46;I&#46; Sznajder"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2017.00757"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol&#46;"
                        "fecha" => "2017"
                        "volumen" => "8"
                        "paginaInicial" => "757"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28725223"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "9"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lung pathology in fatal novel human influenza A &#40;H1N1&#41; infection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Mauad"
                            1 => "L&#46;A&#46; Hajjar"
                            2 => "G&#46;D&#46; Callegari"
                            3 => "L&#46;F&#46; da Silva"
                            4 => "D&#46; Schout"
                            5 => "F&#46;R&#46; Galas"
                          ]
                        ]
                      ]
                    ]
                  ]
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                        "fecha" => "2010"
                        "volumen" => "181"
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;B&#46; Walsh"
                            1 => "J&#46;R&#46; Teijaro"
                            2 => "P&#46;R&#46; Wilker"
                            3 => "A&#46; Jatzek"
                            4 => "D&#46;M&#46; Fremgen"
                            5 => "S&#46;C&#46; Das"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "Revista" => array:6 [
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                        "fecha" => "2011"
                        "volumen" => "108"
                        "paginaInicial" => "12018"
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                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46;L&#46; Lin"
                            1 => "Y&#46; Suzuki"
                            2 => "N&#46; Nakano"
                            3 => "E&#46; Ramsburg"
                            4 => "M&#46;D&#46; Gunn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
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                        "fecha" => "2008"
                        "volumen" => "180"
                        "paginaInicial" => "2562"
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46;A&#46; Arankalle"
                            1 => "K&#46;S&#46; Lole"
                            2 => "R&#46;P&#46; Arya"
                            3 => "A&#46;S&#46; Tripathy"
                            4 => "A&#46;Y&#46; Ramdasi"
                            5 => "M&#46;S&#46; Chadha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "PLoS One&#46;"
                        "fecha" => "2010"
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                      ]
                    ]
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                ]
              ]
            ]
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Article information
ISSN: 15792129
Original language: English
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