CINXE.COM

<!DOCTYPE html>      <html lang='en' class='no-js'>  <head> <meta charset='utf-8'> <meta content='text/html; charset=UTF-8' http-equiv='Content-Type'> <meta content='The Journal of Clinical Investigation' name='AUTHOR'>  <meta content='width=device-width, initial-scale=1.0' name='viewport'> <link href='/rss' rel='alternate' title='JCI New Article RSS' type='application/rss+xml'> <meta name="csrf-param" content="authenticity_token" /> <meta name="csrf-token" content="gmr9jhlQrqSkY7JfYzTdrsCUqsXXfugInseSre4ZJnmkoH1noShYgIf4UVpkcu7JmqV/CtTc28iqPJCS9RYeUw==" /> <link rel="shortcut icon" type="image/x-icon" href="/assets/jci-favicon-378ea4dd43f03bc78136c6a261d9b28f6811fe59d12db426eae78cf0691b0008.ico" /> <title> JCI - Welcome </title> <link rel="stylesheet" media="all" href="/assets/application-4e3473ed7442aa1dc35d11f58ed4edfbd690fa57a3eb3a1daca0cd68dc7fb1e0.css" />  <style> @font-face { font-family: "klavika-bold"; src: url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot") format('eot'), src: url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot?#iefix") format("embedded-opentype"), url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/woff/KlavikaWebBasicBold.woff") format("woff") } </style> <script> //Google Tag Manager Data Layer //Values must be set before GTM tags are triggered window.dataLayer = window.dataLayer || []; window.dataLayer.push({ 'siteName': 'content-jci', 'ipAddress': '8.222.208.146', 'environment': 'production', }); </script> <script src="/assets/vendor/modernizr-2f68aa04c7424c280c5bc9db8b68f7f6ff70bcd38254c5b89383eac8e89b1781.js"></script> <script type='text/javascript'> var googletag = googletag || {}; googletag.cmd = googletag.cmd || []; (function () { var gads = document.createElement('script'); gads.async = true; gads.type = 'text/javascript'; var useSSL = 'https:' == document.location.protocol; gads.src = (useSSL ? 'https:' : 'http:') + '//www.googletagservices.com/tag/js/gpt.js'; var node = document.getElementsByTagName('script')[0]; node.parentNode.insertBefore(gads, node); })(); googletag.cmd.push(function () { // NOTE: This script manages google ads, more info at doc/GoogleAds.md var mapping = googletag.sizeMapping().addSize([800, 600], [300, 250]).addSize([640, 480], [260, 217]).build(); var mapping2 = googletag.sizeMapping() .addSize([1920, 1080], [728, 90])//All desktop like resolutions are set to 728x90 .addSize([800, 600], [728, 90]) .addSize([640, 480], [728, 90]) .addSize([0, 0], [320, 50]) //Smaller than 640x480 screens .build(); googletag.defineSlot('/82117132/jci-homepage-med-rectangle-left-col-top', [[300, 250],[260, 217]], 'jci-homepage-med-rectangle-left-col-top').defineSizeMapping(mapping).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-top', [[728, 90],[320, 50]], 'jci-article-interior-leaderboard-top').defineSizeMapping(mapping2).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-bottom', [728, 90], 'jci-article-interior-leaderboard-bottom').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-skyscraper-right-col', [160, 600], 'jci-article-interior-skyscraper-right-col').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-interior-skyscraper-right-col', [160, 600], 'jci-interior-skyscraper-right-col').addService(googletag.pubads()); // collapseEmptyDivs requires all slots be defined above. googletag.pubads().collapseEmptyDivs(true); googletag.enableServices(); }); </script> </head> <body class='' id='tags_controller'> <div class='off-canvas-wrap' data-offcanvas=''> <div class='inner-wrap'> <div class='fixed show-for-large-up'> <div class='row menu-align' id='logo-bar'> <div class='small-12 columns'> <div class='cross-journal-container'> Go to <a href='http://insight.jci.org'>JCI Insight</a> </div> <a href="/"><img src="/assets/common/jci-spelled-out-white-on-transparent.20160208-958617d51a205b239bcef41eae5703962aee0ae2fcc9fbda0237e635a09ac7f3.png" /></a> </div> </div> <div class='row menu-align' id='journal-bar'> <div class='small-12 columns'> <ul class='inline-list'> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </div> </div> <div id='content-bar'> <nav class='top-bar' data-topbar=''> <section class='top-bar-section'> <ul class='left'> <li class='not-click'> <a href="/tags/141">Clinical Research and Public Health</a> </li> <li class='not-click'> <a id="topmenu_current_issue" href="/current">Current issue</a> </li> <li class='not-click'> <a href="/archive">Past issues</a> </li> <li class='has-dropdown not-click'> <a>By specialty</a> <ul class='dropdown'> <li><a href="/tags/118">COVID-19</a></li> <li><a href="/tags/15">Cardiology</a></li> <li><a href="/tags/21">Gastroenterology</a></li> <li><a href="/tags/25">Immunology</a></li> <li><a href="/tags/28">Metabolism</a></li> <li><a href="/tags/31">Nephrology</a></li> <li><a href="/tags/32">Neuroscience</a></li> <li><a href="/tags/33">Oncology</a></li> <li><a href="/tags/36">Pulmonology</a></li> <li><a href="/tags/42">Vascular biology</a></li> <li><a href="/specialties">All ...</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/videos">Videos</a> <ul class='dropdown'> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/tags/reviews">Reviews</a> <ul class='dropdown'> <li> <label>Reviews</label> </li> <li><a href="/tags/reviews">View all reviews ...</a></li> <li class='divider'></li> <li> <label>Review Series</label> </li> <li><a href="/review_series/131">Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)</a></li> <li><a href="/review_series/130">Microbiome in Health and Disease (Feb 2025)</a></li> <li><a href="/review_series/127">Substance Use Disorders (Oct 2024)</a></li> <li><a href="/review_series/128">Clonal Hematopoiesis (Oct 2024)</a></li> <li><a href="/review_series/129">Sex Differences in Medicine (Sep 2024)</a></li> <li><a href="/review_series/126">Vascular Malformations (Apr 2024)</a></li> <li><a href="/review_series/125">Lung inflammatory injury and tissue repair (Jul 2023)</a></li> <li> <a href="/review_series">View all review series ...</a> </li> </ul> </li> <li class='not-click'> <a href="/tags/111">Viewpoint</a> </li> <li class='has-dropdown not-click'> <a>Collections</a> <ul class='dropdown'> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> </ul> </li> </ul> <ul class='right'> <li class='has-form'> <div id='search-area'> <form action="/search/results" accept-charset="UTF-8" method="get"> <input type="text" name="q" id="q" value="" placeholder="Search the JCI" /> <input type="image" src="/assets/search-black-ba9b554d6f74b1c93d6e6ab71d1c9830c18a20fc6b7e72393f136f5d875141ac.png" value="" /> </form> </div> </li> </ul> </section> </nav> </div> </div> <nav class='tab-bar hide-for-large-up fixed' id='small-navbar'> <section class='left-small'> <a class='left-off-canvas-toggle menu-icon'> <span></span> </a> </section> <section class='middle tab-bar-section'> <h1 class='title'><a href="/"><img width="40" src="/assets/common/jci-only-white-6c989e8f9744a714482158b82319d50aa8437aa4c8524c4f3dcf8450299cd4b7.png" /></a></h1> </section> </nav> <aside class='left-off-canvas-menu'> <ul class='off-canvas-list'> <li> <label>The Journal of Clinical Investigation</label> </li> <li><form action="/search/results" accept-charset="UTF-8" method="get"> <div class='row collapse' id='search-div-offcanvas'> <div class='small-8 columns'> <input name='q' placeholder='Search the JCI' type='text'> </div> <div class='small-4 columns'> <input type="image" src="/assets/common/search-white-530f3f95b9080d73eba51eaeffdf1a3922af42ccc277a2d1d987b8aa24423c96.png" id="search-icon-offcanvas" /> </div> </div> </form> </li> <li><a id="offcanvas_current_issue" href="/current">Current issue</a></li> <li><a href="/archive">Past issues</a></li> <li><a href="/specialties">Specialties</a></li> <li><a href="/tags/reviews">Reviews</a></li> <li><a href="/review_series">Review series</a></li> <li> <label>Videos</label> </li> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> <li> <label>Collections</label> </li> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> <li> <label>Journal Details</label> </li> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </aside> <a class='exit-off-canvas'></a>  <div class='row content-wrapper'> <div class='small-12 columns'> <div class='menu-align'> <div class='row'> <div class='large-10 medium-9 small-12 columns'> <h3>Pulmonology</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>207 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>2 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/36?content=articles&page=2">2</a></li> <li><a href="/tags/36?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/36?content=articles&page=20">20</a></li> <li><a href="/tags/36?content=articles&page=21">21</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/36?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181775">Reactivation of CTLA4-expressing T cells Accelerates Resolution of Lung Fibrosis in a Humanized Mouse Model</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181775">Santosh Yadav, … , Jay Kolls, Victor J. Thannickal</a> <a class='hide-for-small show-more' data-reveal-id='article45880-more' href='#'> <div class='article-authors'> Santosh Yadav, … , Jay Kolls, Victor J. Thannickal </div> </a> <span class='article-published-at'> Published March 18, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181775">https://doi.org/10.1172/JCI181775</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181775">Text</a> | <a href="/articles/view/181775/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181775' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45880-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181775">Reactivation of CTLA4-expressing T cells Accelerates Resolution of Lung Fibrosis in a Humanized Mouse Model</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181775">Text</a></li> <li><a class="button tiny" href="/articles/view/181775/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Tissue regenerative responses involve complex interactions between resident structural and immune cells. Recent reports indicate that accumulation of senescent cells during injury repair contributes to pathological tissue fibrosis. Using tissue-based spatial transcriptomics and proteomics, we identified upregulation of the immune checkpoint protein, cytotoxic T-lymphocyte associated protein 4 (CTLA4) on CD8+ T cells adjacent to regions of active fibrogenesis in human idiopathic pulmonary fibrosis (IPF) and in a murine model of repetitive bleomycin lung injury model of persistent fibrosis. In humanized CTLA4 knock-in mice, treatment with ipilimumab, an FDA-approved drug that targets CTLA4, resulted in accelerated lung epithelial regeneration and diminished fibrosis from repetitive bleomycin injury. Ipilimumab treatment resulted in the expansion of Cd3e+ T cells, diminished accumulation of senescent cells, and robust expansion of type 2 alveolar epithelial cells, facultative progenitor cells of the alveolar epithelium. Ex-vivo activation of isolated CTLA4-expressing CD8+ cells from mice with established fibrosis resulted in enhanced cytolysis of senescent cells, suggesting that impaired immune-mediated clearance of these cells contribute to persistence of lung fibrosis in this murine model. Our studies support the concept that endogenous immune surveillance of senescent cells may be essential in promoting tissue regenerative responses that facilitate the resolution of fibrosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Santosh Yadav, Muralidharan Anbalagan, Shamima Khatun, Devadharshini Prabhakaran, Justin Manges, Yasuka Matsunaga, James B. McLachlan, Joseph A. Lasky, Jay Kolls, Victor J. Thannickal</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179572">AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179572">Manuel A. Torres Acosta, … , Samuel E. Weinberg, Benjamin D. Singer</a> <a class='hide-for-small show-more' data-reveal-id='article45881-more' href='#'> <div class='article-authors'> Manuel A. Torres Acosta, … , Samuel E. Weinberg, Benjamin D. Singer </div> </a> <span class='article-published-at'> Published March 18, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI179572">https://doi.org/10.1172/JCI179572</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179572">Text</a> | <a href="/articles/view/179572/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179572' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45881-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179572">AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179572">Text</a></li> <li><a class="button tiny" href="/articles/view/179572/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Manuel A. Torres Acosta, Jonathan K. Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A. Helmin, Anthony M. Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E. Weinberg, Benjamin D. Singer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186889">Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186889">Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy</a> <a class='hide-for-small show-more' data-reveal-id='article45862-more' href='#'> <div class='article-authors'> Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e186889. <a href="https://doi.org/10.1172/JCI186889">https://doi.org/10.1172/JCI186889</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186889">Text</a> | <a href="/articles/view/186889/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186889' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186889/figure/1' ref='group' title='Selection of lung tissues from patients with asthma, patients with COPD, and lung disease–free individuals acting as controls. The flow diagram shows how tissues were selected from the James Hogg Lung Biobank at the University of British Columbia. It further illustrates the screening of lung tissue sections for mucus-plugged and unplugged airways and the number of samples analyzed by histology, immunofluorescence, and imaging mass cytometry.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186889/small/JCI186889.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45862-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186889">Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186889">Text</a></li> <li><a class="button tiny" href="/articles/view/186889/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODS Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell–eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTS Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13–activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSION Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell–mucin-granulocyte cross-talk.FUNDING NIH grants HL080414, HL107202, and AI077439.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186705">Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186705">Yohei Komaru, … , Daniel Kreisel, Andreas Herrlich</a> <a class='hide-for-small show-more' data-reveal-id='article45835-more' href='#'> <div class='article-authors'> Yohei Komaru, … , Daniel Kreisel, Andreas Herrlich </div> </a> <span class='article-published-at'> Published March 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186705">https://doi.org/10.1172/JCI186705</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186705">Text</a> | <a href="/articles/view/186705/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186705' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45835-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186705">Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186705">Text</a></li> <li><a class="button tiny" href="/articles/view/186705/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal CXCL2 administration during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a driver of AKI-induced hypoxemia.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M. Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177241">CRISPR-mediated detection of <i>Pneumocystis</i> transcripts in bronchoalveolar, oropharyngeal, and serum specimens for <i>Pneumocystis</i> pneumonia diagnosis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177241">Brady M. Youngquist, … , Jay K. Kolls, Tony Y. Hu</a> <a class='hide-for-small show-more' data-reveal-id='article45826-more' href='#'> <div class='article-authors'> Brady M. Youngquist, … , Jay K. Kolls, Tony Y. Hu </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI177241">https://doi.org/10.1172/JCI177241</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177241">Text</a> | <a href="/articles/view/177241/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177241' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45826-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177241">CRISPR-mediated detection of <i>Pneumocystis</i> transcripts in bronchoalveolar, oropharyngeal, and serum specimens for <i>Pneumocystis</i> pneumonia diagnosis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177241">Text</a></li> <li><a class="button tiny" href="/articles/view/177241/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND.Pneumocystis jirovecii pneumonia (PCP) is a leading cause of fungal pneumonia, but its diagnosis primarily relies on invasive bronchoalveolar lavage (BAL) specimens that are difficult to obtain. Oropharyngeal swabs and serum could improve the PCP diagnostic workflow, and we hypothesized that CRISPR could enhance assay sensitivity to allow robust P. jirovecii diagnosis using swabs and serum. Herein we describe the development of an ultrasensitive RT-PCR-coupled CRISPR assay with high active-infection specificity in infant swabs and adult BAL and serum. METHODS. Mouse analyses employed an RT-PCR CRISPR assay to analyze P. murina transcripts in wild-type and Rag2–/– mouse lung RNA, BAL, and serum at 2-, 4-, and 6-weeks post-infection. Human studies used an optimized RT-PCR CRISPR assay to detect P. jirovecii transcripts in infant oropharyngeal swab samples, adult serum, and adult BAL specimens from P. jirovecii-infected and P. jirovecii-non-infected patients. RESULTS. The P. murina assays sensitively detected Pneumocystis RNA in the serum of infected mice throughout infection. Oropharyngeal swab CRISPR assay results identified infants infected with P. jirovecii with greater sensitivity (96.3% vs. 66.7%) and specificity (100% vs. 90.6%) than RT-qPCR compared to mtLSU standard marker, and CRISPR results achieved higher sensitivity than RT-qPCR results (93.3% vs. 26.7%) in adult serum specimens. CONCLUSION. Since swabs are routinely collected in pediatric pneumonia patients and serum is easier to obtain than BAL, this assay approach could improve the accuracy and timing of pediatric and adult Pneumocystis diagnosis by achieving specificity for active infection and potentially avoiding the requirement for BAL specimens.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Brady M. Youngquist, Ayanda Trevor Mnguni, Dora Pungan, Rachel P.J. Lai, Guixiang Dai, Chun Fai Ng, Amy Samson, Yasmean Abdelgaliel, Christopher J. Lyon, Bo Ning, Shahid Husain, Sean Wasserman, Jay K. Kolls, Tony Y. Hu</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186937">Serum cAMP levels are increased in patients with asthma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186937">Steven S. An, … , Sally Wenzel, Reynold A. Panettieri, Jr.</a> <a class='hide-for-small show-more' data-reveal-id='article45670-more' href='#'> <div class='article-authors'> Steven S. An, … , Sally Wenzel, Reynold A. Panettieri, Jr. </div> </a> <span class='article-published-at'> Published January 7, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186937">https://doi.org/10.1172/JCI186937</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186937">Text</a> | <a href="/articles/view/186937/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186937' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45670-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186937">Serum cAMP levels are increased in patients with asthma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186937">Text</a></li> <li><a class="button tiny" href="/articles/view/186937/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p> </p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Steven S. An, Gaoyuan Cao, Kwangmi Ahn, Jordan Lee, Dae Young Jung, Loren Denlinger, John Fahy, Elliot Israel, Wendy Moore, Brenda Phillips, David Mauger, Sally Wenzel, Reynold A. Panettieri, Jr.</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182127">Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182127">LK Metthew Lam, … , Robert P. Dickson, Nilam S. Mangalmurti</a> <a class='hide-for-small show-more' data-reveal-id='article45609-more' href='#'> <div class='article-authors'> LK Metthew Lam, … , Robert P. Dickson, Nilam S. Mangalmurti </div> </a> <span class='article-published-at'> Published December 12, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024. <a href="https://doi.org/10.1172/JCI182127">https://doi.org/10.1172/JCI182127</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182127">Text</a> | <a href="/articles/view/182127/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI182127' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45609-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182127">Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182127">Text</a></li> <li><a class="button tiny" href="/articles/view/182127/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>LK Metthew Lam, Nathan J. Klingensmith, Layal Sayegh, Emily Oatman, Joshua S. Jose, Christopher V. Cosgriff, Kaitlyn A. Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J. Meyer, Robert P. Dickson, Nilam S. Mangalmurti</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177242">Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177242">Nowrin U. Chowdhury, … , Jeffrey C. Rathmell, Dawn C. Newcomb</a> <a class='hide-for-small show-more' data-reveal-id='article45462-more' href='#'> <div class='article-authors'> Nowrin U. Chowdhury, … , Jeffrey C. Rathmell, Dawn C. Newcomb </div> </a> <span class='article-published-at'> Published October 15, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024. <a href="https://doi.org/10.1172/JCI177242">https://doi.org/10.1172/JCI177242</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177242">Text</a> | <a href="/articles/view/177242/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177242' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45462-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177242">Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177242">Text</a></li> <li><a class="button tiny" href="/articles/view/177242/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Nowrin U. Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M. Wolf, Matthew Z. Madden, Shelby N. Kuehnle, Kaitlin E. McKernan, Erin Q. Jennings, Emily N. Arner, Darren R. Heintzman, Channing Chi, Ayaka Sugiura, Matthew T. Stier, Kelsey Voss, Xiang Ye, Kennedi L. Scales, Evan S. Krystofiak, Vivek D. Gandhi, Robert D. Guzy, Katherine N. Cahill, Anne I. Sperling, R. Stokes Peebles Jr., Jeffrey C. Rathmell, Dawn C. Newcomb</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/173861">EMC3 regulates trafficking and pulmonary toxicity of the <i>SFTPC<sup>I73T</sup></i> mutation associated with interstitial lung disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173861">Xiaofang Tang, … , Xinhua Lin, Jeffrey A. Whitsett</a> <a class='hide-for-small show-more' data-reveal-id='article45453-more' href='#'> <div class='article-authors'> Xiaofang Tang, … , Xinhua Lin, Jeffrey A. Whitsett </div> </a> <span class='article-published-at'> Published October 15, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024. <a href="https://doi.org/10.1172/JCI173861">https://doi.org/10.1172/JCI173861</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173861">Text</a> | <a href="/articles/view/173861/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI173861' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45453-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173861">EMC3 regulates trafficking and pulmonary toxicity of the <i>SFTPC<sup>I73T</sup></i> mutation associated with interstitial lung disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173861">Text</a></li> <li><a class="button tiny" href="/articles/view/173861/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Xiaofang Tang, Wei Wei, Yuqing Sun, Timothy E. Weaver, Ernesto S. Nakayasu, Geremy Clair, John M. Snowball, Cheng-Lun Na, Karen S. Apsley, Emily P. Martin, Darrell N. Kotton, Konstantinos-Dionysios Alysandratos, Jiuzhou Huo, Jeffery D. Molkentin, William A. Gower, Xinhua Lin, Jeffrey A. Whitsett</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183161">Neutrophil-specific Shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183161">S. Farshid Moussavi-Harami, … , Clifford A. Lowell, Mark R. Looney</a> <a class='hide-for-small show-more' data-reveal-id='article45425-more' href='#'> <div class='article-authors'> S. Farshid Moussavi-Harami, … , Clifford A. Lowell, Mark R. Looney </div> </a> <span class='article-published-at'> Published October 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024. <a href="https://doi.org/10.1172/JCI183161">https://doi.org/10.1172/JCI183161</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183161">Text</a> | <a href="/articles/view/183161/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183161' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45425-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183161">Neutrophil-specific Shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183161">Text</a></li> <li><a class="button tiny" href="/articles/view/183161/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>S. Farshid Moussavi-Harami, Simon J. Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C. English, Longhui Qiu, Kristin M. Wang, Clare L. Abram, Clifford A. Lowell, Mark R. Looney</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/36?content=articles&page=2">2</a></li> <li><a href="/tags/36?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/36?content=articles&page=20">20</a></li> <li><a href="/tags/36?content=articles&page=21">21</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/36?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/477">Mucus tethering in asthma</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/477"><div class='article-metadata'> Luke Bonser and colleagues characterize the composition and transport of pathogenic, asthma-associated mucus… <br> <span class='published-at smaller'> Published May 16, 2016 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/36"><span style='margin-right: 6px' class="label-specialty">Pulmonology</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/477"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/424/thumb_Presentation1.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/222">Translating mechanical stress to fibrogenesis</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/222"><div class='article-metadata'> Shaik Rahaman and colleagues reveal that TRPV4 channel activity links mechanical stress and pulmonary fibrosis… <br> <span class='published-at smaller'> Published November 3, 2014 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/36"><span style='margin-right: 6px' class="label-specialty">Pulmonology</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/222"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/316/thumb_Olman_75331_small.jpg" /></a> </div> </div> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>