{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:09:16Z","timestamp":1788804556668,"version":"build-2803163510"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["HL-147070,HL131745,HL145478,HL147290,HL147575,HL173940,P01HL169188,P30AR075049"],"award-info":[{"award-number":["HL-147070,HL131745,HL145478,HL147290,HL147575,HL173940,P01HL169188,P30AR075049"]}]},{"DOI":"10.13039\/501100010564","name":"German Center for Lung Research","doi-asserted-by":"crossref","award":["DZL\/ALI 1.5,DZL\/ALI 3.3,DZL\/ALI 3.4"],"award-info":[{"award-number":["DZL\/ALI 1.5,DZL\/ALI 3.3,DZL\/ALI 3.4"]}],"id":[{"id":"10.13039\/501100010564","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the von Behring R\u00f6ntgen Foundation","award":["66-LV07"],"award-info":[{"award-number":["66-LV07"]}]},{"name":"Science Foundation Ireland","award":["SFI 15\/CDA\/3490"],"award-info":[{"award-number":["SFI 15\/CDA\/3490"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    Hypercapnia, elevated carbon dioxide (CO\n                    <jats:sub>2<\/jats:sub>\n                    ), is common in advanced chronic obstructive pulmonary disease (COPD) and predicts poor clinical outcomes. Traditionally considered a consequence of disease severity, hypercapnia may drive disease progression by promoting airway dysfunction. Here, we show that hypercapnia acts as an active stressor, driving airway smooth muscle (ASM) constriction through a stromal interaction molecule 1\u2013dependent (STIM1-dependent) pathway. Hypercapnia rapidly activates ERK, triggering sarcoplasmic reticulum calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) release via phosphorylation of the inositol 1,4,5-trisphosphate receptor. ERK also induces nuclear translocation of the transcription factor c-Fos, enhancing\n                    <jats:italic>STIM1<\/jats:italic>\n                    transcription. These responses were observed under both supraphysiological (~120 mmHg) and clinically relevant (50\u201360 mmHg) hypercapnia. Increased STIM1 abundance sustains store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE), amplifying ASM signaling. In mice, hypercapnia increased ASM and airway contractility in a STIM1-dependent manner. Human genetic analyses revealed noncoding\n                    <jats:italic>STIM1<\/jats:italic>\n                    variants associated with reduced lung expression that were enriched in patients with COPD. These variants correlated with lower airway resistance under normocapnia; however, this benefit was lost during hypercapnia, indicating a potential gene-environment interaction. Together, our findings position STIM1 as a key mechanistic node linking hypercapnia to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dysregulation and airway obstruction, defining a CO\n                    <jats:sub>2<\/jats:sub>\n                    \/ERK\/STIM1\/SOCE axis with translational relevance to chronic lung disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.202475","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:00:52Z","timestamp":1784217652000},"source":"Crossref","is-referenced-by-count":0,"title":["Hypercapnia enhances airway smooth muscle contractility via STIM1-dependent Ca2+ signaling"],"prefix":"10.1172","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-6584","authenticated-orcid":true,"given":"Masahiko","family":"Shigemura","sequence":"first","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Laboratory of Homeostatic Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitalii","family":"Kryvenko","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Cardio-Pulmonary Institute, and Institute for Lung Health, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-2983","authenticated-orcid":true,"given":"Megan J.","family":"Puckelwartz","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine,"},{"name":"Department of Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Aleksic","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia D.","family":"Magnani","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Martin-Romero","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Badajoz, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9346-8299","authenticated-orcid":true,"given":"Eoin P.","family":"Cummins","sequence":"additional","affiliation":[{"name":"University College Dublin School of Medicine, UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1946-0894","authenticated-orcid":true,"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Cardio-Pulmonary Institute, and Institute for Lung Health, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Br\u00e4uninger","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Justus Liebig University, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-3696","authenticated-orcid":true,"given":"Lynn C.","family":"Welch","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3114-5208","authenticated-orcid":true,"given":"G.R. Scott","family":"Budinger","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-1386","authenticated-orcid":true,"given":"Emilia","family":"Lecuona","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-718X","authenticated-orcid":true,"given":"Laura A.","family":"Dada","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Bharat","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1370-9783","authenticated-orcid":true,"given":"Istv\u00e1n","family":"Vad\u00e1sz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Cardio-Pulmonary Institute, and Institute for Lung Health, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murali","family":"Prakriya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob I.","family":"Sznajder","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00003.2019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00022.2024"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29723"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0487OC"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat1662"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.290056"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0354OC"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI196928"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.625715"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0278OC"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2014"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004549"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2114557118"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00470-6"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.4.8887592"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01003-2019"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202006-2382ST"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.349191"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2021-0114OC"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001238"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-136895"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.12.003"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.08.002"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00591"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.07.208"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.067215"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.125054"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.08.010"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2012.02.012"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/srep42758"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.226019"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54683-0"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.570051"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-020-00460-w"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ncb822"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2011.05.006"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1113\/JP273889"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.733650"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28062-9"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01124.2010"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.70278"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000019234"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1159\/000342036"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.202009-1197OC"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.02.006"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.05.055"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nature04147"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702866104"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2022.102551"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(94)00497-G"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1995.268.4.L642"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1113\/JP282502"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1097\/EE9.0000000000000165"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.202409-991RL"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3109\/08958370903555909"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1159\/000430282"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.12.9873-9880.1998"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot070110"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/srep38276"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0170934"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/202475\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:01:49Z","timestamp":1788804109000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/202475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":60,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,7,23]]},"published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1172\/jci.insight.202475"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.202475","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]},"article-number":"e202475"}}