{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:39:32Z","timestamp":1792507172385,"version":"4.5.0"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"674","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,12,7]]},"abstract":"<jats:p>\n            Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after\n            <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n            infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl\n            <jats:sup>\u2212<\/jats:sup>\n            ]\n            <jats:italic>\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            and [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:italic>\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            ). Inhibition of the chloride ion\u2013sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:italic>\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            , whereas WNK1 activation by temozolomide attenuated it. Endothelial [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:italic>\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in\n            <jats:italic>Trpv4<\/jats:italic>\n            (\n            <jats:italic>Trpv4<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            ) developed less lung edema and protein leak than their wild-type littermates after infection with\n            <jats:italic>S. pneumoniae<\/jats:italic>\n            . The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after\n            <jats:italic>S. pneumoniae<\/jats:italic>\n            infection in wild-type mice. In conclusion, lung infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abg8577","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T18:58:12Z","timestamp":1670439492000},"source":"Crossref","is-referenced-by-count":28,"title":["Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4974-154X","authenticated-orcid":true,"given":"Lasti","family":"Erfinanda","sequence":"first","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0605-6051","authenticated-orcid":true,"given":"Lin","family":"Zou","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."},{"name":"German Heart Center, 13353 Berlin, Germany."},{"name":"Department of Endocrinology, Shanghai Pudong New Area Gongli Hospital, 200135 Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitt","family":"Gutbier","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4463-6831","authenticated-orcid":true,"given":"Laura","family":"Kneller","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Weidenfeld","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Michalick","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disi","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."},{"name":"German Heart Center, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Reppe","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5822-4168","authenticated-orcid":true,"given":"Luiz Gustavo","family":"Teixeira Alves","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2991-4474","authenticated-orcid":true,"given":"Bill","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihong","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4474-2025","authenticated-orcid":true,"given":"Diana","family":"Fatykhova","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pulmonary Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3274-777X","authenticated-orcid":true,"given":"Paul","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department for General and Thoracic Surgery, DRK Clinics, 13359 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