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We investigated whether genetic deficit or blockade of calcium\u2010activated potassium (K<jats:sub>Ca<\/jats:sub>3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator\u2010induced lung injury, an experimental model for ARDS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>K<jats:sub>Ca<\/jats:sub>3.1 channel knockout (<jats:italic>Kccn4<\/jats:italic><jats:sup>\u2010\/\u2010<\/jats:sup>) mice were exposed to ventilator\u2010induced lung injury. Control mice exposed to ventilator\u2010induced lung injury were treated with the K<jats:sub>Ca<\/jats:sub>3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio), lung compliance, lung wet\u2010to\u2010dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Ventilator\u2010induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio, increased protein, neutrophils and tumour necrosis factor\u2010alpha (TNF\u2010\u03b1) in BALF from wild\u2010type mice compared with <jats:italic>Kccn4<\/jats:italic><jats:sup>\u2010\/\u2010<\/jats:sup> mice. Pretreatment with senicapoc (10\u201370\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) prevented the reduction in PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio, decrease in lung compliance, increased protein and TNF\u2010\u03b1. Senicapoc (30\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup> senicapoc also improved the PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle\u2010treated mice. In human lung epithelial cells, senicapoc decreased TNF\u2010\u03b1\u2010induced permeability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Genetic deficiency of K<jats:sub>Ca<\/jats:sub>3.1 channels and senicapoc improved the PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio and decreased the cytokines after a ventilator\u2010induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K<jats:sub>Ca<\/jats:sub>3.1 channels is a potential treatment in ARDS\u2010like disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15704","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T08:38:00Z","timestamp":1633768680000},"page":"2175-2192","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Treatment with senicapoc, a K<sub>Ca<\/sub>3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0498-0785","authenticated-orcid":false,"given":"Asbj\u00f8rn Graver","family":"Petersen","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter 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