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Besides antibiotics, current treatments are mostly supportive, and no other targeted therapies exist that improve patient outcomes. Key features of bacterial pneumonia include alveolar inflammation, including inflammatory cell infiltration, mediator release, and alveolar-capillary barrier dysfunction. We previously demonstrated that plasma membrane hyperpolarization via large conductance K<jats:sup>+<\/jats:sup> (BK) channels reduces pro-inflammatory mediator release from TNF-\u03b1- or lipopolysaccharide (LPS)-treated pulmonary endothelial cells. Building on those findings, this study evaluates pharmacological BK channel activation as a potential treatment for LPS-induced pneumonia in a mouse model and explores its molecular mechanisms. We found that BK channel activation with NS1619 in LPS-infected mice reduced broncho-alveolar lavage fluid total cell and neutrophil counts, CCL-2 concentrations, and ROS and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> production, and increased antioxidant superoxide dismutase and catalase levels. These effects were not linked to glutathione, neutrophil myeloperoxidase, elastase, or extracellular traps. These protective effects were replicated with a structurally different BK channel activator, NS19504. At the cellular level, both NS1619 and NS19504 reduced LPS-induced ROS production in primary human alveolar epithelial cells, whereas LPS had no effect on endothelial ROS production. Our findings suggest that pharmacological BK channel activation could serve as a new therapeutic target against bacterial pneumonia.<\/jats:p>","DOI":"10.1038\/s41598-025-08902-6","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T07:00:31Z","timestamp":1755586831000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological activation of BK channels protects against LPS-induced pneumonia"],"prefix":"10.1038","volume":"15","author":[{"given":"Tatiana","family":"Zyrianova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janelle","family":"SooHoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Boehmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nairrita","family":"Majumder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Schwingshackl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"8902_CR1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1542\/peds.2007-2462","volume":"124","author":"JJ Zimmerman","year":"2009","unstructured":"Zimmerman, J. 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