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with pneumococci activates the superoxide-generating enzyme NOX2 (nicotinamide adenine dinucleotide phosphate hydrogen [NADPH] oxidase 2), involving the pneumococcal virulence factor PLY (pneumolysin). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the \u03b1 subunit of ENaC (epithelial sodium channel) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function\u2014measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans blue dye incorporation in mouse lungs\u2014after infection with pneumococci. PLY-induced hyperpermeability in human lung microvascular endothelial cell monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47phox subunit (Western blotting) in vitro and by colocalization of CD31 and gp91phox in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-\u03b1, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-\u03b1 knockout (enENaC-\u03b1 knockout) mice develop increased capillary leak upon intratracheal instillation with PLY or pneumococci, compared with wild-type animals. TIP peptide diminishes capillary leak in Streptococcus pneumoniae\u2013infected wild-type mice, without significantly increasing lung bacterial load. Lung slices from S. pneumoniae\u2013infected enENaC-\u03b1 knockout mice have significantly increased endothelial NOX2 expression, compared with infected cyclization recombination mice. In conclusion, enENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in acute respiratory distress syndrome, without impairing host defense.<\/jats:p>","DOI":"10.1165\/rcmb.2023-0440oc","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T15:42:15Z","timestamp":1729006935000},"page":"429-440","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":7,"title":["Endothelial ENaC-\u03b1 Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia\u2013associated Acute Lung Injury"],"prefix":"10.1093","volume":"72","author":[{"given":"Maritza J.","family":"Romero","sequence":"first","affiliation":[{"name":"Vascular Biology Center"},{"name":"Department of Pharmacology and Toxicology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of 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