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This study seeks to determine the therapeutic potential of direct lung\u2010delivered interleukin (IL)\u201010 following repeated lipopolysaccharide exposures. C57BL\/6 mice were intratracheally instilled with LPS (10\u2009\u03bcg) and treated with IL\u201010 (1\u2009\u03bcg) or vehicle control for 3\u2009days. Lung cell infiltrates were enumerated by flow cytometry. Lung sections were stained for myeloperoxidase (MPO), CCR2, vimentin, and post\u2010translational protein citrullination (CIT) and malondialdehyde\u2010acetaldehyde (MAA) modifications. Lung function testing and longitudinal in\u00a0vivo micro\u2010CT imaging were performed. Whole lungs were profiled using bulk RNA sequencing. IL\u201010 treatment reduced LPS\u2010induced weight loss, pentraxin\u20102, and IL\u20106 serum levels. LPS\u2010induced lung proinflammatory and wound repair mediators (i.e., TNF\u2010\u03b1, IL\u20106, CXCL1, CCL2, MMP\u20108, MMP\u20109, TIMP\u20101, fibronectin) were decreased with IL\u201010. IL\u201010 reduced LPS\u2010induced influx of lung neutrophils, CD8<jats:sup>+<\/jats:sup> T cells, NK cells, recruited monocyte\u2010macrophages, monocytes, and tissue expression of CCR2<jats:sup>+<\/jats:sup> monocytes\u2010macrophages, MPO<jats:sup>+<\/jats:sup> neutrophils, vimentin, CIT, and MAA. IL\u201010 reduced LPS\u2010induced airway hyperresponsiveness and improved lung compliance. Micro\u2010CT imaging confirmed the reduction in LPS\u2010induced lung density by IL\u201010. Lung\u2010delivered IL\u201010 therapy administered after daily repeated endotoxin exposures strikingly reduces lung inflammatory and wound repair processes to decrease lung pathologic changes and mitigate airway dysfunction.<\/jats:p>","DOI":"10.14814\/phy2.70253","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T06:23:46Z","timestamp":1740119026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lung\u2010delivered IL\u201010 mitigates Lung inflammation induced by repeated endotoxin exposures in male mice"],"prefix":"10.14814","volume":"13","author":[{"given":"Aaron D.","family":"Schwab","sequence":"first","affiliation":[{"name":"Division of Allergy &amp; Immunology University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd A.","family":"Wyatt","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care &amp; 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