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This study explored the effects of butorphanol on ALI and investigated its underlying mechanisms. We established a \u201ctwo-hit\u201d rat model and \u201ctwo-hit\u201d cell model to prove our hypothesis. Rats were divided into four groups [control, \u201ctwo-hit\u201d (OA\u2009+\u2009LPS), \u201ctwo-hit\u201d\u2009+\u2009butorphanol (4\u00a0mg\/kg and 8\u00a0mg\/kg) (OA\u2009+\u2009LPS\u2009+\u2009B1 and OA\u2009+\u2009LPS\u2009+\u2009B2)]. RPMVE cells were divided into four groups [control, \u201ctwo-hit\u201d (OA\u2009+\u2009LPS), \u201ctwo-hit\u201d\u2009+\u2009butorphanol (4\u00a0\u03bcM and 8\u00a0\u03bcM) (OA\u2009+\u2009LPS\u2009+\u20094\u00a0\u03bcM and OA\u2009+\u2009LPS\u2009+\u20098\u00a0\u03bcM)]. Inflammatory injury was assessed by the histopathology and W\/D ratio, inflammatory cytokines, and arterial blood gas analysis. Apoptosis was assessed by Western blotting and flow cytometry. The effect of NF-\u03baB p65 was detected by ELISA. Butorphanol could relieve the \u201ctwo-hit\u201d induced lung injury, the expression of TNF, IL-1\u03b2, IL-6, and improve lung ventilation. In addition, butorphanol decreased Bax and cleaved caspase-3, increased an antiapoptotic protein (Bcl-2), and inhibited the \u201ctwo-hit\u201d cell apoptosis ratio. Moreover, butorphanol suppressed NF-\u03baB p65 activity in rat lung injury. Our research showed that butorphanol may attenuate \u201ctwo-hit\u201d-induced lung injury by regulating the activity of NF-\u03baB p65, which may supply more evidence for ALI treatment.<\/jats:p>","DOI":"10.1038\/s41598-024-53483-5","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T08:01:59Z","timestamp":1718870519000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Protective effects of butorphanol in oleic acid-endotoxin \u201ctwo-hit\u201d induced rat lung injury by suppression of inflammation and apoptosis"],"prefix":"10.1038","volume":"14","author":[{"given":"Yanlei","family":"Zheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronghua","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinrong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"issue":"1","key":"53483_CR1","doi-asserted-by":"publisher","first-page":"e58","DOI":"10.1097\/CCM.0000000000004070","volume":"48","author":"X Yan","year":"2020","unstructured":"Yan, X. et al. 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