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Herein, we employed lung tissues and blood samples from C57BL\/6 mice with pneumoperitoneum\u2010induced lung injury and blood samples from patients who received laparoscopic gynecological surgery to investigate the therapeutic role of hydromorphone in pneumoperitoneum\u2010induced lung injury along with the underlying mechanism. We found that pretreatment with hydromorphone alleviated lung injury in mice that underwent CO<jats:sub>2<\/jats:sub> insufflation, decreased the levels of myeloperoxidase (MPO), total oxidant status (TOS), and oxidative stress index (OSI), and increased total antioxidant status (TAS). In addition, after pretreatment with hydromorphone, upregulated HO\u20101 protein expression, reduced mitochondrial DNA content, and improved mitochondrial morphology and dynamics were observed in mice subjected to pneumoperitoneum. Immunohistochemical staining also verified that hydromorphone could increase the expression of HO\u20101 in lung tissues in mice subjected to CO<jats:sub>2<\/jats:sub> pneumoperitoneum. Notably, in mice treated with HO\u20101\u2010siRNA, the protective effects of hydromorphone against pneumoperitoneum\u2010induced lung injury were abolished, and hydromorphone did not have additional protective effects on mitochondria. Additionally, in clinical patients who received laparoscopic gynecological surgery, pretreatment with hydromorphone resulted in lower serum levels of club cell secretory protein\u201016 (CC\u201016) and intercellular adhesion molecule\u20101 (ICAM\u20101), a lower prooxidant\u2010antioxidant balance (PAB), and higher heme oxygenase\u20101 (HO\u20101) activity than morphine pretreatment. Collectively, our results suggest that hydromorphone protects against CO<jats:sub>2<\/jats:sub> pneumoperitoneum\u2010induced lung injury via HO\u20101\u2010regulated mitochondrial dynamics and may be a promising strategy to treat CO<jats:sub>2<\/jats:sub> pneumoperitoneum\u2010induced lung injury.<\/jats:p>","DOI":"10.1155\/2021\/9034376","type":"journal-article","created":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T18:35:32Z","timestamp":1618079732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hydromorphone Protects against CO<sub>2<\/sub> Pneumoperitoneum\u2010Induced Lung Injury via Heme Oxygenase\u20101\u2010Regulated Mitochondrial 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