Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 330 338 Jun Zha Department of Anesthesiology, The Second Affiliated Hospital, Soochow University, Suzhou, China AND Department of Anesthesiology, The Second Affiliated Hospital, Wannan Medical College, Wuhu, China Youjia Yu Department of Anesthesiology, Suzhou Xiangcheng People’s Hospital, Suzhou, China Ji Zhu Department of Anesthesiology, The Second Affiliated Hospital, Wannan Medical College, Wuhu, China Guiru Li Department of Anesthesiology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China Xiaolin Deng Department of Anesthesiology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China Hong Xie Department of Anesthesiology, The Second Affiliated Hospital, Soochow University, Suzhou, China 2024 01 29 2024 03 11 This study aimed to explore the underlying mechanism of nebulized dexmedetomidine (DEX) in ameliorating ventilator-induced lung injury (VILI)-induced oxidative stress in rats. Forty 7 to 8-week-old Sprague-Dawley rats at the specific pathogen-free level were randomized into the control group, model group, nebulized dexmedetomidine (WH-YM) group, and dexmedetomidine intravenous infusion (JM-YM) group, each containing 10 rats. Except for the control group, rats in the other groups underwent mechanical ventilation (tidal volume,  40 mL/kg; respiratory rate, 70 breaths per minute; inspiratory-to-expiratory ratio, 1:2; fraction of inspired oxygen, 21%; positive end-expiratory pressure, 0 cmH2O). Nebulized DEX (6.3 µg/kg), and isodose intravenous DEX  were given to rats of WH-YM and JM-YM groups prior to ventilation. Post 4-hour ventilation, rats were euthanized. Lung tissue wet-to-dry weight ratio, H&E staining for assessing diffuse alveolar damage (DAD), and expression levels of Nrf2 and Keap1 detected by qRT-PCR and Western blot were compared. Inflammatory markers TNF-α, IL-2, and IL-6, and oxidative stress indices malondialdehyde (MDA) and superoxide dismutase (SOD), were quantified in lung tissues and serum samples using commercial kits.  Rats in the WH-YM and JM-YM groups demonstrated significant ameliorations in the wet-to-dry weight ratio and DAD score, decreased Keap1, TNF-α, IL-2, and IL-6 levels in lung tissues and serum samples, but increased Nrf2 and SOD level than those of controls. These changes were more pronounced in the WH-YM group than in the JM-YM group. DEX effectively alleviates VILI-induced oxidative stress and inflammation via the Keap1-Nrf2-ARE signaling pathway., especially in the nebulized administration. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4018 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4018/2079