This paper aims to investigate the effect and mechanism of Waigan Qingre Jiedu Formula on lipopolysaccharide (LSP)-induced acute lung injury (ALI) in rats.Methods:Twenty male Wistar rats were randomly divided into a control group，a model group，a Waigan Qingre Jiedu Formula group，and a miR-495 inhibitor group.The rat model of ALI was successfully induced by intratracheal instillation of LSP (5 mg/kg)，and corresponding interventions were performed.qPCR was used to detect the level of miR-495 in rat lung tissue.HE staining was used to observe the pathological changes in lung tissue.The levels of IL-6，TNF-α，IL-1β，IL-18，and IL-10 inflammatory cytokines and myeloperoxidase (MPO) activity in bronchoalveolar lavage fluid (BALF) were detected by ELISA.Western blot was used to detect the expression of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3)，apoptosis-associated speck-like protein (ASC)，cysteine aspartate protease-1(Caspase-1)，and gasdermin D (GSDMD) proteins in lung tissue.Results:Compared with the control group，the expression of miR-495 in the lung tissue of rats in the model group was down-regulated (P<0.05)，and pathological injury occurred.The content of IL-6，TNF-α，IL-1β，and IL-18 in BALF increased，and that of IL-10 decreased.MPO activity increased.NLRP3，ASC，and Caspase-1 protein expression increased in lung tissue (all P<0.05).Compared with the model group and inhibitor group，the expression of miR-495 in lung tissue of the Waigan Qingre Jiedu Formula group was up-regulated (P<0.05)，and pathological injury was alleviated.The content of IL-6，TNF-α，IL-1β，and IL-18 in BALF was decreased，and that of IL-10 was increased.MPO activity was decreased.NLRP3 and ASC expression were down-regulated (all P<0.05)，and there was no significant difference in Caspase-1 expression (P>0.05).Except for the control group，GSDMD protein cleavage was observed in all groups，and the expression level of protein cleavage in the Waigan Qingre Jiedu Formula group was significantly lower than that of the model group and inhibitor group.Conclusion:Waigan Qingre Jiedu Formula has a protective effect on ALI rats，and its mechanism may be related to the regulation of the miR-495/NLRP3/GSDMD pathway，the reduction of inflammatory responses，and the inhibition of pyroptosis.