AIM:To investigate the effects and mechanisms of sphingosine-1-phosphate receptor-2 (S1P2R) on lipopolysaccharide (LPS)-induced acute lung injury (ALI).METHODS:ALI model was induced by intratracheal ad-ministration of LPS in both wild-type mice and S1P2R-deficient mice.The pathological changes in the lung tissues were ob-served, and the protein concentration , total cell number, neutrophil ratio, TNF-αlevel and IL-6 level were determined in the bronchoalveolar lavage fluid (BALF) 24 h after LPS injection.In order to investigate the mechanisms of S1P2R in LPS-induced ALI, 10 min before LPS injection, both wild-type mice and S1P2R-deficient mice were injected with nitric oxide synthase inhibitor by tail vein injection , the pathological changes of the lung tissues were observed , and the protein concen-tration and total cell number in BALF were determined 12 h after LPS injection .RESULTS: Compared with wild-type mice, S1P2R-deficient mice showed more severe LPS-induced ALI, and the protein concentration , neutrophils and inflam-matory cytokines in BALF were significantly increased in S1P2R-deficient mice.Administration of nitric oxide synthase in-hibitor Nω-L-nitro-arginine methyl ester protected S1P2R-deficient mice from aggravation of ALI .CONCLUSION:S1P2R mediates the protection from LPS-induced ALI possibly through inhibiting nitric oxide synthase .