Polycystin-2(PC2) composed of PKD2 gene encoding a transmembrane protein plays an important role in kidney disease, but the role of which in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was unclear. We overexpressed PC2 in lung epithelial cell in vitro and in vivo and examined the role of PC2 in inflammatory response induced by LPS in vitro and in vivo.We demonstrated that overexpression of PC2 significantly decreased the production of inflammatory factors TNF-α, IL-1β, and IL-6 in LPS-treated lung epithelial cells. Moreover, pre-treatment of 3-Methyladenine (3-MA), an autophagy inhibitor, reversed the inhibiting effects of overexpression of PC2 on the secretion of inflammatory factors in LPS-treated lung epithelial cells. We further demonstrated overexpression of PC2 can inhibit LPS-induced downregulating the protein levels of LC3BII/I and upregulating the protein levels of SQSTM1/P62 in lung epithelial cells. Moreover, we found that LPS-induced lung wet/dry weight ratio, and inflammatory cytokines TNF-α, IL-6 and IL-1β in lung tissue were significantly inhibited in mice with overexpression of PC2 in alveolar epithelial cells. However, the protective role of overexpression of PC2 in LPS-induced ALI was reversed by 3-MA pretreatment. Our studies suggest that overexpression of PC2 in the epithelium may alleviated LPS-induced ALI by activating autophagy.