Objective This study aims to explore the protective effects of the dipeptidyl peptidase 4 inhibitor

Sitagliptin

on lung tissue in a mouse model of acute lung injury (ALI)

as well as its potential molecular mechanisms. Methods Thirty-two male BALB/C mice were randomly divided into 4 groups，Control group，Sitagliptin (DPP4I) group，LPS group，and LPS+DPP4I group，with 8 in each. After 72 hours of interventions，HE staining was used to observe the pathological alterations，subsequently，to evaluate lung injury scores. Wet to dry (W/D) ratio was used to assess pulmonary edema. Inflammatory cells in BALF，including neutrophils，macrophages，lymphocytes，and total cells，were observed and counted using Diff-Quik staining. The mRNA and protein expression of TTF-1 and SP-B were measured by RT-PCR and western blotting. Results After 72 hours of interventions，severe lung injury pathological changes，and increased lung injury scores and W/D ratio were observed. Meanwhile，the counts of neutrophils，macrophages，lymphocytes，and total cells in BALF were increased，and the mRNA and protein expression of TTF-1 and SP-B were reduced by LPS. No pathological alterations were observed both in Control group and DPP4I group. Then，compared to LPS group，the pathological changes were attenuated，lung injury scores，W/D ratio，and neutrophils，macrophages，lymphocytes，and total cells in BALF were decreased，and the mRNA and protein expression of TTF-1 and SP-B were up-regulated in LPS+DPP4I group. Conclusions Collectively，our findings indicated that Sitagliptin，a DPP4I，alleviated LPS-induced ALI through up-regulation of TTF-1/SP-B signal pathway in mice. Therefore，these results suggested that dipeptidyl peptidase 4 inhibitor was a potential and promising drug for the treatment of ARDS in clinical practice.