The goal of a new study published in Respiratory Research was to investigate the anti-endothelial-to-mesenchymal transition (anti-EndMT) effects of the dipeptidyl peptidase (DPP)-4 inhibitor, vildagliptin, in pulmonary fibrosis after systemic endotoxemic injury. In this experiment, a septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice – 5 mg/kg for five consecutive days. These animals were then treated with vehicle or vildagliptin, intraperitoneally – 10 mg/kg, once daily for 14 consecutive days, from 1 day before the first administration of LPS. The results revealed obvious inflammatory reactions and typical interstitial fibrosis, 2 days and 28 days after the LPS challenge. In addition, the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Comparable increases in expression were also confirmed by polymerase chain reaction (qPCR) of mRNA from isolated PVECs. Moreover, EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Furthermore, vildagliptin markedly attenuated EndMT in the absence of immune cells or glucagon-like peptide-1 (GLP-1). Thus, it was concluded that inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.