Dipeptidyl Peptidase IV Inhibition Ameliorates Pulmonary Fibrosis in Lipopolysaccharide-Induced Lung Injury by Inhibiting Endothelial-to-Mesenchymal Transition

SESSION TITLE: Critical Care: ARDS/ALI SESSION TYPE: Original Investigation Poster PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM PURPOSE: Pulmonary fibrosis is the final pathway of acute respiratory distress syndrome (ARDS). Recently, endothelial-to-mesenchymal transition (EndMT) had been shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to play roles in EndMT in kidney. However its effects on EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury remain unknown. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor, vildagliptin in septic lung injury. METHODS: The acute lung injury model was established by intraperitoneal injection of LPS in mice (5mg/kg for 3 consecutive days). The mice were treated with vehicle or vildagliptin (10mg/kg, once daily for 10 consecutive days) intraperitoneally. Lung samples from mice were investigated for cell dynamics and EndMT function using flow cytometry, immunohistochemical staining and quantitative polymerase chain reaction (qPCR) analysis. RESULTS: Lung tissue revealed obvious inflammatory reactions 2 days after LPS challenge, and typical interstitial fibrosis 28 days after LPS challenge. Quantitative flow cytometric analysis revealed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or fibroblast-specific protein 1 (FSP1) was increased since 2 days after LPS challenge, which was also confirmed by qPCR of isolated PVECs. All of these changes were alleviated by intraperitoneal injection of vildagliptin. CONCLUSIONS: Inhibiting DPP-4 signaling could ameliorate pulmonary fibrosis via downregulation of EndMT in LPS-induced lung injury. CLINICAL IMPLICATIONS: Inhibiting DPP-4 may be a therapeutic target for treating post-ARDS pulmonary fibrosis. DISCLOSURE: The following authors have nothing to disclose: Toshio Suzuki, James West, Rintaro Nishimura, Takeshi Kawasaki, Ayumi Sekine, Takashi Urushibara, Yuji Tada, Koichiro Tatsumi No Product/Research Disclosure Information