DPP-4 is overexpressed in lung tissue from idiopathic pulmonary patients and activates lung fibroblasts

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible form of fibrotic interstitial lung disease, characterized by uncontrolled fibroblast invasion. Dipeptidyl peptidase-4 (DPP-4)/ glucagon-like peptide 1 (GLP-1) system is involved in multiple effects, including cardiac, liver or kidney fibrosis. However, its implication in IPF has not been described. Objective: To analyse the implication of DPP4/GLP1 system in IPF. Methods: Protein expression of DPP4, GLP-1 and GLP-1 receptor was analyzed in lung tissues from 7 IPF patients. TGFβ1-induced fibroblast to myofibroblast transition (FMT), epithelial to mesenchymal transition (EMT) and mesothelial to mesenchymal transition (MMT) were evaluated in vitro in lung MRC5 and primary IPF lung fibroblasts, alveolar type II A549, and mesothelial Met5A cells. Antifibrotic effects of sitagliptin, an inhibitor of DPP-4, and liraglutide, a GLP-1 analogue, were evaluated. Results: DPP-4 and GLP-1 protein expression were increased in lung tissue of IPF patients vs healthy subjects, while GLP-1 receptor protein expression was decreased in IPF lung tissue. TGFβ1 promoted FMT by increasing a-SMA, Col-I, CTGF, FN-1 and IL-13 in MRC5 and IPF primary lung fibroblasts. Sitagliptin but not liraglutide, was able to reduce myofibroblast markers. Neither sitagliptin nor liraglutide inhibited the EMT and MMT processes in A549 and Met5A cells. Conclusions: DPP-4 and GLP-1 are increased in IPF patients while GLP1-receptor is decreased. Sitagliptin but not liraglutide reduced the TGFb1-induced FMT in both MRC5 and primary IPF lung fibroblasts. Pharmacological inhibition of DPP-4 may be a promising target for the treatment of IPF.