Evogliptin attenuates bleomycin-induced lung fibrosis via inhibiting TGF-β/Smad signaling in fibroblast.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a pulmonary interstitial fibrosis disease. Excessive activation of fibroblasts in the lung contributes to severe alveoli dysfunction and histological destruction. Evogliptin, a dipeptidyl peptidase IV inhibitor, has been widely used to reduce glucose level in type 2 diabetes, whereas evogliptin treatment to fibrosis process of lung IPF is elusive. The study aimed to investigate the mechanism of evogliptin in transforming growth factor-beta (TGF-β)-activated lung fibroblasts and evaluate the efficacy of evogliptin in lung fibrosis model. In lung fibroblast culture, the RNA expression of α-SMA in lung fibroblasts was detected, and α-SMA/COL-1 immunofluorescence co-staining after TGF-β stimulation and evogliptin administration was displayed. Mechanically, the phosphorylation level of Smad2/3 protein in cells was analyzed using Western blotting, and the scratch assay was used to reflect fibroblast proliferation. Furthermore, bleomycin was employed to induce lung fibrosis in mice, and IHC staining and hematoxylin and eosin (HE) & Masson staining were carried out to examine the extracellular matrix (ECM) expression and tissue fibrosis. The results demonstrated that evogliptin treatment attenuated the activation of fibroblasts and collagen deposition following TGF-β stimulation. Furthermore, the extracellular matrix expression was descended via evogliptin restraining the TGF-β/Smad pathway. Besides, it was also found that evogliptin affected the proliferation degree of lung fibroblasts. In vivo, the COL-1 and α-SMA were significantly reduced through evogliptin treatment compared with the bleomycin group, and fibroblasts and collagenous fiber were remarkably decreased. Evogliptin exerts an anti-fibrosis effect on TGF-β induced lung fibroblast activation, which restrains ECM formation and decreases cell proliferation level in fibroblasts. Moreover, the fibroblast infiltration and collagen deposition were ameliorated following evogliptin administration. Therefore, evogliptin serves as a potential implication to protect lung fibrosis.