Abstract
BACKGROUND Fibroblasts activation-induced fibrosis can cause idiopathic pulmonary fibrosis (IPF). Excessive activation of fibroblasts contributes to poor healing or severe visceral fibrosis and even organ dysfunction. Sitagliptin acts as a dipeptidyl peptidase 4 inhibitor to reduce glucose level in type 2 diabetes, but its role in fibrosis of lung fibroblasts is elusive. We investigated the mechanism of sitagliptin in TGF-ß-activated lung fibroblasts and evaluated the efficacy of sitagliptin in extracellular matrix accumulation and fibroblasts proliferation. MATERIAL AND METHODS By in vitro lung fibroblasts culture, we assessed the expression of lung fibroblasts biomarker (alpha-SMA) and extracellular matrix (Col-1, Col-3, fibronectin) following TGF-ß stimulation and treatment with sitagliptin. Mechanistically, the phosphorylation level of Smad-3 protein in cells was analyzed using Western blotting, and the apoptosis level was assessed by Western blotting and flow cytometry. The degree of proliferation was determined using immunofluorescence and scratch-healing assay. RESULTS We found that treatment with sitagliptin attenuates fibroblasts activation following TGF-ß stimulation. Furthermore, the extracellular matrix was decreased by sitagliptin treatment by suppressing the phosphorylation level of Smad-3 protein. We found that sitagliptin does not affect apoptosis in fibroblasts, but it does affect the degree of proliferation of lung fibroblasts, thus ameliorating fibrosis after TGF-ß stimulation. CONCLUSIONS Sitagliptin inhibits fibrosis in TGF-ß-induced lung fibroblasts activation, which restrains extracellular matrix formation and cell proliferation in fibroblasts. Therefore, sitagliptin appears to have promise as a treatment of fibroproliferative disease caused by activation and proliferation of fibroblasts.