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17 April 2020 : Laboratory Research  

Sitagliptin Inhibits Extracellular Matrix Accumulation and Proliferation in Lung Fibroblasts

Xiuwu Liu1ABDE, Tao Zhang2BCF, Chengcai Zhang3ACDG*

DOI: 10.12659/MSM.922644

Med Sci Monit 2020; 26:e922644

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-β-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 (α-SMA) and extracellular matrix (Col-1, Col-3, fibronectin) following TGF-β 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-β 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-β stimulation.

CONCLUSIONS: Sitagliptin inhibits fibrosis in TGF-β-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.

Keywords: Extracellular Matrix, Fibroblasts, Fibrosis, Cell Line, Dipeptidyl-Peptidase IV Inhibitors, idiopathic pulmonary fibrosis, Lung, Sitagliptin Phosphate

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750