Pirfenidone is an orally active small molecule that has been shown to inhibit the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Although pirfenidone exhibits well documented antifibrotic and antiinflammatory activities, in vitro and in vivo, its molecular targets and mechanisms of action have not been elucidated. In this study, we investigated the effects of pirfenidone on proliferation, TGF-beta-induced differentiation and fibrogenic activity of primary human lung fibroblasts (HLFs). Pirfenidone reduced fibroblast proliferation and attenuated TGF-beta-induced alpha-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels. Importantly, pirfenidone inhibited TGF-beta-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-beta pathway. Together, these results demonstrate that pirfenidone modulates HLF proliferation and TGF-beta-mediated differentiation into myofibroblasts by attenuating key TGF-beta-induced signaling pathways
Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts
Fagone E;VANCHERI, CARLO
2014-01-01
Abstract
Pirfenidone is an orally active small molecule that has been shown to inhibit the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Although pirfenidone exhibits well documented antifibrotic and antiinflammatory activities, in vitro and in vivo, its molecular targets and mechanisms of action have not been elucidated. In this study, we investigated the effects of pirfenidone on proliferation, TGF-beta-induced differentiation and fibrogenic activity of primary human lung fibroblasts (HLFs). Pirfenidone reduced fibroblast proliferation and attenuated TGF-beta-induced alpha-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels. Importantly, pirfenidone inhibited TGF-beta-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-beta pathway. Together, these results demonstrate that pirfenidone modulates HLF proliferation and TGF-beta-mediated differentiation into myofibroblasts by attenuating key TGF-beta-induced signaling pathwaysFile | Dimensione | Formato | |
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