title: Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts.
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-β-induced differentiation and fibrogenic activity of primary human lung fibroblasts (HLFs). Pirfenidone reduced fibroblast proliferation and attenuated TGF-β-induced α-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels. Importantly, pirfenidone inhibited TGF-β-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-β pathway. Together, these results demonstrate that pirfenidone modulates HLF proliferation and TGF-β-mediated differentiation into myofibroblasts by attenuating key TGF-β-induced signaling pathways.
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy. Electronic address: econte@unict.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Conte
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gili
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Fagone
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy.
authors.forename: Mary
authors.initials: M
authors.lastname: Fruciano
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Iemmolo
authors.affiliation: Department of Molecular and Clinical Biomedicine, University of Catania, 95123 Catania, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Vancheri
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011728:Pyridones; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C093844:pirfenidone; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Fibrogenic activity; IPF; Lung fibroblasts; Pirfenidone; Proliferation