Effect of pirfenidone on TGF-β-induced pro-fibrotic effects in primary human lung cells derived from patients with idiopathic pulmonary fibrosis

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Pirfenidone is an orally administered pyridine that exhibits anti-fibrotic, anti-oxidant, and anti-inflammatory effects. In patients with mild-to-moderate IPF pirfenidone slowed down the decline in vital capacity and prolonged the progression-free survival. The inhibition of transforming growth factor-beta (TGF-β)-induced effects has been suggested to be part of pirfenidone's anti-fibrotic properties.

Aim: To determine the in vitro effect of pirfenidone on TGF-β1-stimulated primary human lung myofibroblasts and primary human alveolar epithelial type II cells.

Methods: Primary human myofibroblasts and alveolar epithelial type II cells were isolated from lung parenchyma derived from patients with IPF and from non-fibrotic control lungs. After incubation with pirfenidone and stimulation with TGF-β1, myofibroblast proliferation was assessed by automatic cell counting, and the effect on TGF-β1-induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cells was studied.

Results: In IPF myofibroblasts, pirfenidone (1 – 4 mM) dose-dependently prevented the pro-proliferative effect of TGF-β1 (1 ng/ml). TGF-β1 caused EMT in alveolar epithelial cells as demonstrated by morphologic changes, up-regulation of fibronectin and loss of E-cadherin expression, and these effects were partly prevented by pirfenidone (4 mM).

Conclusion: Our data demonstrate that pirfenidone counteracts TGF-β-induced pro-fibrotic effects, and suggest that the inhibition of EMT may account in part for the drug's documented clinically beneficial effect.