Modulation Of Fibroblast Phenotype In Idiopathic Pulmonary Fibrosis: Role Of NRF2

Abstract

Rationale: Oxidative stress has been implicated in Idiopathic Pulmonary Fibrosis (IPF) pathophysiology especially in myofibroblastic differentiation. Nrf2 signaling pathway, the main regulator of endogenous antioxidant enzymes, could be involved in fibrogenesis. The aim of our study was to analyse human pulmonary fibroblast expression of Nrf2, and, to assess the effects of Nrf2 modulation on fibroblast phenotype in vitro. Methods: We assessed oxidant/antioxidant balance, Nrf2 expression and phenotype of IPF and control fibroblasts in basal conditions, after stimulation by TGF-β, and Nrf2 siRNA transfection. Results: We showed a decrease of nuclear Nrf2 expression in IPF fibroblasts concomitant with myofibroblast phenotype in basal conditions. TGF-β induced an inhibition of nuclear Nrf2 expression and a myofibroblastic differentiation of control fibroblasts. Nrf2 inhibition in control fibroblast led to an increase of oxidative stress in association with a myofibroblastic differentiation. Conversely, Nrf2 activation by Keap1 siRNA, resulted in antioxidant defences restoration and myofibroblastic dedifferentation in IPF fibroblasts. Discussion: Our results suggest an association between decreased nuclear Nrf2 expression and myofibroblastic phenotype of IPF fibroblasts. Nrf2 modulation in human lung fibroblasts confirmed the increased susceptibility of Nrf2 knockout mice to bleomycin induced pulmonary fibrosis. Conclusion: Our study identified Nrf2 as a novel therapeutic target in IPF fibroblasts and suggested a potential antifibrosing effects of Nrf2 pharmacological activators.