Nuclear Factor Erythroid 2-Related Factor 2 Nuclear Translocation Induces Myofibroblastic Dedifferentiation in Idiopathic Pulmonary Fibrosis

Abstract

Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

“…Such inhibition may be protective against pulmonary fibrosis because Nrf-2 is by itself protective through several regulatory pathways (Cho et al, 2004(Cho et al, , 2006Sriram et al, 2009;Cho and Kleeberger, 2010;Kikuchi et al, 2010;Liu et al, 2013;Pekovic-Vaughan et al, 2014). This notion is consistent with the known decreased nuclear Nrf-2 expression in patients with IPF (Artaud-Macari et al, 2013). Similarly, GSNOR inhibition-driven suppression of the NFkB pathway is predicted to be protective against pulmonary fibrosis (Zhang et al, 2000;Krug et al, 2010;Tully et al, 2013;Zhou et al, 2014).…”

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

“…We utilized multiple approaches to activate Nrf2, including genetic activation, via tamoxifen-induced deletion of Keap1, and pharmacological activation, via treatment with the Nrf2 activator TMC. Previous studies demonstrate that patients with severe asthma, chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis contain deficient activity of Nrf2 (3,12,32,51), which suggests that the normal Nrf2 response is not maintained in chronic pulmonary diseases. Thus targeting the Nrf2 response may be a viable potential therapy for asthma and other chronic conditions.…”

Mechanisms of Lung Fibrosis Resolution

“…However, these in vitro observations did not translate in vivo because sulforaphane administration was unsuccessful in altering bleomycininduced pulmonary fibrosis in mice. 52 Endogenous nitrated fatty acids are potent agonists of peroxisome proliferator-activated receptor g, which have been shown to exhibit antifibrotic activity in the lung through SMAD inhibition. 65,66 Cultured IPF myofibroblasts treated with the most common nitrated fatty acids in human plasma, 10-nitro-oleic acid, increased peroxisome proliferator-activated receptor g expression, while reversing myofibroblast differentiation, as assessed by a-SMA levels and contractility.…”