Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.

In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-β signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.
PMID: 31534007 [PubMed - as supplied by publisher]

Source: Journal of Immunology - September 17, 2019 Category: Allergy & Immunology Authors: Tsubouchi K, Araya J, Yoshida M, Sakamoto T, Koumura T, Minagawa S, Hara H, Hosaka Y, Ichikawa A, Saito N, Kadota T, Kurita Y, Kobayashi K, Ito S, Fujita Y, Utsumi H, Hashimoto M, Wakui H, Numata T, Kaneko Y, Mori S, Asano H, Matsudaira H, Ohtsuka T, Naka Tags: J Immunol Source Type: research