Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFβ1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O to hydrogen peroxide (HO), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-β-1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of via an effect upon activity. Further, CD44V6 is part of a positive-feedback loop with TGFβ1/TGFβRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic ( shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

“…c ). Intriguingly, it was recently shown that reversal of the mesenchymal phenotype via inhibition of CD44 signaling ameliorates Bleomycin induced lung fibrosis . Although, radiation induced vascular effects are hypothesized to contribute to fibrosis development, little is known about the mechanism underlying vascular malfunction, the phenotype and functional consequences.…”

“…Intriguingly, it was recently shown that reversal of the mesenchymal phenotype via inhibition of CD44 signaling 55 ameliorates Bleomycin induced lung fibrosis. 56,57 Although, radiation induced vascular effects are hypothesized to contribute to fibrosis development, little is known about the mechanism underlying vascular malfunction, the phenotype and functional consequences. Our data support previous findings reporting global vascular remodeling after low-, intermediate or large lung volume after single high doses of proton irradiation, 58 and sustained remodeling of the pulmonary vasculature after single whole thoracic high dose irradiation.…”

Role of ALK5/SMAD2/3 signaling in the regulation of NOX expression in cerebral ischemia/reperfusion injury

“…Previously, the tumor suppressor TGF-β was also demonstrated to be a key factor in ROS generation (24,25). It has previously been identified that TGF-β may induce ROS generation through the TGF-β/ALK5/SMAD2/3, mitogen-activated protein kinase or c-Jun N-terminal kinase pathways (13).…”

Upregulation of NOX2 and NOX4 Mediated by TGF-β Signaling Pathway Exacerbates Cerebral Ischemia/Reperfusion Oxidative Stress Injury

“…Nevertheless, the detailed mechanism for NOX expression regulation has not been fully elucidated. Tumor suppressor TGF-β was recently considered an important factor in ROS generation [15, 25], but its involvement in NOX2/NOX4 expression regulation has not been fully clarified. Recent studies have reported that TGF-β can induce ROS generation and the underlying mechanism is its role in the TGF-β/ALK5/SMAD2/3, MAPK, and JNK signaling pathways [12].…”