Disruption of extracellular redox balance drives persistent lung fibrosis and impairs fibrosis resolution

Biochim Biophys Acta Mol Basis Dis. 2023 Aug 7:166842. doi: 10.1016/j.bbadis.2023.166842. Online ahead of print.ABSTRACTLung fibrosis is a devastating outcome of various diffuse parenchymal lung diseases. Despite rigorous research efforts, the mechanisms that propagate its progressive and nonresolving nature remain enigmatic. Oxidative stress has been implicated in the pathogenesis of lung fibrosis. However, the role of extracellular redox state in disease progression and resolution remains largely unexplored. Here, we show that compartmentalized control over extracellular reactive oxygen species (ROS) by aerosolized delivery of recombinant extracellular superoxide dismutase (ECSOD) suppresses an established bleomycin-induced fibrotic process in mice. Further analysis of publicly available microarray, RNA-seq and single-cell RNAseq datasets reveals a significant decrease in ECSOD expression in fibrotic lung tissues that can be spontaneously restored during fibrosis resolution. Therefore, we investigate the effect of siRNA-mediated ECSOD depletion during the established fibrotic phase on the self-limiting nature of the bleomycin mouse model. Our results demonstrate that in vivo knockdown of ECSOD in mouse fibrotic lungs impairs fibrosis resolution. Mechanistically, we demonstrate that transforming growth factor (TGF)-β1 downregulates endogenous ECSOD expression, leading to the accumulation of extracellular superoxide via Smad-mediated signaling and the activation of additiona...

Source: Biochimica et Biophysica Acta - August 9, 2023 Category: Biochemistry Authors: Ye Cui Zeran Yang Zhe Lv Jianfeng Lei Source Type: research