CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

Abstract

Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF) -a deadly disease with restricted and limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECII. Deficiency of CYB5R3 in AECII leads to sustained activation of the profibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and sGC-cGMP-protein kinase G axis that modulates activation of TGF-β1 signaling pathway. We demonstrate that sGC agonists are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECII. Taken together, these results establish that CYB5R3 in AECII is required to maintain resilience against lung injury and fibrosis, and that therapeutic manipulation of sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice

“…CYB5R3 transfers electrons from the NADH domain to generate NAD + , which is involved in regulating various cellular metabolic processes. The expression of CYB5R3 displayed a marked decrease in AT2 cells from patients with IPF and bleomycin-induced mice, indicating that the up-regulation of CYB5R3 could be a promising therapeutic approach to restore the epithelial stem function ( 20 ). While maintaining the stem cell identity, regulating AT2 daughter cell transition and fibroblast activation are also crucial parts to terminate pathologic epithelial remodeling and collagen deposition, ultimately rapidly initiating realveolarization ( 7 , 55 ).…”

“…( 18 , 19 ). Compared with healthy lungs, the down-regulation of CYB5R3 mRNA and protein levels in IPF lung AT2 cells is not only related to mitochondrial homeostasis associated with the imbalance of NAD + /NADH but also involved in transforming growth factor–β1 (TGF-β1) signaling abnormally activation ( 20 ). This suggests that CYB5R3 could be a potential candidate to restore epithelial stem function by resisting accelerated cellular senescence due to mitochondrial damage.…”

Adipose-derived mesenchymal stem cell therapy for reverse bleomycin-induced experimental pulmonary fibrosis

“…TGF-β1 is a cytokine that plays a critical role in the pathogenesis of pulmonary fibrosis 44 . It can induce the differentiation of fibroblasts into myofibroblasts, which are the primary effector cells in the development of pulmonary fibrosis 45 . Remarkably, this study revealed a significant reduction in the expression of TGF-β1 in lung fibroblasts upon treatment with the MSCs supernatant.…”