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CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling. 2023
Marta Bueno, and
Jazmin Calyeca, and
Timur Khaliullin, and
Megan P Miller, and
Diana Alvarez, and
Lorena Rosas, and
Judith Brands, and
Christian Baker, and
Amro Nasser, and
Stephanie Shulkowski, and
August Mathien, and
Nneoma Uzoukwu, and
John Sembrat, and
Brenton G Mays, and
Kaitlin Fiedler, and
Scott A Hahn, and
Sonia R Salvatore, and
Francisco J Schopfer, and
Mauricio Rojas, and
Peter Sandner, and
Adam C Straub, and
Ana L Mora
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with 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 AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.
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