摘要：SummaryThe preclinical model of bleomycin-induced lung fibrosis is useful to study mechanisms related to human pulmonary fibrosis. Using BLM in mice, we find low HO-1 expression. Although a unique Rhenium-CO-releasing molecule (ReCORM) up-regulates HO-1, NRF-1, CCN5, and SMAD7, it reduces TGFβ1, TGFβr1, collagen, α-SMA, and phosphorylated Smad2/3 levels in mouse lung and in human lung fibroblasts. ChIP assay studies confirm NRF-1 binding to the promoters of TGFβ1 repressorsCCN5andSmad7. ReCORM did not blunt lung fibrosis inHmox1-deficient alveolar type 2 cell knockout mice, suggesting this gene participates in lung protection. In human lung fibroblasts, TGFβ1-dependent production of α-SMA is abolished by ReCORM or by NRF-1 gene transfection. We demonstrate effective HO-1/NRF-1 signaling in lung AT2 cells protects against BLM induced lung injury and fibrosis by maintaining mitochondrial health, function, and suppressing the TGFβ1 pathway. Thus, protection of AT2 cell mitochondrial integrity via HO-1/NRF-1 presents an innovative therapeutic target.Graphical abstractDisplay OmittedHighlights•ReCORM reduces lung fibrosis in a bleomycin (BLM) model and improves lung function•ReCORM increases antifibrotic and decreases profibrotic genes expression via NRF-1/HO-1•ReCORM preserves mitochondrial function and decreases cell death after BLM exposure•ReCORM reduced lung inflammation and protected lung epithelial cells after BLM exposureBiological sciences; Pathophysiology; Cell biology
