TY - JOUR
T1 - Nuclear respiratory factor-1 negatively regulates TGF-β1 and attenuates pulmonary fibrosis
AU - Suliman, Hagir B.
AU - Healy, Zachary
AU - Zobi, Fabio
AU - Kraft, Bryan D.
AU - Welty-Wolf, Karen
AU - Smith, Joshua
AU - Barkauskas, Christina
AU - Piantadosi, Claude A.
N1 - Funding Information:
We appreciate the technical assistance of Kathy Stempel, Martha Salinas, Kristina Porter, and Linhua Song. The authors thank Dr. John E. Baatz of the Department of Pediatrics, Medical University of South Carolina (MUSC) for insight discussion and technical assistance in developing the murine AT2 cellular respiration experiments. This work was supported by NIH grants R01-AI095424 and VA Merit Review grant to CAP, and by NIH grant K08-HL130557 (BDK).
Publisher Copyright:
© 2021 The Authors
PY - 2022/1/21
Y1 - 2022/1/21
N2 - The 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 repressors CCN5 and Smad7. ReCORM did not blunt lung fibrosis in Hmox1-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.
AB - The 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 repressors CCN5 and Smad7. ReCORM did not blunt lung fibrosis in Hmox1-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.
KW - Biological sciences
KW - Cell biology
KW - Pathophysiology
UR - http://www.scopus.com/inward/record.url?scp=85122545062&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103535
DO - 10.1016/j.isci.2021.103535
M3 - Article
C2 - 34977500
AN - SCOPUS:85122545062
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 1
M1 - 103535
ER -