Nuclear respiratory factor-1 negatively regulates TGF-β1 and attenuates pulmonary fibrosis

Hagir B Suliman; Zachary Healy; Fabio Zobi; Bryan D Kraft; Karen Welty-Wolf; Joshua Smith; Christina Barkauskas; Claude A Piantadosi

doi:10.1016/j.isci.2021.103535

Nuclear respiratory factor-1 negatively regulates TGF-β1 and attenuates pulmonary fibrosis

iScience. 2021 Dec 1;25(1):103535. doi: 10.1016/j.isci.2021.103535. eCollection 2022 Jan 21.

Authors

Hagir B Suliman^{1

2

3}, Zachary Healy¹, Fabio Zobi⁴, Bryan D Kraft¹, Karen Welty-Wolf¹, Joshua Smith¹, Christina Barkauskas¹, Claude A Piantadosi^{1

2

3}

Affiliations

¹ Department of Medicine, Duke University School of Medicine, 200 Trent Drive, Durham, NC 27710, USA.
² Department of Anaesthesiology, Duke University School of Medicine, Durham, NC, USA.
³ Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
⁴ Department of Chemistry, University of Fribourg, Fribourg, Switzerland.

Abstract

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.

Keywords: Biological sciences; Cell biology; Pathophysiology.

Abstract

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