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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Suliman, HB; Healy, Z; Zobi, F; Kraft, BD; Welty-Wolf, K; Smith, J; Barkauskas, C; Piantadosi, CA

Published Date

  • January 21, 2022

Published In

Volume / Issue

  • 25 / 1

Start / End Page

  • 103535 -

PubMed ID

  • 34977500

Pubmed Central ID

  • PMC8683592

Electronic International Standard Serial Number (EISSN)

  • 2589-0042

Digital Object Identifier (DOI)

  • 10.1016/j.isci.2021.103535

Language

  • eng

Conference Location

  • United States