SIRT3 overexpression ameliorates asbestos-induced pulmonary fibrosis, mt-DNA damage and lung fibrogenic monocyte recruitment

Paul Cheresh, Seok Jo Kim, Renea Jablonski, Satoshi Watanabe, Ziyan Lu, Monica Chi, Kathryn A. Helmin, David Gius, G. R. Scott Budinger, David W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Alveolar epithelial cell (AEC) mitochondrial (mt) DNA damage and fibrotic monocyte-derived alveolar macrophages (Mo-AMs) are implicated in the pathobiology of pulmonary fibrosis. We showed that sirtuin 3 (SIRT3), a mitochondrial protein regulating cell fate and aging, is deficient in the AECs of idiopathic pulmonary fibrosis (IPF) patients and that asbestos- and bleomycin-in-duced lung fibrosis is augmented in Sirt3 knockout (Sirt3−/−) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpres-sion (Sirt3Tg) protects mice from asbestos-induced pulmonary fibrosis by mitigating lung mtDNA damage and Mo-AM recruitment. Crocidolite asbestos (100 μg/50 μL) or control was instilled in-tratracheally in C57Bl6 (Wild-Type) mice or Sirt3Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3Tg mice were protected from asbestos-induced pulmonary fibrosis and had diminished lung mtDNA damage and Mo-AM recruitment. Further, pharmacologic SIRT3 inducers (i.e., resveratrol, vinif-erin, and honokiol) each diminish oxidant-induced AEC mtDNA damage in vitro and, in the case of honokiol, protection occurs in a SIRT3-dependent manner. We reason that SIRT3 preservation of AEC mtDNA is a novel therapeutic focus for managing patients with IPF and other types of pulmonary fibrosis.

Original languageEnglish (US)
Article number6856
JournalInternational journal of molecular sciences
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2021
Externally publishedYes

Keywords

  • Alveolar epithelial cell
  • Monocytes
  • Oxidative stress
  • Pulmonary fibrosis
  • SIRT3
  • mtDNA damage

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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