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SIRT3 Overexpression Ameliorates Asbestos-Induced Pulmonary Fibrosis, mt-DNA Damage, and Lung Fibrogenic Monocyte
Paul Cheresh1,2, Seok-Jo Kim1,2, Renea Jablonski3
1Jesse Brown VA Medical Center, Division of Pulmonary & Critical Care Medicine, Chicago, IL 60612, USA.
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-induced lung fibrosis is augmented in Sirt3 knockout (Sirt3-/-) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (Sirt3) 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 intratracheally in C57Bl6 (Wild-Type) mice or Sirt3 mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3 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, viniferin, 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.
Insights
Sirtuin 3 (SIRT3) deficiency worsens pulmonary fibrosis by damaging mitochondrial DNA in alveolar epithelial cells. Overexpressing SIRT3 protects against fibrosis, reduces mitochondrial DNA damage, and lowers fibrotic macrophages.
Area of Science:
- Mitochondrial biology
- Pulmonary medicine
- Cellular aging
Background:
- Alveolar epithelial cell (AEC) mitochondrial DNA (mtDNA) damage and fibrotic macrophages are key in pulmonary fibrosis.
- Sirtuin 3 (SIRT3), a mitochondrial protein, is reduced in idiopathic pulmonary fibrosis (IPF) patients' AECs.
- Sirt3 knockout mice show increased lung fibrosis, AEC mtDNA damage, and apoptosis.
Purpose of the Study:
- To investigate if whole-body transgenic SIRT3 overexpression protects mice from asbestos-induced pulmonary fibrosis.
- To determine if SIRT3 overexpression mitigates lung mtDNA damage and fibrotic macrophage recruitment.
- To explore the therapeutic potential of SIRT3 in pulmonary fibrosis.
Main Methods:
- Crocidolite asbestos was instilled intratracheally in Wild-Type and Sirt3 transgenic mice.
- Lung fibrosis was assessed using histology, fibrosis scoring, and Sircol assay at 21 days.
- Lung fibrotic monocyte-derived alveolar macrophages (Mo-AMs) were quantified via flow cytometry.
Main Results:
- Sirt3 transgenic mice exhibited protection against asbestos-induced pulmonary fibrosis compared to controls.
- These mice showed significantly reduced lung mtDNA damage and Mo-AM recruitment.
- Pharmacologic SIRT3 inducers reduced oxidant-induced AEC mtDNA damage in vitro, with honokiol showing SIRT3-dependent protection.
Conclusions:
- SIRT3 overexpression protects against pulmonary fibrosis by preserving AEC mitochondrial DNA integrity.
- Reduced lung mtDNA damage and fibrotic Mo-AMs contribute to SIRT3-mediated protection.
- SIRT3 activation represents a potential therapeutic strategy for managing pulmonary fibrosis, including IPF.
