SIRT3 Overexpression Ameliorates Asbestos-Induced Pulmonary Fibrosis, mt-DNA Damage, and Lung Fibrogenic Monocyte Recruitment

• Published in: International journal of molecular sciences Vol. 22; no. 13; p. 6856
• Main Authors: Cheresh, Paul, Kim, Seok-Jo, Jablonski, Renea, Watanabe, Satoshi, Lu, Ziyan, Chi, Monica, Helmin, Kathryn A, Gius, David, Budinger, G R Scott, Kamp, David W
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25-06-2021; MDPI
• Subjects: Aging; alveolar epithelial cell; Alveoli; Animals; Apoptosis; Asbestos; Asbestos - adverse effects; Biomarkers; Bleomycin; Cell fate; Crocidolite; Disease Models, Animal; DNA Damage; DNA, Mitochondrial; Epithelial cells; Epithelium; Fibroblasts; Fibrosis; Flow cytometry; Gene Expression; Histology; Humans; Idiopathic Pulmonary Fibrosis - etiology; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Immunohistochemistry; Kinases; Lung diseases; Lungs; Macrophages; Mice; Mice, Transgenic; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Monocytes; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; mtDNA damage; Oxidants; Oxidative Stress; Oxidizing agents; Pulmonary fibrosis; Recruitment; Resveratrol; Senescence; SIRT3; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; monocytes; mtDNA damage; oxidative stress; pulmonary fibrosis; SIRT3; alveolar epithelial cell
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22136856

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 (
) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (
) 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
(Wild-Type) mice or
mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls,
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.