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

International Journal of Molecular Sciences

Monica Chi¹  Kathryn A. Helmin¹  Satoshi Watanabe¹  David Gius²  Paul Cheresh³  Seok-Jo Kim³  G. R. Scott Budinger³  Ziyan Lu³  David W. Kamp³  Renea Jablonski⁴ 

[1] Department of Medicine, Feinberg School of Medicine, Pulmonary and Critical Care Medicine, Northwestern University, Simpson & Querrey Biomedical Research Center 5-303, 303 E Superior St., Chicago, IL 60611, USA;Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;Jesse Brown VA Medical Center, Division of Pulmonary & Critical Care Medicine, Chicago, IL 60612, USA;Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA;

关键词: SIRT3;    mtDNA damage;    oxidative stress;    alveolar epithelial cell;    monocytes;    pulmonary fibrosis;   

DOI  :  10.3390/ijms22136856

来源: DOAJ

【 摘 要 】

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^Tg) 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^Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3^Tg 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.

【 授权许可】

Unknown