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

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

doi:10.3390/ijms22136856

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 (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 intratracheally 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, 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.

Highlights

Licensee MDPI, Basel, Switzerland.Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive, age-associated pulmonary disease with a median survival of only 3–5 years [1,2]
We reported that mitochondrial catalase enforced-expression (MCAT) transgenic mice are protected against asbestos- and bleomycin-induced lung fibrosis due in part to diminished Alveolar epithelial cell (AEC) mitochondrial reactive oxygen species
Our group has established a causal role for the recruitment of pro-fibrotic monocyte-derived alveolar macrophages (Mo-AMs) in the development of both bleomycin- and asbestos-induced lung fibrosis, but the role of sirtuin 3 (SIRT3) in modulating recruitment of monocytederived alveolar macrophages (Mo-AMs) is unclear [40,41,42]. These findings suggest that SIRT3 is crucial for maintaining mitochondrial DNA (mtDNA) integrity in the setting of fibrogenic oxidative stress and thereby limits AEC apoptosis and lung fibrosis; it is unclear whether transgenic whole body SIRT3 overexpression (Sirt3Tg ) mice are protected against lung fibrosis following asbestos exposure, a non-resolving model of lung fibrosis unlike bleomycin, and if so, whether the protective effects are mediated in part by attenuating lung and AEC mtDNA

Summary

Introduction

Licensee MDPI, Basel, Switzerland.Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive, age-associated pulmonary disease with a median survival of only 3–5 years [1,2]. Two FDAapproved drugs (pirfenidone and nintedanib) can slow lung function deterioration in patients with IPF and other fibrotic lung diseases, neither agent improves pulmonary function, suggesting that there is an important need for identifying novel cellular and molecular targets that can diminish pulmonary fibrosis and promote lung repair. Our group and others have focused on the mitochondria because they are prominently involved in mediating the age-associated changes occurring in patients with IPF and murine models of lung fibrosis, including bleomycin and asbestos, because they are both the source and target of reactive oxygen species (ROS) that can promote mitochondrial DNA (mtDNA)

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Results

Conclusion