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ID: 117: SIRT3, THE MAJOR ANTI-AGING MITOCHONDRIAL DEACETYLASE, IS IMPORTANT FOR PREVENTING PULMONARY FIBROSIS
  1. RP Jablonski,
  2. S Kim,
  3. P Cheresh,
  4. DB Williams,
  5. DW Kamp
  1. Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Abstract

Objectives Alveolar epithelial cell (AEC) injury from ‘exaggerated’ lung aging and mitochondrial dysfunction play vital roles in the development of lung fibrosis. Our group, using the asbestos lung fibrosis paradigm, has shown that AEC mitochondrial reactive oxygen species (ROS) mediate asbestos-induced AEC mitochondrial DNA (mtDNA) damage and apoptosis by a mitochondria-regulated (intrinsic) death pathway. Sirtuin 3 (SIRT3), the anti-aging major mitochondrial deacetylase governing mitochondrial function, mitigates oxidative stress and fibrosis in non-lung models though deacetylation of diverse substrates including MnSOD (Chen et al EMBO Rep 2011) and OGG1 (Cheng et al Cell Death Dis 2013). We previously reported that SIRT3 deficient (Sirt3−/−) mice have increased lung fibrosis following asbestos exposure associated with exaggerated AEC mtDNA damage and apoptosis. Herein, we determined whether SIRT3 deficiency augments bleomycin-induced lung fibrosis and whether AEC acetylation is increased in lung biopsy samples from patients with idiopathic pulmonary fibrosis (IPF).

Methods Male 8- to 10- week-old 129SJ (Sirt3+/+) and Sirt3−/− mice were treated with a single intratracheal instillation of saline or bleomycin (0.01U). At 3 weeks, the lungs were harvested for various endpoints including Sircol collagen assay, fibrosis scoring and measurement of lung compliance. Specimens from explanted lungs of patients with IPF were subject to immunohistochemistry with antibodies to MnSODK68, Ac-OGG1 and IgG (negative control) to assess acetylation.

Results Compared to wild type, Sirt3−/− mice developed increased pulmonary fibrosis following bleomycin exposure as measured by fibrosis score (7.8 vs. 11.25, p<0.05), Sircol assay (0.90 vs. 1.35, p<0.05) and lung compliance (0.0688 mL/cmH2O vs. 0.0449 mL/cm H2O, p<0.05). Notably, increased expression of MnSODK68 and Ac-OGG1 was evident in the lungs of patients with IPF. Co-localization studies evaluating MnSODK68 and SFPTC are ongoing.

Conclusions SIRT3 deficiency enhances bleomycin-induced pulmonary fibrosis in a manner similar to asbestos fibers. An important role for augmented human IPF lung parenchymal cell mitochondrial acetylation is suggested by our pilot studies. Taken together, this suggests that SIRT3 plays a key role in the pathogenesis of IPF in part by preserving AEC mitochondrial function and mtDNA through modulation of the SIRT3/ACO-2/OGG1/apoptosis axis. Given the crucial role for aging in IPF as well as changes in SIRT3 expression with aging, our findings suggest a novel therapeutic target for modulating lung fibrosis.

Funding VA Merit and NIH R01 ES02037-01A1 (DK), NIH/NHLBI T32 HL076139-11A1 (RJ).

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