Restoration of SIRT3 gene expression by airway delivery resolves age-associated persistent lung fibrosis in mice

Autor: Sunad Rangarajan, Victor J. Thannickal, Naomi J. Logsdon, Samuel R. Smith, Ashish Kurundkar, Deepali Kurundkar, Jessy S. Deshane, Jaroslaw W. Zmijewski, Yan Y. Sanders, K.G. Dsouza, Mohammad Rehan, Karen Bernard, Diptiman Chanda
Rok vydání: 2021
Předmět:
Zdroj: Nature aging
ISSN: 2662-8465
Popis: Aging is a risk factor for progressive fibrotic disorders involving diverse organ systems, including the lung. Idiopathic pulmonary fibrosis, an age-associated degenerative lung disorder, is characterized by persistence of apoptosis-resistant myofibroblasts. Here we demonstrate that sirtuin 3 (SIRT3), a mitochondrial deacetylase, is downregulated in the lungs of humans with idiopathic pulmonary fibrosis and in mice subjected to lung injury. Overexpression of Sirt3 cDNA via airway delivery restored the capacity for fibrosis resolution in aged mice, in association with activation of the forkhead box transcription factor FoxO3a in fibroblasts, upregulation of pro-apoptotic members of the Bcl2 family and recovery of apoptosis susceptibility. While transforming growth factor-β1 reduced levels of SIRT3 and FOXO3A in lung fibroblasts, cell non-autonomous effects involving macrophage-secreted products were necessary for SIRT3-mediated activation of FOXO3A. Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that restore susceptibility to apoptosis in fibroblasts via a FOXO3A-dependent mechanism. Using a mouse model of lung fibrosis, the authors find that overexpression of SIRT3 in myofibroblasts lowers their threshold for apoptosis, allowing their clearance from tissues and restoration of the lost capacity for fibrosis resolution in aged mice.
Databáze: OpenAIRE
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