ALDH2 Deficiency Aggravates Lung Fibrosis through Mitochondrial Dysfunction and Aging in Fibroblasts
The American Journal of Pathology(2024)
Abstract
Idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix (ECM) accumulation. Effective therapeutic development is limited due to incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here we show acetaldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in IPF patients and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, Young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-β1 induction and ALDH2 depletion constitute a positive feedback loop that exacerbates fibroblast activation. TGF-β1 downregulated ALDH2 through a TGF-β receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and ECM production. ALDH2 overexpression markedly suppressed fibroblast activation and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the pro-fibrotic effects of ALDH2 are PINK1-dependent. Furthermore, Alda-1-induced ALDH2 activation reversed the established pulmonary fibrosis in both young and aged mice. In conclusions, ALDH2 expression inhibits the pathogenesis of pulmonary fibrosis. Strategies to upregulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.
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Key words
Acetaldehyde dehydrogenase 2,Idiopathic pulmonary fibrosis,Mitochondrial autophagy,Senescence,Fibroblasts
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