Alpha-lipoic acid attenuates silica-induced pulmonary fibrosis by improving mitochondrial function via AMPK/PGC1α pathway activation in C57BL/6J mice. (10th October 2021)

• Record Type: Journal Article
• Authors: Chang, Meiyu; Xu, Guangcui; Xiong, Cheng; Yang, Xuesi; Yan, Sensen; Tao, Yingjun; Li, Haibin; Li, Yuchun; Yao, Sanqiao; Zhao, Yingzheng
• Is Part Of: Toxicology letters. Volume 350(2021)
• Page Start: 121
• Page End: 132
• Publication Date: 2021-10-10
• Subjects: ALA alpha-lipoic acid -- ROS reactive oxygen species -- AMPK adenosine monophosphate-activated protein kinase -- PGC1α peroxisome proliferator-activated receptor‑γ co-activator 1α -- NRF2 nuclear factor erythroid-2-related factor 2 -- LIAS lipoic acid synthase -- SiO2 crystalline silica -- OCR O2 consumption rate -- FCCP carbonyl cyanide p-trifluoromethoxy phenylhydrazone -- H&E hematoxylin and eosin -- DAPI 4', 6-diamidine-2-phenylindole dihydrochloride -- DHE dihydroethidium -- PDH pyruvate dehydrogenase -- TG triglycerides -- TC total cholesterol -- HDL-C high-density lipoprotein cholesterol -- LDL-C low-density lipoprotein cholesterol -- qPCR quantitative polymerase chain reaction -- COL1 type I collagen -- COL3 type Ⅲ collagen -- LKB-1 liver kinase B1 -- TFAM mitochondrial transcription factor A -- COXIV cytochrome c oxidase -- ATPase adenosine triphosphate synthase -- SOD superoxide dismutase -- CAT catalase -- TGF-β1 transforming growth factor -- GCLC glutamate cysteine ligase catalytic -- PAI-1 plasminogen activator inhibitor 1 -- α-SMA α-smooth muscle actin -- H2O2 hydrogen peroxide -- KEAP1 kelch-like ECH-associated protein1; Silicosis -- Alpha-lipoic acid -- Antioxidant response -- Mitochondrial biogenesis -- Pulmonary fibrosis; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.07.003
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: α-Lipoic acid opposes silica-induced pulmonary fibrosis. Mechanisms include mitoprotection and decreased oxidative stress. Mitochondrial energy metabolism disorder contributes to silica-induced fibrosis. Anti-fibrotic effects of α-lipoic acid co-occur with AMPK/PGC1α activation. Abstract: Silicosis is characterized by pulmonary interstitial fibrosis that arises as a result of chronic exposure to silica. The few available treatments only delay its progression. As α-lipoic acid (ALA) has been shown to have various beneficial effects, including mitoprotective, antioxidant, and anti-inflammatory effects, we hypothesized that it may exhibit therapeutic effects in pulmonary fibrosis. Therefore, in the present study, we used a murine model of silicosis to investigate whether supplementation with exogenous ALA could attenuate silica-induced pulmonary fibrosis by improving mitochondrial function. ALA was administered to the model mice via continuous intragastric administration for 28 days, and then the antioxidant and mitoprotective effects of ALA were evaluated. The results showed that ALA decreased the production of reactive oxygen species, protected mitochondria from silica-induced dysfunction, and inhibited extracellular matrix deposition. ALA also decreased hyperglycemia and hyperlipidemia. Activation of the mitochondrial AMPK/PGC1α pathway might be responsible for these ALA-mediated anti-fibrotic effects. Exogenous ALA blocked oxidative stress by activating NRF2. Taken together, these findings demonstrate that exogenous ALA effectively prevents the progression of silicosis in a murine model, likely by stimulating mitochondrial biogenesis and endogenous antioxidant responses. Therefore, ALA can potentially delay the progression of silica-induced pulmonary fibrosis.