1. Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.
- Author
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Liang L, Chung SI, Guon TE, Park KH, Lee JH, and Park JW
- Subjects
- Animals, Male, Mice, PCSK9 Inhibitors, Atorvastatin pharmacology, Atorvastatin therapeutic use, Mice, Obese, Proprotein Convertase 9 metabolism, Proprotein Convertase 9 genetics, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Bronchial Hyperreactivity prevention & control, Bronchial Hyperreactivity drug therapy, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity physiopathology, Antibodies, Monoclonal, Humanized, Mice, Inbred C57BL, Diet, High-Fat adverse effects, Obesity drug therapy, Obesity metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Pulmonary Fibrosis prevention & control, Pulmonary Fibrosis pathology, Pulmonary Fibrosis metabolism, Pulmonary Fibrosis drug therapy, Mice, Transgenic
- Abstract
Background: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity., Methods: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-β1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed., Results: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-β1, IL-1β, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-β1 over-expressed transgenic mice with normal diet., Conclusions: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity., (© 2024. The Author(s).)
- Published
- 2024
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