Graduate School of Medicine, Yonsei University College of Medicine, Seoul, Korea.
Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
Respir Res. 2024 May 18;25(1):213. doi: 10.1186/s12931-024-02842-x.
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.
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.
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.
Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.
肥胖与气道高反应性和肺纤维化有关，这可能会降低同时患有这两种疾病的个体对标准哮喘治疗的效果。他汀类药物和脯氨酰肽酶枯草溶菌素/激肽释放酶 9 抑制剂不仅能降低血清胆固醇和游离脂肪酸，还能抑制肾素-血管紧张素系统的活性并发挥抗炎作用。这些机制可能在减轻与肥胖相关的肺部病变中发挥作用。
雄性 C57BL/6 小鼠通过高脂肪饮食喂养 16 周来诱导肥胖。条件性 TGF-β1 转基因小鼠喂食正常饮食。给予这些小鼠阿托伐他汀或脯氨酰肽酶枯草溶菌素/激肽释放酶 9 抑制剂（alirocumab），并评估其对气道高反应性和肺部病变的影响。
高脂肪饮食诱导的肥胖增强了气道高反应性、肺纤维化、支气管肺泡灌洗液中的巨噬细胞和肺部的促炎介质。这些降脂药物可减弱气道高反应性、BALF 中的巨噬细胞、肺纤维化、血清瘦素、游离脂肪酸、TGF-β1、IL-1β、IL-6 和 IL-17a。此外，肥胖小鼠肺组织中增加的 RAS、NLRP3 炎性体和胆囊收缩素被他汀类药物或 alirocumab 降低。这些药物还抑制了正常饮食下 TGF-β1 过表达转基因小鼠的促炎免疫反应和肺纤维化。
降脂治疗有可能通过抑制 NLRP3 炎性体、RAS 和胆囊收缩素的活性，减轻肥胖引起的气道高反应性和肺纤维化。
