Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
Department of Pediatric Allergy and Immunology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
Respir Res. 2023 Feb 17;24(1):56. doi: 10.1186/s12931-023-02361-1.
Obesity increases the severity of airway hyperresponsiveness (AHR) in individuals with asthma, but the mechanism is not well elucidated. G-protein coupled receptor 40 (GPR40) has been found to induce airway smooth muscle contraction after activated by long-chain fatty acids (LC-FFAs), suggesting a close correlation between GPR40 and AHR in obese. In this study, C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization, the regulatory effects of GPR40 on AHR, inflammatory cells infiltration, and the expression of Th1/Th2 cytokines were evaluated by using a small-molecule antagonist of GPR40, DC260126. We found that the free fatty acids (FFAs) level and GPR40 expression were greatly elevated in the pulmonary tissues of obese asthmatic mice. DC260126 greatly reduced methacholine-induced AHR, ameliorated pulmonary pathological changes and decreased inflammatory cell infiltration in the airways in obese asthma. In addition, DC260126 could down-regulate the levels of Th2 cytokines (IL-4, IL-5, and IL-13) and pro-inflammatory cytokines (IL-1β, TNF-α), but elevated Th1 cytokine (IFN-γ) expression. In vitro, DC260126 could remarkedly reduce oleic acid (OA)-induced cell proliferation and migration in HASM cells. Mechanistically, the effects that DC260126 alleviated obese asthma was correlated with the down-regulation of GTP-RhoA and Rho-associated coiled-coil-forming protein kinase 1 (ROCK1). Herein, we proved that targeting of GPR40 with its antagonist helped to mitigate multiple parameters of obese asthma effectively.
肥胖症会增加哮喘患者气道高反应性（AHR）的严重程度，但具体机制尚不清楚。现已发现，G 蛋白偶联受体 40（GPR40）在被长链脂肪酸（LC-FFAs）激活后可引起气道平滑肌收缩，这表明 GPR40 与肥胖症患者的 AHR 密切相关。在这项研究中，C57BL/6 小鼠喂食高脂肪饮食（HFD）以诱导肥胖症，并进行卵清蛋白（OVA）致敏，然后使用 GPR40 的小分子拮抗剂 DC260126 来评估 GPR40 对 AHR、炎症细胞浸润和 Th1/Th2 细胞因子表达的调节作用。我们发现肥胖哮喘小鼠的肺组织中游离脂肪酸（FFAs）水平和 GPR40 表达显著升高。DC260126 可显著降低乙酰甲胆碱诱导的 AHR，改善肥胖哮喘小鼠的肺部病理变化并减少气道中的炎症细胞浸润。此外，DC260126 可以下调 Th2 细胞因子（IL-4、IL-5 和 IL-13）和促炎细胞因子（IL-1β、TNF-α）的水平，但可上调 Th1 细胞因子（IFN-γ）的表达。在体外，DC260126 可以显著降低油酸（OA）诱导的 HASM 细胞增殖和迁移。在机制上，DC260126 减轻肥胖型哮喘的作用与 GTP-RhoA 和 Rho 相关卷曲螺旋形成蛋白激酶 1（ROCK1）的下调有关。本研究证明，用其拮抗剂靶向 GPR40 有助于有效减轻肥胖型哮喘的多种参数。
