Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Biomed Pharmacother. 2024 Aug;177:117111. doi: 10.1016/j.biopha.2024.117111. Epub 2024 Jul 15.
Mitochondrial dysfunction is critical in the pathogenesis of asthma. Mitochondrial permeability transition pore (mPTP) regulates the release of mitochondrial damage-associated molecular patterns (mtDAMPs) to maintain mitochondrial homeostasis. Bongkrekic acid (BKA) is a highly selective inhibitor of mPTP opening, participates the progression of various diseases. This research investigated the exact roles of BKA and mPTP in the pathogenesis of asthma and elucidated its underlying mechanisms. In the present study, cytochrome c, one of the mtDAMPs, levels were elevated in asthmatic patients, and associated to airway inflammation and airway obstruction. BKA, the inhibitor of mPTP markedly reversed TDI-induced airway hyperresponsiveness, airway inflammation, and mitochondrial dysfunction. Pretreatment with mitochondrial precipitation, to simulate the release of mtDAMPs, further increased TDI-induced airway inflammation and the expression of RAGE in mice. Administration of the inhibitor of RAGE, FPS-ZM1, alleviated the airway inflammation, the abnormal open of mPTP and mitochondrial dysfunction induced by mtDAMPs and TDI. Furthermore, stimulation with different mtDAMPs activated RAGE signaling in human bronchial epithelial cells. Accordingly, our study indicated that mPTP was important and BKA was efficient in alleviating inflammation in TDI-induced asthma. A positive feedback loop involving mPTP, mtDAMPs and RAGE was present in TDI-induced asthma, indicating that mPTP might serve as a potential therapeutic target for asthma.
线粒体功能障碍在哮喘发病机制中至关重要。线粒体通透性转换孔（mPTP）调节线粒体损伤相关分子模式（mtDAMPs）的释放，以维持线粒体的内稳态。苯甲酰甲硫氨酸（BKA）是 mPTP 开放的高度选择性抑制剂，参与多种疾病的进展。本研究探讨了 BKA 和 mPTP 在哮喘发病机制中的确切作用，并阐明了其潜在机制。在本研究中，细胞色素 c 作为 mtDAMPs 之一，在哮喘患者中升高，并与气道炎症和气道阻塞相关。mPTP 抑制剂 BKA 显著逆转 TDI 诱导的气道高反应性、气道炎症和线粒体功能障碍。用线粒体沉淀预处理，模拟 mtDAMPs 的释放，进一步增加了 TDI 诱导的气道炎症和 RAGE 在小鼠中的表达。RAGE 抑制剂 FPS-ZM1 的给药减轻了 mtDAMPs 和 TDI 诱导的气道炎症、mPTP 的异常开放和线粒体功能障碍。此外，不同 mtDAMPs 的刺激激活了人支气管上皮细胞中的 RAGE 信号。因此，我们的研究表明 mPTP 对于 TDI 诱导的哮喘中的炎症具有重要性，BKA 是有效的抑制剂。在 TDI 诱导的哮喘中存在涉及 mPTP、mtDAMPs 和 RAGE 的正反馈环，表明 mPTP 可能是哮喘的潜在治疗靶点。
