Zhang Qian, Wu Jie, Lan Yisheng, Wang Yanhong, Chen Meijia, Wang Junrao, Zhao Xueying, Liu Laiyu, Zhao Wenqu, Zhao Haijin
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Department of Respiratory Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine and Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China.
Free Radic Biol Med. 2025 Feb 16;228:207-220. doi: 10.1016/j.freeradbiomed.2025.01.003. Epub 2025 Jan 3.
Previous studies have demonstrated that high-mobility group box protein 1(HMGB1) was increased and released to the extracellular and participated in the pathogenesis of steroid-insensitive asthma induced by toluene diisocyanate (TDI). Mitochondrial dysfunction of bronchial epithelia is a critical feature in TDI asthma. However, whether mitochondrial dysfunction regulated HMGB1 release in asthma remains unknown. The aim of this study was to explore whether phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein, can regulate HMGB1 release in TDI-induced asthma. The gene expression data series (GSE) 67472 from gene expression omnibus (GEO) database was analyzed to compare the levels of PGAM5 in airway epithelial cells from asthma patients and healthy individuals. Male C57BL/6J mice were sensitized and challenged with TDI and treated with the PGAM5 inhibitor LFHP-1c. In vitro, human bronchial epithelial cells(16HBE) were stimulated by TDI-human serum albumin (HSA) and pretreated with PGAM5 siRNA. In this study, we observed PGAM5 expression was notably increased in airway epithelial cells of asthma patients and TDI-induced asthma mice. In vivo, inhibition of PGAM5 significantly ameliorated airway inflammation, airway hyperresponsiveness (AHR) and mucus hypersecretion, coupled with the decrease of pulmonary HMGB1 expression and release in TDI-exposed mice. In vitro, inhibition of PGAM5 improved mitochondrial dysfunction, decreased the production of reactive oxygen species (ROS) in mitochondrial. Knockdown of PGAM5 reduced the release of cytochrome C (cyt c) and HMGB1 release in TDI-induced asthma. Mechanistically, PGAM5 in bronchial epithelial cells treated by TDI-HSA significantly increased the dephosphorylation of Bax at the S184 residue, promoted the translocation of Bax to mitochondria, and contributed to the activation of mitochondrial-dependent apoptosis in TDI-induced asthma. Based on these findings, we uncovered a novel regulatory mechanism by which high PGAM5 expression promotes airway inflammation by mediating HMGB1 release in TDI-induced asthma, identifying the therapeutic effects of targeting PGAM5 in steroid-insensitive asthma model.
先前的研究表明，高迁移率族蛋白B1（HMGB1）水平升高并释放到细胞外，参与了甲苯二异氰酸酯（TDI）诱导的激素抵抗性哮喘的发病机制。支气管上皮细胞的线粒体功能障碍是TDI哮喘的一个关键特征。然而，线粒体功能障碍是否在哮喘中调节HMGB1释放仍不清楚。本研究的目的是探讨线粒体蛋白磷酸甘油酸变位酶家族成员5（PGAM5）是否能调节TDI诱导的哮喘中HMGB1的释放。分析来自基因表达综合数据库（GEO）的基因表达数据系列（GSE）67472，以比较哮喘患者和健康个体气道上皮细胞中PGAM5的水平。雄性C57BL/6J小鼠用TDI致敏和激发，并用PGAM5抑制剂LFHP-1c治疗。在体外，人支气管上皮细胞（16HBE）用TDI-人血清白蛋白（HSA）刺激，并用PGAM5 siRNA预处理。在本研究中，我们观察到哮喘患者和TDI诱导的哮喘小鼠的气道上皮细胞中PGAM5表达显著增加。在体内，抑制PGAM5可显著改善气道炎症、气道高反应性（AHR）和黏液高分泌，同时降低TDI暴露小鼠肺组织中HMGB1的表达和释放。在体外，抑制PGAM5可改善线粒体功能障碍，减少线粒体中活性氧（ROS）的产生。敲低PGAM5可减少TDI诱导的哮喘中细胞色素C（cyt c）的释放和HMGB1的释放。机制上，TDI-HSA处理的支气管上皮细胞中的PGAM5显著增加了Bax在S184位点的去磷酸化，促进Bax向线粒体的转位，并导致TDI诱导的哮喘中线粒体依赖性凋亡的激活。基于这些发现，我们揭示了一种新的调节机制，即高PGAM5表达通过介导TDI诱导的哮喘中HMGB1的释放来促进气道炎症，确定了靶向PGAM5在激素抵抗性哮喘模型中的治疗作用。
