He Sirong, Tian Ruoyuan, Zhang Xinying, Yao Qingmei, Chen Quan, Liu Bicui, Liao Lele, Gong Yuxuan, Yang Hua, Wang Dan
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, PR China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
Clin Immunol. 2023 May;250:109293. doi: 10.1016/j.clim.2023.109293. Epub 2023 Mar 17.
The role of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) in alveolar macrophages(AMs) polarization homeostasis is closely associated with airway remodeling in COPD, but the definite mechanism remains unclear. In this study, elevated percentage of M1-type AMs and the expression of functionally cytokines were found in COPD patients and mice, which closely related to the disease severity. PPARγ was markedly up-regulated in M2-type AMs and down-regulated in M1-type AMs, and was associated with disease severity in COPD. Co-cultured with M1- or M2-type AMs promoted the epithelial-mesenchymal transition (EMT) of airway epithelial cells and the proliferation of airway smooth muscle cells. Moreover, airway remodeling and functional damage were observed in both IL4R COPD mice with runaway M1-type AMs polarization and TLR4 COPD mice with runaway M2-type AMs polarization. Cigarette extract (CS) or lipopolysaccharide (LPS) stimulated PPARγ AMs showed more serious polarization disorder towards M1, as well as CS induced PPARγ COPD mice, which led to more severe airway inflammation, lung function damage, and airway remodeling. Treatment with PPARγ agonist significantly improved the polarization disorder and function activity in CS/LPS stimulated-AMs by inhibiting the JAK-STAT, MAPK and NF-κB pathways, and alleviated the airway inflammation, restored the lung function and suppressed airway remodeling in CS induced-COPD mice. Our research demonstrates that polarization homeostasis of AMs mediated by PPARγ has the protective effect in airway remodeling, and may be a novel therapeutic target for the intervention and treatment of airway remodeling in COPD.
过氧化物酶体增殖物激活受体γ（PPARγ）在肺泡巨噬细胞（AMs）极化稳态中的作用与慢性阻塞性肺疾病（COPD）的气道重塑密切相关，但其确切机制仍不清楚。在本研究中，在COPD患者和小鼠中发现M1型AMs百分比升高以及功能性细胞因子的表达，这与疾病严重程度密切相关。PPARγ在M2型AMs中显著上调，在M1型AMs中下调，并且与COPD的疾病严重程度相关。与M1型或M2型AMs共培养促进了气道上皮细胞的上皮-间质转化（EMT）和气道平滑肌细胞的增殖。此外，在M1型AMs极化失控的IL4R COPD小鼠和M2型AMs极化失控的TLR4 COPD小鼠中均观察到气道重塑和功能损害。香烟提取物（CS）或脂多糖（LPS）刺激的PPARγAMs向M1型的极化紊乱更严重，CS诱导的PPARγCOPD小鼠也是如此，这导致更严重的气道炎症、肺功能损害和气道重塑。用PPARγ激动剂治疗通过抑制JAK-STAT、MAPK和NF-κB途径显著改善了CS/LPS刺激的AMs中的极化紊乱和功能活性，并减轻了CS诱导的COPD小鼠的气道炎症、恢复了肺功能并抑制了气道重塑。我们的研究表明，由PPARγ介导的AMs极化稳态在气道重塑中具有保护作用，并且可能是干预和治疗COPD气道重塑的新治疗靶点。
