Proinflammatory macrophage polarization is driven by NOX4/PPARγ axis-mediated oxidative-inflammatory crosstalk in CEES-induced lung injury

作者：Meng Cao, Zhen Wang, Hao Wu, Rui Liu, Deqin Kong, Jiangzheng Liu, Zhao Wang, Xiaodi Zhang, Xinyue Xu, Tianpeng Gao, Zi Long, Weihua Yu, Chunxu Hai · 发表于：International Immunopharmacology · 年份：2025 · DOI：10.1016/j.intimp.2025.115701 · 被引用次数：3 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Eicosanoids and Hypertension Pharmacology、Nitric Oxide and Endothelin Effects

Sulfur mustard (SM), a well-known vesicant chemical warfare agent, induces acute lung injury through mechanisms that remain incompletely understood. This study aimed to delineate the specific contributions of oxidative stress and inflammatory pathways in SM-mediated pulmonary damage. A C57BL/6 J mouse model exposed to aerosolized 2-chloroethyl ethyl sulfide (CEES, a sulfur mustard analogue) and an in vitro macrophage model were established. Evaluations were conducted using pulmonary function tests, transcriptome sequencing, RT-qPCR, Western blot, and ELISA. Functional validation was performed through pharmacological activation of peroxisome proliferator-activated receptor γ (PPARγ) and application of a NADPH oxidase 4 (NOX4) inhibitor. CEES exposure was found to induce airway obstruction in mice, accompanied by alveolar structural damage and significant infiltration of pro-inflammatory macrophages. Levels of ROS and MDA were elevated in lung tissues, and antioxidant enzyme activity showed an initial compensatory increase followed by exhaustion. Increased levels of TNF-α and IL-6, together with decreased levels of Arg-1 and IL-10, were observed in serum and lung homogenates. Transcriptomic analysis and subsequent validation experiments indicated that CEES up-regulated the expression of NOX4 and suppressed PPARγ. In vitro, overexpression of PPARγ promoted the expression of IL-10, Arg-1, and CD206, while suppressing TNF-α, IL-6, and iNOS. Inhibition of NOX4 expression reduced RO...