Lin Chin-Kuo, Chen Zheng-Wei, Lin Yu-Hao, Yang Cheng-Ta, Shi Chung-Sheng, Lin Chieh-Mo, Huang Tzu Hsiung, Lu Justin Ching Hsien, Lu Kwok-Tung, Yang Yi-Ling
Division of Pulmonary Infection and Critical Care, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi 20401, Taiwan.
Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Int J Mol Sci. 2025 Aug 5;26(15):7571. doi: 10.3390/ijms26157571.
Fat embolism is a critical medical emergency often resulting from long bone fractures or amputations, leading to acute respiratory distress syndrome (ARDS). The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is activated by reactive oxygen species and tissue damage, contributing to inflammatory responses. This study examines the role of NLRP3 in fat embolism-induced ARDS and evaluates the therapeutic potential of MCC950, a selective NLRP3 antagonist. Fat embolism was induced by fatty micelle injection into the tail vein of Sprague Dawley rats. Pulmonary injury was assessed through lung weight gain as an edema indicator, NLRP3 expression via Western blot, and IL-1β levels using ELISA. Histological damage and macrophage infiltration were evaluated with hematoxylin and eosin staining. Fat embolism significantly increased pulmonary NLRP3 expression, lipid peroxidation, IL-1β release, and macrophage infiltration within four hours, accompanied by severe pulmonary edema. NLRP3 was localized in type I alveolar cells, co-localizing with aquaporin 5. Administration of MCC950 significantly reduced inflammatory responses, lipid peroxidation, pulmonary edema, and histological damage, while attenuating MAPK cascade phosphorylation of ERK and Raf. These findings suggest that NLRP3 plays a critical role in fat embolism-induced acute respiratory distress syndrome, and its inhibition by MCC950 may offer a promising therapeutic approach.
脂肪栓塞是一种严重的医疗急症，通常由长骨骨折或截肢引起，可导致急性呼吸窘迫综合征（ARDS）。含NOD样受体吡啉结构域3（NLRP3）炎性小体是先天免疫的关键调节因子，可被活性氧和组织损伤激活，促进炎症反应。本研究探讨NLRP3在脂肪栓塞诱导的ARDS中的作用，并评估选择性NLRP3拮抗剂MCC950的治疗潜力。通过将脂肪微滴注入Sprague Dawley大鼠尾静脉诱导脂肪栓塞。通过肺重量增加作为水肿指标评估肺损伤，通过蛋白质印迹法检测NLRP3表达，使用酶联免疫吸附测定法检测IL-1β水平。用苏木精和伊红染色评估组织学损伤和巨噬细胞浸润。脂肪栓塞在4小时内显著增加肺NLRP3表达、脂质过氧化、IL-1β释放和巨噬细胞浸润，并伴有严重肺水肿。NLRP3定位于I型肺泡细胞，与水通道蛋白5共定位。给予MCC950可显著降低炎症反应、脂质过氧化、肺水肿和组织学损伤，同时减弱ERK和Raf的MAPK级联磷酸化。这些发现表明，NLRP3在脂肪栓塞诱导的急性呼吸窘迫综合征中起关键作用，MCC950对其的抑制作用可能提供一种有前景的治疗方法。
