巨噬细胞来源外泌体ANPEP调控肺泡上皮细胞坏死性凋亡促进脓毒症急性肺损伤的机制研究

脓毒症急性肺损伤（ALI）是危重症患者死亡的主要原因。外泌体作为细胞间信息传递的介质在炎症损伤中扮演重要角色。我们前期研究发现脓毒症ALI患者血浆和脓毒症ALI小鼠血浆及肺泡灌洗液中外泌体ANPEP含量增高；LPS刺激巨噬细胞（Mφ）分泌大量外泌体ANPEP，后者可促进肺泡上皮细胞（AEC）坏死性凋亡。目前还未见外泌体ANPEP调控ALI作用机制的研究。我们推测：脓毒症时Mφ释放的外泌体ANPEP，作用于AEC表面的TNFR和TLR4，激活下游信号通路，介导RIP1/RIP3坏死凋亡，促进急性肺损伤。本项目拟进一步阐明脓毒症时Mφ释放的外泌体ANPEP，通过细胞间信息传递介导AEC坏死性凋亡及机制；从临床样本和动物水平评估外泌体ANPEP在脓毒症ALI中的临床应用价值。本项目将揭示外泌体ANPEP在脓毒症ALI发生发展中的作用，从外泌体细胞信号传递方面为脓毒症ALI的诊断与治疗提供新策略。

Sepsis-related acute lung injury (ALI) remains a major cause of mortality in critically ill patients. Exosomes are involved in inflammatory processes that play a pivotal role in intercellular communication under physiological and pathological conditions. In our previous study, we found that ANPEP increased in plasma exosomes from patients with septic ALI, as well as in exosomes of plasma and bronchoalveolar lavage fluid (BALF) from mouse models of septic ALI. We also found that LPS stimulated macrophages (Mφ) could secrete a large amount of exosomes- ANPEP, which promoted necroptosis of alveolar epithelial cells (AEC). So far, there has been no report on the effect and mechanism of exosomes-ANPEP regulating ALI. We speculate that，exosomes-ANPEP released by M φ act on TNFR /TLR4 of AEC to activate downstream signal pathways, mediate RIP1/RIP3 necroptosis, and promote acute lung injury in sepsis. The purpose of this project is to elucidate the mechanism of regulating necroptosis of AEC by cell intercellular communication, and to evaluate the clinical value of exosomes ANPEP in septic animal model and blood samples of ALI patients. We expect this project would explore the role of plasma exosomes ANPEP in the occurrence and development of septic ALI, and provide a new strategy for the diagnosis and treatment of septic ALI from the aspect of exosome cell signal transduction.