血小板P选择素在肾移植术后重度肺损伤中的作用机制

In an immunocompetent host, the excess infiltration of polymorphonuclear (PMN) in the lung is a key factor in severe lung injury induced by infection. The PMN infiltration in the lung in a renal transplant recipient suffering from pulmonary infection, an immunocompromised host, is significantly fewer than in an immunocompetent host, but, the extent of lung injury is more serious. The mechanism by which it takes place, however, remains unknown. Our research group has preliminarily discovered that the P-selectin expression on the surface of platelets increases after administration of immunosuppressive drugs in renal transplantation mice, and the extent of lung injury induced by infection decreases after the depletion of platelets using a specific antibody. In recent years, numerous studies have confirmed that platelet plays important role not only in coagulation function but also in immune reaction. Thus we further hypothesize that when the lung is infected after renal transplantation, a large number of abnormally functioning platelets adhere to the surface of vascular endothelial cell via activation through the combination of P-selectin, PSGL-1, and GPIb, leading to the release of inflammatory cytokines, thus breaking the air-blood barrier with the involvement of immune cells, and ultimately resulting in severe lung injury. To test this hypothesis, our project proposes the use of the sever lung injury model induced by klebsiella pneumoniae following renal transplantation with P-selectin gene knockout mice to investigate the effect of platelet on lung injury by intravital microscopy imaging. Then we use bone marrow transplantation and antibody blocking method to explore the regulation of platelet P-selectin pathway under renal transplantation with pulmonary infection. We hope to contribute to the ongoing pursuit of novel approaches in both the prevention and treatment of lung injury by further defining the role of platelets in the context of a severe lung injury status post renal transplantation.

在免疫正常宿主，肺部感染时，过度中性粒细胞（PMN）肺内浸润是导致重度肺损伤的关键因素。肾移植患者免疫受限，感染时PMN肺内浸润明显较少，但肺损伤程度反而更重，机制不明。本课题组发现：在使用抗排斥药物肾移植小鼠，血小板表面P选择素表达增高，用抗体耗竭血小板后，感染诱发的肺损伤较血小板正常组显著减轻。结合血小板在炎症反应中发挥关键作用的研究进展，我们推测：肾移植术后肺部感染时，P选择素介导血小板在肺微血管床大量聚集，活化后释放大量活性介质，导致气血屏障通透性显著增加，在免疫细胞的参与下，发生重度肺损伤。本项目选用P选择素基因敲除小鼠行肾移植，经气道接种细菌建立感染诱发的重度肺损伤模型，借助活体荧光显微镜成像技术，研究血小板和PMN在肺内聚集的特征，及其对肺通透性的作用；使用骨髓移植和抗体封闭方法，阐明血小板P选择素的信号通路。明确血小板在肾移植重度肺损伤中作用机制，为其预防和治疗提供新思路。

急性肺损伤是器官移植术后常见的并发症之一，能够严重危害人类生命健康，人们对急性肺损伤的发生机制目前仍未完全了解。本研究围绕肺部炎症和急性肺损伤的发生机制这一关键科学问题展开研究，着重分析了血小板P选择素在肺部炎症和损伤发生过程中的扮演的角色和生物学意义，揭示其对血小板聚集、肺内炎性浸润等产生的影响；阐明了血小板通过调控P选择素参与肺部“炎症-急性重度损伤”的机制及意义。通过分子-细胞-动物整体水平的研究，证实了血小板P选择素在急性重度肺损伤中主要作用机理，为深入理解肺部“免疫-炎症-急性重度损伤”作用模式和器官移植术后肺感染所致肺损伤的发病机制提供新的线索。相关研究成果已发表SCI论文10余篇，在投SCI论文1篇，培养研究生4名。

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