补体替代途径调控平滑肌细胞稳态及炎症反应促进主动脉夹层的发生机制研究

Thoracic aortic dissection (TAD) is one of cardiovascular emergencies which have high mortality. Recent studies have found that imbalance of smooth muscle cell(SMC) homeostasis（phenotype change, survival, proliferation) and inflammatory response contribute to TAD formation. The immune and inflammatory system regulate vascular wall homeostasis, including the complement system. Our previous study found that the level of plasma complement 3a and complement 5a increased significantly in aortic dissection patients, the expression of its receptors also increased significantly in aorta tissue of aortic dissection patients, and also its receptor mainly expressed in smooth muscle cell and inflammatory cell. Furthermore, we proved that alternative pathway of complement cascade promote aortic dissection formation. However the detailed role of complement in aortic dissection formation remains unclear. Previous study supported by NSFC Youth Program, we showed the mechanism of complement 5a on inflammatory response, and inflammation also involved in the TAD formation. Therefore, we hypothesized that complement system may regulate SMC homeostasis and inflammatory response and promote the development of TAD. In the present study, we will induce aortic dissection formation in wild type and complement related gene(C4, Factor B, C3aR and c5aR) knockout mice, combined with bone marrow transplantation, ultrasonography, pathology, cellular and molecular biology technique, to clarify the role of complement system in aortic dissection formation. Our results indicate a new and potentially promising therapeutic application of complement system related inhibitor to the treatment of aortic dissection.

胸主动脉夹层(TAD)是死亡率最高的心血管急症之一。平滑肌细胞(SMC)稳态失衡及炎症反应是促进TAD发生的重要机制。免疫炎症系统调节血管壁稳态，包括补体系统。我们前期发现TAD患者血浆补体C3a、C5a明显升高，其受体在病变组织中表达也明显增高，且主要表达在SMC与炎症细胞中。进而在小鼠TAD模型中证实，补体系统主要通过替代途径激活，最终引起TAD，但具体机制不明。前期在青年基金资助下，我们探讨了补体C5a调节炎症反应的机制，而炎症也参与TAD发生发展。由此假设：补体替代途径调节SMC稳态促进炎症反应，同时补体系统激活也可直接引起过度的炎症反应，促进TAD发生发展。本研究拟在补体相关基因(C4、FB、C3aR、C5aR)敲除小鼠中诱导TAD模型，结合骨髓移植、病理、细胞及分子生物学技术，明确补体替代途径如何影响SMC稳态(表型转化、存活、增殖等)及炎症反应，促进TAD发生发展的具体机制。

胸主动脉夹层(TAD)呈血管壁退行性变及扩张，破裂后死亡率达90%。平滑肌细胞(SMC)稳态失衡及炎症反应是促进AAD发生的重要机制。近年来发现补体系统参与TAD的发生发展过程，但补体系统如何激活，进而影响免疫炎症系统调节血管壁稳态机制尚不清楚。本课题拟阐明补体系统通过激活免疫炎症及血管平滑肌细胞稳态促进主动脉夹层的机制。我们首先构建两种主动脉瘤/夹层模型，BAPN诱导的小鼠主动脉夹层模型及FBN1C1039G突变小鼠胸主动脉瘤模型，以上述模型为基础进行了补体系统在TAD发生发展过程中的具体机制研究；其次，我们在主动脉夹层动脉瘤患者及BAPN诱导的小鼠血清中确认补体活化片段（C3a, C5a）水平明显升高，并利用补体相关基因(C4、FB、C3aR、C5aR)敲除小鼠中诱导AAD模型，结合血清回输实验，明确是补体替代途径参与TAD的发生发展，同时我们利用FBN1C1039G突变小鼠(马凡综合征) 明确是阻断替代途径将减少主动脉瘤的发生；进而，我们发现在主动脉夹层动脉瘤患者及BAPN诱导的小鼠主动脉组织中发现补体活化分子C3a受体与C5a受体主要表达在炎症细胞及平滑肌细胞，补体相关基因(FB、C3aR、C5aR)敲除小鼠中诱导TAD模型，发现炎症细胞浸润明显减少；最后，我们证实补体系统在主动脉夹层发生发展过程中主要通过平滑肌细胞C3a-C3aR信号通路影响MMP-2活性发挥作用的。总之，我们在此项课题的支持下发现了补体系统通过激活替代途径激活炎症反应及血管壁稳态参与TAD的发生发展；同时我们还发现补体活化分子C3a-C3aR信号通路，通过影响平滑肌细胞MMP-2促进TAD的发生发展的具体机制，这为C3阻断药物在TAD治疗应用提供新的理论依据。我们分别以上工作为基础发表5篇SCI文章（J Immunol 2018，Exp Cel Res 2018，JCMM 2019，Can Imm Imm 2019，Cel Immun 2020）还有一篇文章目前正在撰写中。

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