MIF在调控心梗后心肌炎症反应的作用机制及其靶向干预研究

Myocardial infarction (MI) is a leading cause of heart failure and mortality worldwide and its prevalence is expected to increase with population aging. Innate immune response following MI is a necessary step for proper healing. However, excessive systemic and regional inflammatory responses lead to adverse outcome with high risk of heart rupture and severe cardiac dilatation and failure. Therefore, successful modulation of acute inflammatory responses following MI requires more precise understanding of the mechanisms involved. A great challenge to modern cardiology is to limit heart damage and preserve function after MI. Recently, our serial pioneering studies have identified that macrophage migration inhibitory factor (MIF), a well known multifunctional cytokine, plays a pivotal role in modulating post-infarct inflammation and MIF derived from different cellular sources has distinct action on post-infarct inflammation and healing. In this project, we will systemically study the underlying mechanisms by which MIF regulates post-MI inflammation and explore the therapeutic potential. First, using genetically modified mouse strains i.e. MIF gene knockout (MIFKO) mice, in vivo MI model and various methodologies, we will study how MIF activates systemic inflammation post MI. Second, applying bone marrow transplant technology, we will generate chimeric mice with MIF gene either only expressed in the heart (WT-KO) or only expressed in inflammatory cells (KO-WT). Using these chimeric mice together with MIFKO and wild type (WT) control mice, we will distinguish the role of MIF from different cellular sources in promoting regional inflammation after MI. Third, taking advantages of these genetic modified strains, we will investigate the potential mechanisms of cardiac- or leukocyte-derived MIF in regulating post-infarct healing and fibroblast biology. Finally, we will test therapeutic potential of anti-MIF strategies targeting on two different waves of MIF release following MI in protecting the heart from severe ischemic injury and preventing adverse cardiac remodeling. Results from this project will largely advance our knowledge and understanding in the role of MIF in modulating post-infarct inflammation and will provide critical information for the design of anti-inflammatory strategy targeting on MIF following acute MI.

心肌梗塞是世界范围内导致心力衰竭及心源性死亡的首要病因。心梗后的自身免疫反应是损伤心肌愈合的关键要素。然而，过度的全身及局部的炎症反应将导致心脏破裂，心室扩张及心力衰竭。因此，成功调控心梗后的炎性反应需要对其机制的精确理解。近年来，本申请人的系列研究发现巨噬细胞移动抑制因子MIF在介导心梗后的炎性反应方面具有重要作用，且不同细胞来源的MIF对炎性反应及愈合过程有着截然不同的影响。本课题拟采用基因干预小鼠品系并通过骨髓移植技术构建嵌合体小鼠。在在体心梗模型中，通过检测全身及心肌的各项炎性指标，在器官、细胞以及分子水平研究MIF介导、调控心梗后全身及局部炎症反应的作用机理。同时研究心源性MIF对损伤心肌愈合的调控机制。采用针对心梗后不同MIF高峰的抗MIF治疗策略，对心肌损伤，炎性反应程度，愈合进程，心脏破裂的风险及远期心脏重塑进行系统评估，为缺血心肌的保护探索更加有效的治疗措施。

心肌梗死是导致心力衰竭及心源性死亡的首要病因。精准调控全身及局部的炎症反应影响心肌梗死预后。本研究以临床实际问题为出发点，结合临床研究和动物实验研究MIF对心肌梗死后炎症调节作用及机制。首先利用病例-对照研究分析新疆人群冠状动脉疾病及急性冠脉综合征患者中MIF SNP分布及表达差异，发现冠状动脉疾病及急性冠脉综合征患者血浆MIF水平升高，MIF基因多态性（rs755622）与中国新疆人群冠状动脉疾病及急性冠脉综合征的患病风险显著相关。MIF基因rs755622位点C等位基因是冠状动脉疾病及急性冠脉综合征的危险因素，且携带MIF基因多态性rs755622 C等位基因者，血浆MIF水平明显增高；随后利用病例-对照研究分析发现高入院MIF水平与ST段抬高型心肌梗死伴代谢综合征患者的远期不良预后相关，高入院MIF水平对ST段抬高型心肌梗死伴代谢综合征患者的远期不良心脑血管事件（MACCE）发生具有预测作用，且预测效能明显优于其他传统预测指标；利用野生型及MIF基因敲除小鼠建立心肌梗死模型，研究MIF在心肌梗死后第一阶段在整体水平发挥促进炎症反应的作用，发现MIF促进循环系统中白细胞升高，炎症因子表达增加，促进脾脏炎性细胞动员及促炎性Ly-6Chigh单核细胞释放入血，促进外周血单核细胞中促炎性Ly-6Chigh单核细胞增多及心脏局部的炎性细胞浸润增加。利用嵌合体制备技术，产生只有体细胞表达MIF而骨髓和炎症细胞不表达MIF的WTKO小鼠以及只有骨髓和炎症细胞表达MIF而体细胞不表达MIF的KOWT小鼠，建立心肌梗死模型，研究不同细胞源性MIF在心肌梗死后系统性及局部炎症反应中的不同作用，发现炎性细胞源性MIF促进系统性炎症反应，促进炎症因子表达，增加循环促炎性Ly-6Chigh单核细胞；炎性细胞源性MIF促进脾脏促炎性Ly-6Chigh单核细胞动员，促进心脏局部炎性细胞浸润，影响心肌梗死后局部炎症反应。通过对心肌梗死后的两个MIF高峰进行中和治疗发现降低心梗后第一及第二MIF高峰均能够减轻心肌梗死后全身及局部炎性反应，降低心脏破裂发生率，以MIF高峰为靶点的抗MIF治疗可以显著改善心肌梗死的预后。