The role of MIF in myocardial ischemic preconditioning

细胞因子是免疫应答中的良好表征的介质，已知其参与心血管疾病的发生和进展。巨噬细胞移动抑制因子（macrophage migration inhibitor factor，MIF）是最早发现的细胞因子之一。它是一种具有趋化因子样活性的结构独特的炎性细胞因子，作为先天性和获得性免疫应答的关键介质。MIF是初始免疫应答的上游调节因子，其引发并加重各种慢性和急性炎症性疾病，例如动脉粥样硬化和败血症。以前已经观察到MIF对心脏的有害作用，例如诱导心肌细胞凋亡和脓毒症中的收缩功能障碍。相比之下，越来越多的证据表明，在长时间缺氧和/或心肌缺血/再灌注（I/R）期间，MIF分别具有时间依赖性的双重作用模式。事实上，新出现的证据表明，在I/R的临床环境中，MIF的总体心脏保护作用对于心肌梗死患者或接受心脏手术的患者尤其相关。在这种情况下，我们已经提供了第一个证据，表明围手术期MIF释放对心脏手术后心肌I/R患者器官功能障碍的发生具有重要意义。迄今为止，已经确定了几种保护机制和信号通路，以在心脏缺血和再灌注期间提供MIF介导的心脏保护。预处理已多次被证明是一种有效的心肌缺血保护策略。这种现象通过持续数小时的复杂和多个快速作用的信号步骤在心肌中建立瞬时保护性细胞状态。鉴于MIF诱导的心脏保护作用在本质上与缺血诱导的预处理和我们自己的初步研究结果（表明预处理诱导的MIF释放和心脏保护激酶的激活之间存在关联）具有可比性，因此需要对MIF在预处理中的功能作用进行更全面的研究。由于缺血预处理属于罕见的有前途的保存策略，这是众所周知的，赋予心脏保护，我们的目的是调查的功能作用的MIF在潜在的途径。我们预测能够揭示这种多效性细胞因子在预处理复杂相互作用中的潜在作用，并发现可能影响暴露于心肌I/R的患者中MIF分泌程度的潜在因素。

Cytokines are well-characterized mediators in the immune response, which are known to be involved in the development and progression of cardiovascular diseases. Macrophage migration inhibitory factor (MIF) belongs to the first cytokines that has been discovered. It is a structurally unique inflammatory cytokine with chemokine-like activities that acts as a key mediator of the innate and acquired immune response. MIF is an upstream regulator of the initial immune response that initiates and exacerbates various chronic and acute inflammatory disorders such as atherosclerosis and sepsis. Detrimental effects of MIF on the heart such as induction of apoptosis in cardiomyocytes and contractile dysfunction in sepsis have been previously observed. In contrast, increasing evidence suggests a time-dependent dual mode of action of MIF during prolonged hypoxia and/or myocardial ischemia/reperfusion (I/R), respectively. In fact, emerging evidence suggests an overall cardioprotective role of MIF within the clinical setting of I/R that becomes in particular relevant for patients with myocardial infarction or for those patients that undergo cardiac surgery. In this context, we already provided first evidence about the significance of perioperative MIF release on the occurrence of organ dysfunctions in cardiac surgical patients with following myocardial I/R. To date, several protective mechanisms and signaling pathways have been identified to provide MIF mediated cardioprotection during ischemia and reperfusion in the heart. Preconditioning has repeatedly been shown to be a powerful strategy to effect myocardial protection against ischemia. This phenomenon establishes a transient protective cellular state in the myocardium by complex and multiple fast-acting signaling steps lasting for few hours. Given the fact that MIF-induced cardioprotective effects are comparable in nature to those that have been identified for ischemic-induced preconditioning and our own preliminary findings that indicated an association between preconditioning-induced MIF release and the activation of the cardioprotective kinases, demonstrate the need for a more comprehensive investigation about the functional role of MIF in preconditioning. Since ischemic preconditioning belongs to the rare promising preservation strategies, which are known to confer cardioprotection, we aim to investigate the functional role of MIF in the underlying pathways. We predict to be able to reveal the potential role of this pleiotropic cytokine in the complex interplay in preconditioning and to discover potential factors, which might influence the extent of MIF secretion in patients exposed to myocardial I/R.