The Lung as a Source of Inflammation in Sepsis

描述（由申请人提供）：在美国，败血症是每年约70万人发病和死亡的主要原因。脓毒症患者的呼吸功能障碍很常见。然而，这些患者的肺功能通常可以得到充分的支持，死亡通常是由于未解决的败血症或多器官衰竭。以前的研究主要集中在败血症的全身表现如何影响肺部。在这里，我们将检查在败血症期间肺是如何对心脏有害的。巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是脓毒症的重要介质，近年来被证明是一种心脏抑制因子，并在脓毒症相关的死亡率中发挥关键作用。我们的研究表明，MIF在败血症期间在肺内积累，并在心功能障碍发作的同时释放到肺循环中。因此，我们假设在脓毒症期间，肺作为炎症器官，以时间依赖的方式将MIF释放到肺泡和肺循环中。从肺部释放的MIF直接进入冠状动脉循环，在那里它与心肌细胞相互作用，导致心功能障碍。为了解决这一假设，该提案有三个具体目标：1)确定肺中MIF的细胞来源，确定其在脓毒症期间肺泡积聚和释放到肺循环的时间；2)确定肺源性、mif依赖性、心肌细胞功能障碍的机制；3)确定MIF在败血症期间的特异性抑制是否通过降低心肌细胞活化来保护心功能障碍。脓毒性腹膜炎和重组MIF，在正常动物和MIF基因被删除的动物中（无论是完全删除，还是在特定细胞类型中），将用于检查脓毒症期间MIF介导的肺和心脏之间的相互作用。使用我们的特异性MIF抑制剂来最小化MIF活性，或通过细胞阻断或消耗参与肺源性MIF生成的细胞，将确定在败血症期间减少心肌细胞MIF负担的益处。因此，我们期望这项研究将确定脓毒症期间肺- mif衍生的心功能障碍的作用和机制，并提出抑制其产生和从肺释放的具体策略。

DESCRIPTION (provided by applicant): In the US, sepsis is a major cause of morbidity and mortality occurring in around 700,000 individuals per year. Respiratory dysfunction in individuals with sepsis is common. However, lung function in these patients can often be adequately supported, and mortality most often results from unresolved sepsis or multiple organ failure. Previous studies have focused on how systemic manifestations of sepsis affect the lung. Here, we will examine how the lung can be detrimental to the heart during sepsis. Macrophage migration inhibitory factor (MIF), an important mediator in sepsis, has been shown recently to be a cardiac depressant factor, and to play a critical role in the mortality associated with sepsis. Our studies suggest that MIF accumulates within the lung during sepsis and is released into the pulmonary circulation contemporaneous with the onset of cardiac dysfunction. Therefore, we hypothesize that during sepsis, the lung acts as an inflammatory organ, releasing MIF into the alveolae and the pulmonary circulation in a time dependent manner. MIF released from the lung passes directly into the coronary circulation where it interacts with the cardiac myocytes causing cardiac dysfunction. To address this hypothesis, the proposal has three specific aims: 1) To identify the cellular source of MIF in the lung, and determine the timing of its alveolar accumulation, and release into the pulmonary circulation during sepsis; 2) To identify mechanisms involved in lung-derived, MIF-dependent, cardiac myocyte cell dysfunction; and 3) To determine whether specific inhibition of MIF during sepsis protects against cardiac dysfunction by reducing cardiac myocyte activation. Septic peritonitis and recombinant MIF, in normal animals and in animals in which the MIF gene has been deleted (either totally, or in specific cell types) will be used to examine the MIF mediated interactions between the lung and heart during sepsis. Using our specific MIF inhibitor to minimize MIF activity, or by cell blockade or depletion of cells involved in the generation of lung-derived MIF, the benefit of reducing the MIF burden on cardiac myocytes during sepsis will be determined. Thus we expect that the study will identify the role and mechanisms involved in pulmonary-MIF derived cardiac dysfunction during sepsis and suggest specific strategies to inhibit its production and release from the lung.