The Lung as a Source of Inflammation in Sepsis

在美国，败血症是发病率和死亡率的主要原因，每年约有70万人死亡 年。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，死亡最常见的原因是未解决的脓毒症或多发性 器官衰竭。以前的研究主要集中在败血症的全身性表现如何影响肺部。 在这里，我们将研究肺如何在脓毒症期间对心脏有害。巨噬细胞迁移 抑制因子(MIF)是脓毒症中的重要介质，近年来被证明是一种心脏事件。 抑制因子，并在与脓毒症相关的死亡率中发挥关键作用。我们的研究表明 在脓毒症期间，MIF在肺内蓄积，并被释放到肺循环中 与心脏功能障碍的发作同时发生。因此，我们假设在脓毒症期间， 肺作为炎症器官，在一段时间内向肺泡和肺循环释放MIF。 依赖的态度。从肺释放的MIF直接进入冠脉循环，在那里它 与心肌细胞相互作用，导致心脏功能障碍。为了解决这一假设，该提案 有三个特定的目标：1)确定肺中MIF的细胞来源，并确定其发生的时间 脓毒症时肺泡堆积和释放到肺循环中；2)确定机制 参与肺来源的、MIF依赖的心肌细胞功能障碍；以及3)确定 脓毒症时特异性抑制MIF通过减少心肌细胞来保护心功能不全 激活。感染性腹膜炎和重组MIF，在正常动物和MIF基因阳性的动物中 已被删除(或完全删除，或在特定细胞类型中)将被用于检测MIF介导的 脓毒症时肺和心脏之间的相互作用。使用我们特定的MIF抑制剂将MIF降至最低 活性，或通过细胞阻断或耗尽参与产生肺源性MIF的细胞，受益于 在脓毒症期间减少心肌细胞的MIF负荷将被确定。因此，我们预计 研究将确定肺MIF所致心功能不全的作用和机制 脓毒症，并建议具体的策略，以抑制其产生和释放从肺。

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.