The Lung as a Source of Inflammation in Sepsis

描述(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，死亡最常见的原因是未解决的脓毒症或多器官衰竭。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。巨噬细胞移动抑制因子(MIF)是脓毒症发病过程中的重要介质，近年来发现它是一种心脏抑制因子，在脓毒症相关死亡中起重要作用。我们的研究表明，在脓毒症期间，MIF在肺内蓄积，并在心功能不全发生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。为了解决这一假说，该提议有三个具体目标：1)确定MIF在肺中的细胞来源，并确定其在脓毒症时肺泡蓄积和释放到肺循环的时间；2)确定肺衍生的、MIF依赖的心肌细胞功能障碍的机制；以及3)确定在脓毒症期间特异性抑制MIF是否通过减少心肌细胞的激活来保护心脏功能不全。脓毒症腹膜炎和重组MIF，在正常动物和MIF基因缺失的动物(完全或特定细胞类型)中，将被用来研究MIF在脓毒症过程中介导的心肺之间的相互作用。使用我们特定的MIF抑制剂将MIF活性降至最低，或者通过细胞阻断或耗尽参与肺源性MIF生成的细胞，将确定在脓毒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所致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.