The Lung as a Source of Inflammation in Sepsis

肺部是脓毒症炎症的来源

• 批准号: 7093259
• 负责人: EDMUND J MILLER
• 金额: $ 41.38万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093259
• 关键词: CD44 molecule; animal mortality; cardiac myocytes; cytoprotection; echocardiography; genetically modified animals; inflammation; inhibitor /antagonist; laboratory mouse; laboratory rat; lung alveolus; lung disorder; macrophage; migration inhibition factor; mitogen activated protein kinase; myocardium disorder; neutralizing antibody; neutrophil; pulmonary circulation; recombinant proteins; respiratory insufficiency /failure; septicemia

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.

描述（由申请人提供）：在美国，败血症是每年约700，000人发病和死亡的主要原因。呼吸功能障碍在脓毒症患者中很常见。然而，这些患者的肺功能通常可以得到充分的支持，死亡率最常见的原因是未解决的脓毒症或多器官衰竭。以往的研究主要集中在脓毒症的全身表现如何影响肺部。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（macrophagemigrationinhibitoryfactor，MIF）是脓毒症的重要介质，近年来研究表明，MIF是一种心脏抑制因子，在脓毒症的死亡率中起重要作用。我们的研究表明，MIF在脓毒症期间在肺内积聚，并在心功能不全发作的同时释放到肺循环中。因此，我们假设在脓毒症期间，肺充当炎症器官，以时间依赖性方式将MIF释放到肺泡和肺循环中。从肺释放的MIF直接进入冠状动脉循环，在那里它与心肌细胞相互作用，引起心脏功能障碍。为了解决这一假设，该提案有三个具体目标：1）确定MIF在肺中的细胞来源，并确定其肺泡积聚的时间，并在脓毒症期间释放到肺循环中; 2）确定肺源性、MIF依赖性、心肌细胞功能障碍的机制;和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活化来保护心脏功能障碍。将使用正常动物和MIF基因缺失（完全缺失或特定细胞类型缺失）的动物中的脓毒性腹膜炎和重组MIF来检查脓毒症期间肺和心脏之间的MIF介导的相互作用。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产生的细胞，将确定在脓毒症期间减少MIF对心肌细胞的负担的益处。因此，我们期望该研究将确定脓毒症期间肺MIF衍生的心功能不全的作用和机制，并提出抑制其产生和从肺释放的具体策略。