IL-6 and hepatic dysfunction in sepsis

描述（由申请人提供）：败血症是一种重要的、危及生命的疾病，其发病率正在上升。在美国，它造成20多万人死亡，医疗支出超过167亿美元。这种致命疾病的治疗是支持性的，因为其潜在的病理生理机制尚不清楚。脓毒症的正常自然史已被明确定义。它表现为高代谢、高炎症状态。幸运的是，临床医生已经非常擅长处理这一阶段的综合症，因此早期死亡的情况很少见。随着时间的推移，患者的病情发展到器官功能下降的状态，即多器官功能障碍综合征（MODS）。大多数败血症相关死亡发生在MODS患者中，通常反映免疫系统功能下降。免疫功能障碍可能是由于免疫细胞停止功能或改变其功能模式而发生的。如果免疫功能障碍是MODS的一个组成部分，那么假设类似的变化——功能下降或改变——发生在其他器官中是合乎逻辑的。在我们的研究中，我们在肝细胞或肝细胞中检查了这种可能性。使用小鼠脓毒症模型，我们已经证明肝细胞功能随着时间的推移发生了巨大的变化，面对严重的脓毒症，而不是轻微的脓毒症。这种变化的性质尚不清楚，因此缺乏治疗方法。我们认为这种变化是由于肝细胞对单个细胞外产生的信号作出反应的途径发生了改变。这些信号可能是由其他肝细胞、血液中的细胞或溶解在血液中的分子发起的。潜在的缺陷可能是由于细胞不能为生化反应产生能量。我们将检查对单一介质EL-6的反应，并确定IL-6信号通路是否在败血症中受损。我们还将研究败血症对肝细胞中负责产生能量的关键酶的影响。最后，我们将确定EL-6是否可以逆转缺陷。这些研究应该提供有关脓毒症生物学的重要信息，并提出新的治疗方法。

DESCRIPTION (provided by applicant): Sepsis is an important, life-threatening disease whose incidence is rising. In the United States, it accounts for more than 200,000 deaths and over $16.7 billion in health care expenditures. Treatment of this lethal disorder is supportive because the underlying pathophysiology is poorly understood. The normal natural history of sepsis has been well-defined. It presents with a hypermetabolic, hyperinflammatory state. Fortunately, clinicians have become quite adept at managing this phase of the syndrome so death early on is rare. Over time, the patient's condition evolves to a state of reduced organ function, the Multiple Organ Dysfunction Syndrome (MODS). Most sepsis-associated deaths occur in patients with MODS and often reflect decreased immune system function. Immune dysfunction may occur because immune cells cease to function or change their pattern of function. If immune dysfunction represents one component of MODS, it is logical to assume that similar changes - either decreased or altered function - occur in other organs. In our studies, we examine this possibility in liver cells, or hepatocytes. Using a mouse model of sepsis, we have shown that hepatocyte function changes dramatically over time and in the face of severe, as opposed to mild, sepsis. The nature of this change is unknown and therefore therapeutic approaches are lacking. We propose that the change results from an alteration in the pathways by which hepatocytes respond to signals that arise outside an individual cell. These signals may be initiated by others liver cells, cells in the blood stream or molecules dissolved in the blood. The underlying defect may result from a failure of cells to generate energy for biochemical reactions. We will examine the response to a single mediator, EL-6, and determined if the IL-6 signaling pathway is impaired in sepsis. We also will investigate the effects of sepsis on a key enzyme that is responsible for generating energy in liver cells. Finally, we will determine if EL-6 administration can reverse the defect. These studies should provide important information regarding septic biology and suggest novel therapeutic approaches.