IL-6 and hepatic dysfunction in sepsis

脓毒症是一种重要的、危及生命的疾病，其发病率正在上升。在美国， 超过20万人死亡，超过167亿美元的医疗保健支出。治疗这种致命的疾病 是支持的，因为对潜在的病理生理学了解甚少。正常的自然历史 epsis已经被很好地定义了。它呈现出高代谢，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征，因此早期死亡是罕见的。超过 随着时间的推移，患者的病情发展到器官功能降低的状态，即多器官功能障碍 综合征（MODS）。大多数脓毒症相关死亡发生在MODS患者中， 免疫系统功能。免疫功能障碍可能是因为免疫细胞停止发挥功能或发生变化 他们的功能模式。如果免疫功能障碍是MODS的一个组成部分， 其他器官也会发生类似的变化--功能下降或改变。在我们的研究中， 这种可能性存在于肝细胞或肝细胞中。使用脓毒症小鼠模型，我们已经表明肝细胞 随着时间的推移，在面对严重的败血症时，而不是轻度的败血症时，功能会发生显著变化。的性质 这种变化是未知的，因此缺乏治疗方法。我们建议， 来自肝细胞对个体外部信号的反应途径的改变 cell.这些信号可能是由其他肝细胞、血流中的细胞或溶解在血液中的分子引发的。 血潜在的缺陷可能是由于细胞不能产生能量进行生化反应， 反应.我们将检测对单一介质IL-6的反应，并确定IL-6信号转导是否 在脓毒症中受损。我们还将研究败血症对一种关键酶的影响， 负责在肝细胞中产生能量。最后，我们将确定EL-6给药是否可以逆转 缺陷。这些研究应该提供关于脓毒症生物学的重要信息， 治疗方法。

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 $16.7billion in health care expenditures. Treatment of this lethal disorder is supportive because the underlying pathophysiology is poorly understood. The normal natural history of epsis 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, weexamine 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 anindividual 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-6signaling 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-6administration can reverse the defect. These studies should provide important information regarding septic biology and suggest novel therapeutic approaches.