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，它占到了 超过20万人死亡，医疗保健支出超过167亿美元。对这种致命疾病的治疗 是支持的，因为人们对潜在的病理生理学知之甚少。人类正常的自然历史 Epsis已经被很好地定义了。它呈现出一种高代谢、高炎症状态。幸运的是， 临床医生已经非常熟练地处理这一阶段的综合征，因此早期死亡是罕见的。完毕 随着时间的推移，患者的病情发展到器官功能减退、多器官功能障碍的状态 综合征(MODS)。大多数败血症相关死亡发生在MODS患者中，通常表现为减少。 免疫系统功能。由于免疫细胞停止功能或改变，可能会发生免疫功能障碍 他们的功能模式。如果免疫功能障碍代表了MODS的一个组成部分，那么我们就有理由认为 类似的变化--功能降低或改变--发生在其他器官中。在我们的研究中，我们检查 这种可能性存在于肝细胞或肝细胞中。使用脓毒症的小鼠模型，我们已经证明了肝细胞 随着时间的推移，在面对严重的、而不是轻微的脓毒症时，功能会发生戏剧性的变化。的性质 这种变化是未知的，因此缺乏治疗方法。我们认为，更改的结果 由于肝细胞对来自个体外的信号做出反应的路径的改变 手机。这些信号可能是由其他肝细胞、血流中的细胞或溶解在 鲜血。潜在的缺陷可能是细胞未能产生生化所需的能量。 反应。我们将检查对单个介质EL-6的反应，并确定IL-6信号是否 脓毒症时通路受损。我们还将研究脓毒症对一种关键酶的影响，即 负责在肝细胞中产生能量。最后，我们将确定El-6政府是否可以逆转 这个缺陷。这些研究应该提供有关败血症生物学的重要信息，并提出新的 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.