Endogenous regulators of inflammation in liver ischemia/reperfusion

描述（由申请人提供）：深入了解肝脏缺血再灌注（I/R）的病理生理学至关重要，因为临床上在择期肝脏外科手术、实体器官移植、创伤和低血容量性休克期间经常遇到这种情况。尽管I/R损伤后导致肝损伤的炎症反应中涉及的远端事件已经得到了充分的研究，但对决定炎症反应传播和进一步组织损伤的近端事件了解甚少。该提案将研究高迁移率族蛋白1（HMGB 1）的机制，HMGB 1是一种参与调节DNA和转录因子之间相互作用的核蛋白，在缺血应激期间细胞外释放时可以作为一种关键的警报分子，以激活炎症反应。我们提出，在缺血应激期间，肝实质细胞（肝细胞）最初动员并释放核HMGB 1。HMGB 1然后被模式识别受体（例如Toll样受体（TLR）家族）感测，其在邻近免疫细胞上表达以提供组织损伤与先天免疫应答的激活和募集之间的关键联系。在目标1中，我们将确定的信号转导途径，管理的积极释放HMGB 1从肝细胞氧化应激。我们将证明钙/钙调蛋白依赖性蛋白激酶II通过组蛋白脱乙酰酶活性的修饰控制乙酰化状态和随后释放HMGB 1的机制。在目标2中，我们将使用肝脏I/R模型显示TLR 4在体内HMGB 1介导的炎症中发挥的关键作用。在目标3中，我们将重点关注肝树突状细胞作为主要的免疫细胞类型，其响应于HMGB 1并调节对缺血性损伤的炎症反应。这些研究将为更全面地了解先天免疫细胞在肝脏I/R期间如何激活提供基础，并应证明在设计新疗法以最大限度地减少各种手术环境中的肝损伤方面是有用的。重要的是，由HMGB 1释放介导的炎症机制可能在肝脏内发现的许多感染性和非感染性炎症性疾病中很常见，并且这项工作的影响可能扩展到各种其他缺血性疾病（例如心肌梗死和脑缺血）。

DESCRIPTION (provided by applicant): Thorough understanding of the pathophysiology of liver ischemia reperfusion (I/R) is vital as it is commonly encountered clinically during elective liver surgical procedures, solid organ transplantation, trauma, and hypovolemic shock. Although the distal events involved in the inflammatory response resulting in liver damage after I/R injury has been well-studied, the proximal events dictating the propagation of the inflammatory response and further tissue damage is poorly understood. This proposal will study the mechanisms by which high mobility group box 1 (HMGB1), a nuclear protein involved in regulating interactions between DNA and transcription factors, can act as a key alarm molecule when released extracellularly during ischemic stress to active inflammatory responses. We propose that during ischemic stress, the parenchymal cells of the liver (hepatocyte), initially mobilize and release nuclear HMGB1. HMGB1 is then sensed by pattern recognition receptors, such as the family of toll-like receptors (TLR), expressed on neighboring immune cells to provide a critical link between tissue damage and activation and recruitment of the innate immune response. In Aim 1, we will determine the signaling pathways governing the active release of HMGB1 from hepatocytes following oxidative stress. We will demonstrate the mechanisms by which calcium/ calmodulin-dependent protein kinase II control the acetylation status and subsequent release of HMGB1 through modification of histone deacetylase activity. In Aim 2, we will show the key roles TLR4 play in HMGB1-mediated inflammation in vivo using a model of liver I/R. In Aim 3, we will focus on hepatic dendritic cells as the primary immune cell type that responds to HMGB1 and regulates the inflammatory response to ischemic injury. These studies will serve as a basis for developing both a more comprehensive understanding of how innate immune cells are activated during liver I/R, and should prove useful in the design of novel therapies to minimize liver damage in a variety of surgical settings. Importantly, the mechanisms of inflammation mediated by HMGB1 release is likely common in a number of infectious and non-infectious inflammatory conditions found within the liver and the implications of this work likely extend to a variety of other ischemic conditions (e.g. myocardial infarction and cerebral ischemia).