Endogenous regulators of inflammation in liver ischemia/reperfusion

 描述(由申请人提供)：彻底了解肝脏缺血再灌注(I/R)的病理生理学是至关重要的，因为它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中临床上经常遇到。尽管I/R损伤后导致肝脏损伤的炎症反应的远端事件已经被很好地研究，但近端事件指示炎症反应的传播和进一步的组织损伤却知之甚少。这一建议侧重于一组内源性损伤相关分子模式(DAMP)分子，它们在感染和损伤过程中从细胞核发出，启动先天炎症反应的激活。我们最近的研究结果表明，在肝脏I/R过程中，中性粒细胞生物学即中性粒细胞胞外陷阱(Net)的形成与核抑制有关，IL-33是IL-1家族中与核染色质相关的新成员，在肝脏I/R后释放时可起到抑制作用，从而刺激Net的形成。除了核组蛋白的存在外，我们还发现细胞内高迁移率族蛋白1(HMGB1)对中性粒细胞形成Net的能力有新的要求。重要的是，靶向Net改善了小鼠肝脏以及全身I/R诱导的损伤。因此，我们认为核抑制物(如IL-33、组蛋白和HMGB1)介导了肝I/R后Net的形成和随后的器官损伤，这些机制也将在接受肝切除的患者的临床结果中得到验证。在目标1中，我们将确定IL-33在缺血性肝损伤中的网络形成和炎症信号中的作用。目的2确定HMGB1在调节Net中性粒细胞形成中的细胞内作用。在目标3中，我们将建立肝脏I/R后网络介导的局部和系统器官损伤的机制。这些研究将作为更全面地理解在非感染性炎症过程中阻滞剂如何介导有害和适应性反应的基础，并将被证明在设计新的治疗方法方面是有用的，具有广泛的适用性，在各种临床环境中将组织损伤降至最低。

 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 focuses on a group of endogenous damage-associated molecular pattern (DAMP) molecules that emanate from the cell nucleus during infection and injury to initiate the activation of innate inflammatory responses. Our recent findings demonstrate that nuclear DAMPs are involved in neutrophil biology, namely neutrophil extracellular trap (NET) formation, in the setting of liver I/R. IL-33, novel member of the IL-1 family associated with chromatin in the nucleus, can act as a DAMP when released following liver I/R to stimulate NET formation. In addition to the presence of nuclear histones, we have also identified a novel requirement of intracellular high mobility group box-1 (HMGB1) protein in the ability of neutrophils to form NETs. Importantly, targeting NETs ameliorates the hepatic as well as systemic I/R-induced injury in mice. Thus, we propose that nuclear DAMPs (such as IL-33, histones, and HMGB1) mediate NET formation and subsequent organ injury following liver I/R. These mechanisms will also be validated in clinical outcomes of patients undergoing liver resection. In Aim 1, we will determine the role of IL-33 in NET formation and inflammatory signaling during ischemic liver injury. Aim 2 will identify the intracellular roles of HMGB1 in regulating neutrophil formation of NETs. In Aim 3, we will establish the mechanisms of NET-mediated local and systemic organ injury following liver I/R. These studies will serve as a basis for developing both a more comprehensive understanding of how DAMPs mediate both harmful and adaptive responses during non-infectious inflammation, and should prove useful in the design of novel therapies, broadly applicable, to minimize tissue damage in a variety of clinical settings.