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。该提议集中于一组内源性损伤相关分子模式（DAMP）分子，其在感染和损伤期间从细胞核发出以启动先天性炎症反应的激活。我们最近的研究结果表明，核DAMPs参与中性粒细胞生物学，即中性粒细胞胞外陷阱（NET）的形成，在肝脏I/R的设置。IL-33是与细胞核中的染色质相关的IL-1家族的新成员，当在肝脏I/R后释放以刺激NET形成时，IL-33可以充当DAMP。除了核组蛋白的存在，我们还确定了一个新的要求，细胞内高迁移率族蛋白-1（HMGB 1）蛋白的中性粒细胞形成NET的能力。重要的是，靶向NET改善了小鼠中肝脏以及全身I/R诱导的损伤。因此，我们认为，核DAMP（如IL-33，组蛋白和HMGB 1）介导NET的形成和随后的器官损伤后，肝脏I/R。这些机制也将在接受肝切除术的患者的临床结局中得到验证。在目的1中，我们将确定IL-33在缺血性肝损伤期间NET形成和炎症信号传导中的作用。目的2：研究HMGB 1在中性粒细胞形成过程中的作用。目的3：研究NET介导的肝脏I/R后局部和全身器官损伤的机制。这些研究将为更全面地了解DAMP如何在非感染性炎症期间介导有害和适应性反应奠定基础，并应证明在设计广泛适用的新型疗法中有用，以最大限度地减少各种临床环境中的组织损伤。

 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.