Endogenous regulators of inflammation in liver ischemia/reperfusion

肝脏缺血/再灌注炎症的内源性调节因子

• 批准号: 9315847
• 负责人: Allan Tsung
• 金额: $ 32.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315847
• 关键词: Applications Grants; Biology; Blood Circulation; Cell Nucleus; Cells; Chromatin; Clinical; Coagulation Process; DNA; Data; Development; Disease; Distal; Endothelial Cells; Event; Excision; Family; Fiber; Functional disorder; Germ Cells; Goals; HMGB1 Protein; Hepatic; Hepatocyte; Histones; Homeostasis; Host Defense Mechanism; Hypovolemic Shock; Immune; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-1; Internet; Ischemia; Kidney; Laboratories; Liver; Mediating; Molecular; Morbidity - disease rate; Mus; Nuclear; Nuclear Protein; Operative Surgical Procedures; Organ; Organ Transplantation; Organ Viability; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Platelet Activation; Play; Process; Protein-arginine deiminase; Proteins; Reperfusion Injury; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Solid; Source; Sterility; Structure; Thrombosis; Tissues; Trauma; Work; combat; design; extracellular; immune activation; improved; intrahepatic; liver function; liver injury; liver ischemia; member; mortality; neutrophil; novel; novel therapeutics; pathogen; prevent; public health relevance; response; tissue repair

 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.

 描述（由适用提供）：对肝脏缺血再灌注（I/R）的病理生理学的透彻理解至关重要，因为在选修肝外科手术程序，固体器官移植，创伤和低血容量冲击过程中通常在临床上遇到它。尽管对炎症反应涉及的远端事件进行了充分研究，导致I/R损伤后肝损伤，但对炎症反应传播和进一步组织损害的传播的代理事件却鲜为人知。该提案的重点是一组内源性损伤相关的分子模式（潮湿）分子，这些分子在感染和损伤过程中从细胞核中散发出来，以引发先天炎症反应的激活。我们最近的发现表明，在肝I/R的环境中，核潮湿与中性粒细胞生物学有关，即中性粒细胞外陷阱（净）形成。 IL-33是核中与染色质相关的IL-1家族的新成员，当肝脏I/R释放以刺激净形成时，可以作为潮湿。除了存在核组蛋白外，我们还确定了对中性粒细胞形成网的能力的细胞内高迁移率组1（HMGB1）蛋白的新需求。重要的是，靶向网可以改善肝脏和全身I/R诱导的小鼠损伤。这就是我们提出的，肝脏I/R后核潮湿（例如IL-33，组蛋白和HMGB1）介导净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AIM 1中，我们将确定IL-33在缺血性肝损伤过程中IL-33在净形成和炎症信号传导中的作用。 AIM 2将确定HMGB1在确定网状中性粒细胞形成中的细胞内作用。在AIM 3中，我们将建立肝I/R后网介导的局部和全身器官损伤的机制。这些研究将成为对非感染感染期间潮湿如何介导有害和适应性反应的更全面理解的基础，并应证明在广泛适用的新型疗法的设计中有用，以最大程度地减少各种临床环境中的组织损害。