Inflammation Resolution in Liver Ischemia-Reperfusion Injury

肝脏缺血再灌注损伤的炎症消退

• 批准号: 10622472
• 负责人: YUAN ZHAI
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622472
• 关键词: Address; Adult; Affect; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Bone Marrow; Ca(2+)-Calmodulin Dependent Protein Kinase; Complement; Cre lox recombination system; Cryopreservation; Data; Development; Dichloromethylene Diphosphonate; Disease; Down-Regulation; Embryo; Enzymes; Excision; Experimental Designs; Fibrosis; Future; Gene Expression; Genes; Graft Rejection; Hepatocellular Damage; Hepatocyte; Histologic; Histopathology; Homeostasis; Human; ITGAM gene; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Ischemia; Kinetics; Kupffer Cells; Lead; Liposomes; Lipoxygenase; Liver; Liver X Receptor; Liver neoplasms; Macrophage; Measures; Mediating; Mediator; Modeling; Molecular; Mus; Myelogenous; Myeloid Cell Activation; Neutrophil Infiltration; Outcome; Pathogenesis; Pathway interactions; Pattern; Pattern recognition receptor; Play; Process; Property; Quantitative Reverse Transcriptase PCR; Receptor Protein-Tyrosine Kinases; Recovery; Reperfusion Injury; Resolution; Risk Factors; Role; Source; Specificity; Stress; Testing; Tissues; Transplantation; Up-Regulation; Warm Ischemia; calmodulin-dependent protein kinase II; cell type; clinical application; experimental study; immune activation; immunoregulation; isoimmunity; liver function; liver inflammation; liver ischemia; liver transplantation; monocyte; mouse genetics; neutrophil; novel; pharmacologic; programs; reconstitution; repaired; restoration; success; therapeutic target; tissue injury; tool; transplant model; validation studies

Project Summary: Ischemia reperfusion injury (IRI) is the major risk factor in liver tumor resection and transplantation. Innate immune activation drives the development of tissue injury via interactions of danger associated molecular pattern (DAMP) and pattern recognition receptors. As an integral part of the disease process, inflammation resolution in liver IRI has not been well defined. Questions of whether and how IRI may lead to transplant rejection remain to be answered. Inflammation resolution is an active process, initiated by or overlapped with immune activation. Thus, anti-inflammatory strategy by itself may potentially interfere with inflammation resolution. The pro-resolution strategy is, therefore, is critical for the true restoration of tissue homeostasis. Preliminary experiments have been performed to define inflammation resolution in a murine liver partial warm ischemia model with data on the kinetic changes in histopathology, inflammatory gene expressions and macrophages (MФs). KCs are the dominant player in the liver inflammation resolution. Their depletion by clodronate-liposomes (CL) results in significant delays in the resolution of liver IRI (14 days) with increased expressions of pro-inflammatory and fibrosis genes, as compared with the depletion of CD11b+iMФ (in CD11b- DTR mice). The KC reconstitution in these CL-treated mice restored the resolution kinetics. Experiments with TAM RTK deficient mice and TIM-4 depleting Abs showed that both Mer receptor tyrosine kinase (RTK) and TIM-4 are critical for the KC function in the resolution of liver IRI. The current project will take advantage of novel mouse genetic tools to elucidate KC-specific function in liver IRI in both partial warm ischemia, as well as liver transplantation models. Experiments are designed to test the hypothesis that embryonic KCs are the most effective reparative MФs in the resolution of liver IRI in MerTK/TIM-4 dependent manner via Liver X Receptor (LXR) - and lipoxygenase (LOX) -mediated effector pathways. Enhancement of pro-resolution function of KCs protects liver Tx and inhibits alloimmune activation. Aim 1 will determine the functional mechanism of KCs in the resolution of liver IRI. Aim 2 will define MerTK-mediated pro-resolution effector pathways in KCs. Aim 3 will determine roles of KCs in liver transplantation. Results of the study will help to delineate the inflammation resolution mechanism in liver IRI and identify novel pro-resolving therapeutic targets for future clinical application.

项目概要： 缺血再灌注损伤（IRI）是肝肿瘤切除和移植的主要危险因素。先天 免疫激活通过危险相关分子的相互作用驱动组织损伤的发展 模式（DAMP）和模式识别受体。作为疾病过程的一个组成部分，炎症 肝脏 IRI 的分辨率尚未明确定义。 IRI 是否以及如何导致移植的问题 拒绝仍有待答复。炎症消退是一个主动的过程，由以下因素引发或与之重叠： 免疫激活。因此，抗炎策略本身可能会干扰炎症 解决。因此，促解决策略对于组织稳态的真正恢复至关重要。 已经进行了初步实验来确定小鼠肝脏部分的炎症消退 热缺血模型，包含组织病理学动力学变化、炎症基因表达和 巨噬细胞（MФs）。 KC 是解决肝脏炎症的主要参与者。他们的耗尽 氯膦酸盐脂质体 (CL) 导致肝脏 IRI 的消退显着延迟（14 天），且增加 与 CD11b+iMФ 的耗竭相比，促炎和纤维化基因的表达（在 CD11b- DTR 小鼠）。这些 CL 处理的小鼠中的 KC 重建恢复了分辨率动力学。实验与 TAM RTK 缺陷小鼠和 TIM-4 消耗抗体表明 Mer 受体酪氨酸激酶 (RTK) 和 TIM-4 对于 KC 解决肝脏 IRI 的功能至关重要。 当前的项目将利用新型小鼠遗传工具来阐明 KC 的特异性功能 部分热缺血以及肝移植模型中的肝脏IRI。实验旨在 检验胚胎 KC 是解决肝脏 IRI 中最有效的修复性 MФ 的假设 通过肝脏 X 受体 (LXR) 和脂氧合酶 (LOX) 介导的效应器实现 MerTK/TIM-4 依赖性方式 途径。 KC 促分解功能的增强可保护肝脏 Tx 并抑制同种免疫激活。 目标 1 将确定 KC 在解决肝脏 IRI 中的功能机制。目标 2 将定义 KC 中 MerTK 介导的促解析效应通路。目标 3 将确定 KC 在肝脏中的作用 移植。研究结果将有助于阐明肝脏 IRI 的炎症消退机制 并为未来的临床应用确定新的促解决治疗靶点。