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.

项目摘要： 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 免疫激活通过舞者相关分子的相互作用驱动组织损伤的发展 模式（潮湿）和模式识别受体。作为疾病过程不可或缺的一部分，炎症 肝脏IRI的分辨率尚未得到很好的定义。关于IRI是否可能导致移植的问题 拒绝还有待回答。炎症分辨率是一个主动过程，由 免疫激活。那样，抗炎策略本身可能会可能干扰炎症 解决。因此，促分辨率策略对于真正恢复组织稳态至关重要。 已经进行了初步实验以定义鼠肝部分的注射分辨率 温暖的缺血模型，以及有关组织病理学，炎症基因表达和动力学变化的数据 巨噬细胞（MOS）。 KC是肝脏注射分辨率的主要参与者。他们的耗尽 克氯膦酸 - 脂质体（CL）导致肝脏IRI（14天）的分辨率显着延迟，增加 与CD11b+IMO的耗竭相比，促炎和纤维化基因的表达（在CD11b-中 DTR小鼠）。这些经过CL治疗的小鼠的KC重建恢复了分辨率动力学。实验 TAM RTK缺乏小鼠和TIM-4耗尽的ABS表明MER受体酪氨酸激酶（RTK）和 TIM-4对于肝脏IRI解决方案的KC功能至关重要。 当前项目将利用新型的鼠标遗传工具来阐明KC特异性功能 肝脏IRI在两种部分温暖的缺血以及肝移植模型中。实验被设计为 检验胚胎KC是肝脏IRI分辨率最有效的MOS的假设 MERTK/TIM -4通过肝X受体（LXR）和脂氧合酶（LOX）介导的效应器的依赖性方式 途径。 KCS的促分辨率功能的增强可保护肝脏TX并抑制同种免疫性激活。 AIM 1将确定KC在肝脏IRI分辨率中的功能机制。 AIM 2将定义 MERTK介导的KCS中的促分辨率效应子途径。 AIM 3将确定KC在肝脏中的作用 移植。该研究的结果将有助于描述肝脏IRI的注射分辨率机制 并确定新型的促分解治疗靶标，以实现未来的临床应用。