Inflammation Resolution in Liver Ischemia-Reperfusion Injury

项目摘要： 缺血再灌注损伤（IRI）是肝脏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组成部分，炎症 肝脏IRI的消退尚未得到很好的定义。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过程，由炎症消退启动或与炎症消退重叠。 免疫激活因此，抗炎策略本身可能会干扰炎症 分辨率因此，前分辨率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以确定小鼠肝脏部分移植物中的炎症消退。 热缺血模型的组织病理学，炎症基因表达和 巨噬细胞（M β）。KC是肝脏炎症消退的主要参与者。它们的消耗， 氯膦酸盐脂质体（CL）导致肝脏IRI消退显著延迟（14天）， 促炎基因和纤维化基因的表达，与CD 11b +iM β的耗竭（在CD 11b- DTR小鼠）。这些CL处理小鼠中的KC重建恢复了消退动力学。实验 TAM RTK缺陷型小鼠和TIM-4耗竭Ab显示Mer受体酪氨酸激酶（RTK）和 TIM-4对KC在肝脏IRI消退中的功能至关重要。 目前的项目将利用新的小鼠遗传工具来阐明KC的特异性功能， 在部分热缺血以及肝移植模型中的肝IRI。实验旨在 检验胚胎KCs是解决肝脏IRI中最有效的修复性M细胞的假设， 通过肝X受体（LXR）和脂氧合酶（LOX）介导的效应器的MerTK/TIM-4依赖性方式 途径。增强KCs的促消退功能可保护肝脏Tx并抑制同种免疫激活。 目的1探讨KCs在肝脏IRI消退中的作用机制。目标2将定义 KCs中MerTK介导的促消退效应子途径。目的3探讨KCs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鉴定新的促消退治疗靶点。

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.