Inflammation Resolution in Liver Ischemia-Reperfusion Injury

项目总结： 缺血再灌注损伤(IRI)是肝肿瘤切除和移植的主要危险因素。先天的 免疫激活通过危险相关分子的相互作用推动组织损伤的发展 模式(潮湿)和模式识别受体。作为疾病过程中不可或缺的一部分，炎症 肝脏IRI的分辨率尚未得到很好的定义。IRI是否以及如何导致移植的问题 拒绝仍有待回答。炎症消退是一个主动的过程，由其发起或与其重叠 免疫激活。因此，抗炎策略本身可能会潜在地干扰炎症。 决议。因此，支持分解的策略对于组织内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炎症的消退 热缺血模型，组织病理学动态变化，炎症基因表达和 巨噬细胞(MФS)。KCS在肝脏炎症消退中起主导作用。他们的耗尽被 氯屈膦酸脂质体(CL)可显著延迟肝脏IRI的消退时间(14天)。 促炎症和纤维化基因的表达与CD11b+ImФ缺失(CD11b- DTR小鼠)。这些CL处理的小鼠体内的KC重建恢复了拆分动力学。实验： RTK缺陷小鼠和TIM-4耗竭抗体表明，Mer受体酪氨酸激酶和 在肝脏IRI中，TIM-4对KC功能起关键作用。 目前的项目将利用新的小鼠遗传工具来阐明KC在 肝脏部分热缺血模型和肝移植模型中的肝脏IRI。实验的目的是为了 验证胚胎KCs是修复M-Ф最有效的假说S对小鼠肝脏IR的影响 通过肝X受体(LXR)和脂氧合酶(LOX)介导的效应分子依赖MerTK/Tim-4 小路。KCs促分解功能增强可保护肝脏TX，抑制同种免疫激活。 目的1探讨KCs在肝脏IRI中的作用机制。目标2将定义 KCs中MerTK介导的前分辨效应通路。目标3将确定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寻找新的促拆分治疗靶点。

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.