The Role of IL-18 in Ischemic Acute Renal Failure

描述(由申请人提供)： IL-18是一种独特的细胞因子，在心、肺和脑的炎症、T细胞介导的免疫反应和缺血性组织损伤中发挥关键作用。到目前为止，IL-18介导这些器官的缺血性损伤的机制被归因于它在炎症和中性粒细胞募集中的作用。IL-18在缺血性急性肾功能衰竭(ARF)的发病机制中也起重要作用。然而，IL-18介导缺血性ARF的机制不依赖于中性粒细胞。本研究旨在探讨IL-18参与缺血性ARF损伤的中性粒细胞非依赖性机制。缺血性ARF以近端肾小管(PT)坏死为特征，称为急性肾小管坏死(ATN)。缺血性ARF是住院患者的常见情况；在重症监护病房环境中，相关死亡率为50%至80%。需要更好地了解缺血性ARF的发病机制，以促进缩短其病程和提高存活率的干预措施的发展。IL-18可能通过两种机制参与缺血性ARF的发生：1)CD4T淋巴细胞的募集和激活；2)直接作用于PT细胞。将探讨以下假设：1)Caspase-1激活肾内皮细胞和PT上的IL-18，2)内皮细胞IL-18上调内皮细胞表面VCAM-1的表达，从而促进CD4T细胞的黏附，3)PT产生的IL-18刺激趋化因子(MIP-2和MCP-1)的产生，从而吸引CD4T细胞进入间质，从而导致缺血损伤，4)缺血上调PT细胞表面IL-18受体的表达，5)IL-18直接作用于PT导致坏死。实验将使用体内模型(小鼠双侧肾蒂夹闭)和体外模型(新鲜分离的PT暴露在低氧中)进行。制作缺血性ARF模型，研究caspase-1、IL-18、VCAM-1、MIP-2和MCP-1的激活情况。这些蛋白在缺血性ARF中的致病性质将在各种环境中进行检测，包括caspase-1缺陷小鼠、VCAM-1阻断抗体治疗和CD4T细胞耗尽。这些实验结果将有助于了解缺血性ARF的发病机制，以及其他器官的缺血。

DESCRIPTION (provided by applicant): IL-18 is a unique cytokine that plays a key role in inflammation, T-cell mediated immune responses and ischemic tissue injury in the heart, lung and brain. To date, the mechanism by which IL-18 mediates ischemic injury in these organs has been attributed to its role in inflammation and neutrophil recruitment. IL-18 is also important in the pathogenesis of ischemic acute renal failure (ARF). The mechanism by which IL-18 mediates ischemic ARF, however, is independent of neutrophils. This proposal investigates the neutrophil-independent mechanisms by which IL-18 contributes to injury in ischemic ARF. Ischemic ARF is characterized by proximal tubule (PT) necrosis, known as acute tubular necrosis (ATN). Ischemic ARF is a common condition in hospitalized patients; in the intensive care unit setting, the associated mortality is 50 to 80%. A better understanding of the pathogenesis of ischemic ARF is needed to facilitate the development of interventions that shorten its course and improves survival. IL-18 may contribute to the pathogenesis of ischemic ARF by two proposed mechanisms: 1) recruitment and activation of CD4 T lymphocytes and 2) direct action on the PT cell. The following hypotheses will be investigated: 1) Caspase-1 activates IL-18 in both the renal endothelium and PT, 2) Endothelial IL-18 upregulates the expression of VCAM-1 on the endothelial surface which facilitates CD4 T cell adherence, 3) IL-18 from the PT stimulates the production of chemokines (MIP-2 and MCP-1) which attract CD4 T cells into the interstitium, contributing to ischemic injury 4) ischemia upregulates the expression of the IL-18 receptor on the PT cell surface, and 5) IL-18 acts directly on the PT to cause necrosis. Experiments will be carried out using an in vivo model (bilateral renal pedicle clamping in mice) as well as an in vitro model (freshly isolated PT exposed to hypoxia). A time course of ischemic ARF to study the activation of caspase-1, IL-18, VCAM-1, MIP-2 and MCP-1 will be performed. The pathogenic nature of these proteins in ischemic ARF will be examined in a variety of settings including caspase-1 deficient mice, treatment with VCAM-1 blocking antibody and CD4 T cell depletion. The results of these experiments will contribute to the understanding of the pathogenesis of ischemic ARF, as well as ischemia in other organs.