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，在心脏、肺和脑中的炎症、T细胞介导的免疫应答和缺血性组织损伤中起关键作用。迄今为止，IL-18介导这些器官中的缺血性损伤的机制归因于其在炎症和中性粒细胞募集中的作用。IL-18在缺血性急性肾衰竭（ARF）的发病机制中也是重要的。然而，IL-18介导缺血性ARF的机制不依赖于中性粒细胞。该提案研究了IL-18在缺血性ARF中促进损伤的非嗜中性粒细胞依赖性机制。 缺血性ARF的特征是近端小管（PT）坏死，称为急性肾小管坏死（ATN）。缺血性ARF是住院患者的常见疾病;在重症监护室环境中，相关死亡率为50 - 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生存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的发病机制：1）募集和激活CD 4 T淋巴细胞和2）直接作用于PT细胞。将研究以下假设：1）Caspase-1激活肾内皮和PT中的IL-18，2）内皮IL-18上调内皮表面上VCAM-1的表达，这促进CD 4 T细胞粘附，3）来自PT的IL-18刺激趋化因子的产生，（MIP-2和MCP-1），其将CD 4 T细胞吸引到胸腺中，导致缺血性损伤4）缺血上调PT细胞表面上IL-18受体的表达，和5）IL-18直接作用于PT引起坏死。 将使用体内模型（小鼠双侧肾蒂钳夹）以及体外模型（暴露于缺氧的新鲜分离PT）进行实验。将进行缺血性ARF的时程，以研究半胱天冬酶-1、IL-18、VCAM-1、MIP-2和MCP-1的活化。这些蛋白质在缺血性ARF中的致病性质将在多种环境中进行检查，包括半胱天冬酶-1缺陷小鼠，VCAM-1阻断抗体治疗和CD 4 T细胞耗竭。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.