Caspase-1 and IL-18 in Ischemic Acute Renal Failure

描述(申请人提供)：caspase-1，以前被称为白介素1β(IL-1β)转换酶，在炎症和细胞死亡中发挥关键作用。Caspase-1将促炎症细胞因子IL-1β和IL-18(IL-18)加工成成熟的形式。Caspase-1和IL-18是缺血性急性肾功能衰竭(ARF)的重要介质，而IL-1β不是。这项资助研究了IL-18在缺血性ARF损伤中的作用机制。缺血性急性肾功能衰竭是住院患者的常见情况，其死亡率仍然很高。 Caspase-1介导的IL-18的产生可能通过启动一系列事件而参与缺血性ARF的发病，最终导致间质中性粒细胞聚集和近端肾小管细胞(PT)坏死。将探讨以下假设：1)IL-18产生的部位是肾内皮细胞和PT。2)内皮细胞分泌的IL-18上调血管细胞黏附分子-1(VCAM-1)的表达，从而促进中性粒细胞与肾血管系统的黏附。3)来自PT的IL-18进入间质，诱导巨噬细胞产生趋化因子巨噬细胞炎性蛋白-2(MIP-2)。然后，MIP-2吸引中性粒细胞进入间质。4)中性粒细胞进入间质参与了缺血性ARF的发病过程。5)IL-18对肾损伤的作用不依赖于中性粒细胞。实验将使用体内缺血模型(小鼠双侧肾蒂夹闭)和体外模型(新鲜分离的近端小管暴露在低氧中)进行。

DESCRIPTION (provided by applicant): Caspase- 1, formerly known as interleukin-1 beta (IL-1beta) converting enzyme, plays a key role in inflammation and cell death. Caspase-1 processes the pro-inflammatory cytokines IL-1beta and interleukin- 18 (IL- 18) to their mature forms. Caspase-1 and IL-18, but not IL-1beta, are important mediators of ischemic acute renal failure (ARF). This grant investigates the mechanism by which IL-18 contributes to injury in ischemic ARF. lschemic ARF is a common condition in hospitalized patients which continues to have a high mortality rate. Caspase-1 mediated production of IL-18 may contribute to the pathogenesis of ischemic ARF by initiating a series of events which culminates in interstitial neutrophil accumulation and proximal tubular cell (PT) necrosis. The following hypotheses will be investigated: 1) The sites of IL-18 production are the renal endothelium and PT. 2) IL-18 from the endothelium upregulates expression of vascular cell adhesion molecule-1 (VCAM- 1) which facilitates neutrophil adherence to the renal vasculature. 3) IL-18 from the PT enters the interstitium where it induces production of the chemokine macrophage-inflammatory protein-2 (MIP-2) by macrophages. MIP-2 then attracts neutrophils into the interstitium. 4) The entry of neutrophils into the interstitium contributes to the pathogenesis of ischemic ARF. 5) IL- 18 also contributes to renal injury independent of neutrophils. Experiments will be carried out using an in vivo model of ischemia (bilateral renal pedical clamping in mice) as well as an in vitro model (freshly isolated proximal tubules exposed to hypoxia).