Tumor necrosis factor in cisplatin nephrotoxicity

描述（由申请人提供）：本项目关注肿瘤坏死因子α（TNF α）在急性肾衰竭发病机制中的作用。急性肾衰竭影响约5%的住院患者，死亡率超过50%。如果不更好地理解细胞损伤的细胞和分子机制，就不可能降低这种高死亡率和相关成本。TNF α是一种促炎细胞因子，与缺血性和毒性急性肾损伤的发病机制有关。然而，TNF α导致肾衰竭的机制尚不清楚。这些知识对于开发通过抑制炎症来限制肾损伤的方法至关重要。我们的长期目标是通过有针对性的机械干预降低与急性肾衰竭相关的发病率和死亡率。本申请的目的是确定炎症机制如何导致临床相关形式的毒性肾病，顺铂肾毒性。中心假设是顺铂增加肾脏中TNF α的产生，并且TNF α通过TNFR2起作用，引起炎症反应，这有助于顺铂诱导的急性肾衰竭的发病机制。我们根据大量的初步数据提出了这一假设。这些研究背后的基本原理是，一旦确定了细胞损伤的特定炎症介质，就可以在预防和治疗急性肾衰竭的创新方法中操纵它们的产生和/或作用。我们计划通过追求以下三个具体目标来检验我们的假设并实现本申请的目的：1）确定响应顺铂的肾TNF α产生和TNF作用的位点2）确定顺铂诱导的TNF α产生的机制3）确定顺铂毒性中TNF α诱导的肾损伤的机制。这项工作是创新的，因为TNF α以前没有被认为是重要的毒性急性肾功能衰竭。此外，虽然TNF α在各种形式的ARF中增加，但TNF α参与损伤的机制尚不清楚。这些研究是重要的，因为它们预计将导致正式的临床试验，以测试目前可用的抗TNF α治疗预防顺铂肾毒性的疗效。此外，这些研究将确定临床干预的潜在新靶点。最后，预期这些结果不仅对顺铂肾毒性具有意义，而且对其他形式的急性和慢性肾脏疾病也具有意义。

DESCRIPTION (provided by applicant): This project focuses on the role of tumor necrosis factor alpha(TNFalpha) in the pathogenesis of acute renal failure. Acute renal failure affects about 5% of all hospitalized patients and carries a mortality rate of over 50%. It is unlikely that this high mortality and associated cost will be reduced without a better understanding of the cellular and molecular mechanisms of cell injury. TNFalpha, a proinflammatory cytokine, has been implicated in the pathogenesis of ischemic and toxic acute renal injury. However, the mechanism whereby TNFalpha produces renal failure is unknown. Such knowledge is crucial for the development of approaches to limit renal injury through inhibition of inflammation. Our long-term goal is to reduce the morbidity and mortality associated with acute renal failure through mechanistically targeted interventions. The objective of this application is to determine how inflammatory mechanisms contribute to a clinically relevant form of toxic nephropathy, cisplatin nephrotoxicity. The central hypothesis is that cisplatin increases TNFalpha production in the kidney and that TNFalpha, acting via the TNFR2, provokes an inflammatory response, which contributes to the pathogenesis of cisplatin-induced acute renal failure. We have formulated this hypothesis based on extensive preliminary data. The rationale behind these studies is that once specific inflammatory mediators of cell injury are identified, their production and/or action can be manipulated in innovative approaches to the prevention and treatment of acute renal failure. We plan to test our hypothesis and achieve the objective of this application by pursuing the following three specific aims: 1) Determine the sites of renal TNFalpha production and TNF action in response to cisplatin 2) Determine the mechanisms of cisplatin-induced TNFalpha production 3) Determine the mechanisms of TNFalpha-induced renal injury in cisplatin toxicity. The proposed work is innovative because TNFalpha has not previously been considered important in toxic acute renal failure. Moreover, while TNFalpha is increased in a variety of forms of ARF, the mechanism whereby TNFalpha participates in injury is not known. These studies are significant because they are expected to lead to a formal clinical trial to test the efficacy of currently available anti-TNFalpha treatments for the prevention of cisplatin nephrotoxicity. In addition, these studies will identify potential new targets for clinical interventions. Finally, these results are expected to have significance not only to cisplatin nephrotoxicity, but also to other forms of acute and chronic kidney disease.