Tumor necrosis factor in cisplatin nephrotoxicity

描述（由申请人提供）：本项目主要研究肿瘤坏死因子α (TNFalpha)在急性肾功能衰竭发病机制中的作用。急性肾衰竭影响约5%的住院病人，死亡率超过50%。如果不更好地了解细胞损伤的细胞和分子机制，这种高死亡率和相关成本不太可能降低。TNFalpha是一种促炎细胞因子，与缺血性和中毒性急性肾损伤的发病机制有关。然而，TNFalpha导致肾功能衰竭的机制尚不清楚。这些知识对于通过抑制炎症来限制肾损伤的方法的发展至关重要。我们的长期目标是通过机械定向干预降低与急性肾功能衰竭相关的发病率和死亡率。本应用程序的目的是确定炎症机制如何促进临床相关形式的中毒性肾病，顺铂肾毒性。中心假设是顺铂增加肾脏中TNFalpha的产生，而TNFalpha通过TNFR2起作用，引发炎症反应，这有助于顺铂诱导的急性肾功能衰竭的发病机制。我们根据大量的初步数据提出了这个假设。这些研究背后的基本原理是，一旦确定了细胞损伤的特异性炎症介质，它们的产生和/或作用可以在预防和治疗急性肾功能衰竭的创新方法中被操纵。我们计划通过以下三个具体目标来验证我们的假设并实现本应用的目标：1)确定顺铂对肾脏TNFalpha产生的部位和TNF的作用；2)确定顺铂诱导TNFalpha产生的机制；3)确定顺铂毒性中TNFalpha诱导肾损伤的机制。提出的工作是创新的，因为TNFalpha以前没有被认为在毒性急性肾功能衰竭中很重要。此外，虽然TNFalpha在各种形式的ARF中增加，但TNFalpha参与损伤的机制尚不清楚。这些研究意义重大，因为它们有望导致正式的临床试验，以测试目前可用的抗tnfalpha治疗预防顺铂肾毒性的有效性。此外，这些研究将确定临床干预的潜在新目标。最后，这些结果预计不仅对顺铂的肾毒性有意义，而且对其他形式的急慢性肾脏疾病也有意义。

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.