Tumor necrosis factor in cisplatin nephrotoxicity

描述(由申请人提供)：本项目重点研究肿瘤坏死因子α在急性肾功能衰竭发病机制中的作用。急性肾功能衰竭影响了大约5%的住院患者，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。肿瘤坏死因子α是一种促炎细胞因子，参与了缺血性和中毒性急性肾损伤的发病机制。然而，肿瘤坏死因子α导致肾功能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。这项应用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。中心假说是顺铂增加了肾脏中肿瘤坏死因子α的产生，而肿瘤坏死因子α通过肿瘤坏死因子受体2起作用，引起炎症反应，从而导致顺铂诱导的急性肾功能衰竭。我们根据大量的初步数据提出了这一假设。这些研究背后的理论基础是，一旦确定了细胞损伤的特定炎症介质，它们的产生和/或作用就可以通过创新的方法来预防和治疗急性肾功能衰竭。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这一应用的目的：1)确定顺铂引起的肾肿瘤坏死因子α产生的部位和肿瘤坏死因子的作用；2)确定顺铂诱导的肿瘤坏死因子α产生的机制；3)确定顺铂毒性中肿瘤坏死因子α所致肾损伤的机制。这项拟议的工作是创新的，因为以前并不认为肿瘤坏死因子α对中毒性急性肾功能衰竭有重要作用。此外，尽管肿瘤坏死因子α在各种形式的急性肾衰中增加，但肿瘤坏死因子α参与损伤的机制尚不清楚。这些研究意义重大，因为它们有望导致一项正式的临床试验，以测试目前可用的抗肿瘤坏死因子α疗法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性和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.