NITRIC OXIDE IN RENAL DISEASE

肾脏疾病中的一氧化氮

• 批准号: 2856761
• 负责人: LAWRENCE S HONIG
• 金额: $ 23.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856761
• 关键词: cell adhesion molecules; chemoattractants; chemokine; cytotoxicity; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hormone therapy; inflammation; kidney circulation; laboratory mouse; laboratory rat; melanocyte stimulating hormone; neuropeptide receptor; nitric oxide; nonhuman therapy evaluation; polymerase chain reaction; receptor expression; renal ischemia /hypoxia; renal tubular transport; vasodilators

DESCRIPTION (Adapted from the Applicant's Abstract): Ischemia/reperfusion injury is caused by activation of cytotoxic and inflammatory cascades during the reperfusion period. Injury in experimental animals can be modestly decreased by inhibition of either of these two pathways. They recently found the a-MSH protects against severe renal ischemia/reperfusion injury, even when started during the reperfusion period. a-MSH is a neuropeptide with broad anti-inflammatory properties. They found that a-MSH inhibits the synthesis of cytokines, chemoattractive chemokines and NO. It is not known why a-MSH is so effective in preventing ischemia/reperfusion injury. They hypothesize that a-MSH prevents the maladaptive activation of both the cytotoxic (NO) and inflammatory (neutrophile) cascade. They will investigate the following Specific Aims: In Aim #1, they will define the spectrum of activity of a-MSH in treating ischemia/reperfusion injury. They will determine when a-MSH is active during the reperfusion period and if a-MSH accelerates recovery from established renal failure. In Aim #2, they will localize the MSH receptors to specific portions of the nephron and vasculature using in situ hybridization and RT/PCR. They will also determine where a-MSH is produced. In Aim #3, they will determine the effect of a-MSH on ischemia induced cytotoxicity mediated by NO. They have preliminary evidence that a-MSH inhibits the production of iNOS during ischemia/reperfusion. They will determine if NO is responsible for tissue injury in kidneys, isolated perfused kidneys and isolated tubules subjected to ischemia. In Aim #4, they will determine the effect of a-MSH on the ischemia-induced injury mediated by neutrophiles. They will study the effect of a-MSH on neutrophile infiltration, expression of renal chemattractants and endothelial cell adhesion molecules in the ischemic models.

描述（根据申请人的摘要改编）：缺血/再灌注 受伤是由细胞毒性和炎症级联反应引起的 再灌注期。 实验动物的伤害可能适度 通过抑制这两种途径中的任何一个而减少。 他们最近 发现A-MSH防止严重的肾脏缺血/再灌注损伤， 即使在再灌注期开始。 A-MSH是神经肽 具有广泛的抗炎特性。 他们发现A-MSH抑制了 细胞因子，化学吸引力趋化因子和NO的合成。 这是不知道的 为什么A-MSH在预防缺血/再灌注损伤方面如此有效。 他们 假设A-MSH可防止两者的适应不良激活 细胞毒性（NO）和炎症（嗜中性粒子）级联反应。 他们会的 调查以下具体目的：在AIM＃1中，他们将定义 A-MSH在治疗缺血/再灌注损伤中的活性范围。 他们 将确定在再灌注期间A-MSH何时活跃 A-MSH加速了从已建立的肾衰竭中恢复。 在AIM＃2中，他们 将将MSH受体定位到肾单位的特定部分和 使用原位杂交和RT/PCR进行脉管系统。 他们也会 确定在哪里产生A-MSH。 在AIM＃3中，他们将确定 A-MSH对缺血诱导的细胞毒性的影响。 他们有 初步证据表明A-MSH抑制iNOS的产生 缺血/再灌注。 他们将确定是否不负责组织 肾脏受伤，孤立的灌注肾脏和孤立的小管 缺血。 在AIM＃4中，他们将确定A-MSH对 缺血诱导的损伤是由中性粒细胞介导的。 他们将研究 A-MSH对中性粒细胞浸润的影响，肾脏的表达 缺血性的化学吸引剂和内皮细胞粘附分子 型号。