NITRIC OXIDE IN RENAL DISEASE

肾脏疾病中的一氧化氮

• 批准号: 6138005
• 负责人: LAWRENCE S HONIG
• 金额: $ 1.49万
• 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 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138005
• 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（改编自申请人的摘要）：缺血/再灌注 损伤是由细胞毒性和炎症级联反应的激活引起的 再灌注期。 实验动物的伤害可能是轻微的 通过抑制这两种途径中的任何一种而减少。 他们最近 发现 a-MSH 可以预防严重的肾缺血/再灌注损伤， 即使在再灌注期间开始。 a-MSH 是一种神经肽 具有广泛的抗炎特性。 他们发现a-MSH 抑制 细胞因子、趋化因子和NO的合成。 目前尚不清楚 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 可以防止两种细胞的适应不良激活 细胞毒性（NO）和炎症（中性粒细胞）级联反应。 他们会 调查以下具体目标：在目标 #1 中，他们将定义 a-MSH 在治疗缺血/再灌注损伤中的活性谱。 他们 将确定再灌注期间 a-MSH 何时处于活动状态以及是否 a-MSH 加速肾功能衰竭的恢复。 在目标#2中，他们 将 MSH 受体定位于肾单位的特定部分 使用原位杂交和 RT/PCR 检测脉管系统。 他们还将 确定 a-MSH 的产生位置。 在目标#3中，他们将确定 a-MSH 对 NO 介导的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 NO 是否对组织负责 肾脏损伤、孤立的灌注肾脏和孤立的肾小管 至缺血。 在目标 4 中，他们将确定 a-MSH 对 由中性粒细胞介导的缺血引起的损伤。 他们将研究 a-MSH对中性粒细胞浸润、肾组织表达的影响 缺血区中的趋化剂和内皮细胞粘附分子 模型。