NITRIC OXIDE IN RENAL DISEASE

描述(改编自申请者摘要)：缺血/再灌注 损伤是由激活细胞毒性和炎性级联反应引起的 再灌注期。对实验动物的伤害可能是轻微的 通过抑制这两条通路中的任何一条而降低。他们最近 发现α-MSH对严重的肾脏缺血/再灌注损伤具有保护作用， 即使在再灌注期开始。α-MSH是一种神经肽 具有广泛的抗炎特性。他们发现，a-MSH可以抑制 细胞因子、趋化因子和一氧化氮的合成。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阻止了两个脑区的非适应性激活 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 α-MSH治疗缺血/再灌注损伤的活性谱。他们 将确定a-MSH在再灌注期何时激活以及是否 A-MSH可加速已建立的肾功能衰竭的恢复。在目标2中，他们 会将MSH受体定位于肾单位的特定部分 用原位杂交法和RT/PCR法检测血管构筑。他们还将 确定a-MSH的生产地。在目标3中，他们将确定 α-MSH对NO介导的缺血细胞毒作用的影响。他们有 初步证据表明，α-MSH抑制iNOS的产生。 缺血/再灌流。他们将确定一氧化氮是否对组织负责 肾脏损伤，孤立的灌流肾和孤立的小管 到脑缺血。在目标4中，他们将确定a-MSH对 中性粒细胞介导的缺血损伤。他们将研究 α-MSH对中性粒细胞浸润及肾脏表达的影响 化学诱导剂与内皮细胞黏附分子在脑缺血中的作用 模特们。

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.