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HEMOGLOBIN INDUCED VASOACTIVITY AND RENAL INJURY

血红蛋白引起的血管活性和肾损伤

基本信息

批准号：
2460077
负责人：
WILFRED LIEBERTHAL
金额：
$ 35.62万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2460077
关键词：
blood toxicology endothelin free radical scavengers hemodynamics hemorrhagic shock kidney circulation kidney circulation disorder laboratory rat leukocyte adhesion molecules nitric oxide protein purification renal failure renal ischemia /hypoxia tissue /cell culture vasoconstriction vasomotion

项目摘要

Our application is focused on the concern that purification and protein modification of stroma free hemoglobin (SFH) will not prevent toxicity in animals or humans. We will examine the hypothesis that SFH will cause prolonged systemic and intrarenal vasoconstriction persisting after the oxyhemoglobin is metabolized. We also will examine the hypothesis that both unmodified and modified preparations of SFH have the potential to cause acute renal failure (ARF) in two distinct settings: a. We hypothesize that SFH will exacerbate renal injury when administered shortly after established renal failure has been caused by a period of renal ischemia. b. We hypothesize that the SFH will cause "de novo" ARF (in the absence of established renal injury) when administered in large, "therapeutic" doses following hemorrhagic shock. Our specific aims are: 1. To examine and compare the mechanisms of vasoconstriction induced by unmodified and modified SFH. We will examine the mechanism by which oxyhemoglobin inhibits nitric oxide mediated vasorelaxation to determine whether protein modification is likely to reduce this cause of vasoconstriction associated with unmodified SFH We will examine the role of endothelin release in SFH-associated vasoconstriction. 2. To test the hypothesis that SFH will induce neutrophil mediated endothelial injury. We will examine the effects of unmodified and modified forms of SFH and its metabolite hemin on neutrophil-endothelial cell adhesion and neutrophil-induced endothelial injury. The pathogenetic mechanisms involved in the SFH induced neutrophil-adhesion interactions will be elucidated. 3. To examine and compare the extent to which unmodified and modified SFH exacerbates underlying established ischemic renal injury. 4. To examine the extent to which unmodified and modified SFH cause de novo ARF after the administration of large amounts of SFH to hypovolemic animals. We will examine our hypothesis that renal failure will be induced days after the administration of SFH to hypotensive rats resulting from the combined effects of a) prolonged intrarenal vasoconstriction b) the accumulation of toxic metabolites (hemin and free iron) in the renal parenchyma and c) neutrophil-induced endothelial injury.

我们的应用集中在纯化和蛋白质基质游离血红蛋白（SFH）的修饰不能预防毒性在动物或人类身上。我们将检验SFH会导致持续的全身和肾内血管收缩，氧合血红蛋白被代谢。我们还将检验以下假设：未改性和改性的SFH制剂都有可能在两种不同的情况下引起急性肾衰竭（ARF）： a. 我们假设，SFH会加重肾损伤，在确定肾衰竭后不久给予，一段时间的肾缺血 B. 我们假设SFH将导致“新发”ARF（在缺乏确定的肾损伤），当大量给药时，“治疗” 失血性休克后的剂量。我们的具体目标是： 1. 检查并比较血管收缩的机制未修饰的和修饰的SFH。我们将研究氧合血红蛋白抑制一氧化氮的机制，氧化物介导的血管舒张，以确定蛋白质修饰是否很可能会减少血管收缩的原因未改性SFH 我们将研究内皮素释放在SFH相关的血管收缩 2. 为了验证SFH将诱导中性粒细胞介导的内皮损伤我们将研究未修饰和修饰形式的SFH的影响，其代谢产物氯化血红素对嗜中性粒细胞-内皮细胞粘附和嗜酸性粒细胞诱导的内皮损伤。的发病机制参与SFH诱导的嗜中性粒细胞-粘附相互作用的将是阐明。 3. 检查和比较未修改和修改的 SFH加重了基础缺血性肾损伤。 4. 为了检查未修饰和修饰的SFH引起de 在给予大量SFH以降低血容量后新发ARF 动物我们将检验我们的假设，即肾功能衰竭将诱导天 SFH给药后， a）延长的肾内血管收缩B）毒性代谢物（氯化血红素和游离铁）在肾脏中的蓄积实质和c）嗜酸性粒细胞诱导的内皮损伤。