ACUTE RENAL FAILURE--IMPACT OF FLUORINATED ANESTHETICS

急性肾功能衰竭——氟化麻醉剂的影响

• 批准号: 2665685
• 负责人: Richard A. Zager
• 金额: $ 24.83万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2665685
• 关键词: acute renal failure; anesthetics; cysteine; cytochrome P450; cytotoxicity; drug adverse effect; drug metabolism; drug screening /evaluation; enzyme inhibitors; fluoride ion; glutathione; intracellular transport; isoflurane; kidney cell; laboratory rat; mitochondria; pharmacokinetics; phospholipase A2; postoperative complications; sodium potassium exchanging ATPase; tissue /cell culture

Despite new insights into the pathogenesis of acute renal failure (ARF), neither the incidence nor mortality from this disease has declined over 30 years. This may be due to the fact that most newly defined pharmacologic therapies must be administered during the induction phase of renal damage. Since ARF patients are typically seen only after the onset of renal damage, it may be too late to initiate renal protective therapy. One notable exception to this may be high risk patients undergoing surgery. Since this setting confers a high risk of ARF (>= 30% in some series), the intra-operative period could be an ideal time for initiating renal "prophylactic" therapy . Our recent investigations (cell culture, isolated rat tubules, whole rats, surgical patients) indicate that currently used fluorinated anesthetics (e.e. isoflurane, sevoflurane, desflurane) and some of their degradative products (e.g. inorganic fluoride, fluorinated vinyl ethers) can markedly affect proximal tubule cell homeostasis. In high doses, overt nephrotoxicity results. Conversely, in low doses, some rapidly (<=3 hrs) trigger a potent cytoprotective state which is capable of mitigating superimposed ATP depletion/nephrotoxin- induced tubule necrosis and ARF. The proposed research seeks to ascertain determinants and mechanisms of this cytoprotective state in order to optimize its expression thereby potentially decreasing the risk of post-operative ARF. Towards these ends, three specific aims are proposed 1) Define the role of anesthetic metabolism as a determinant of anesthetic toxicity and cytoprotection. The available data suggests that cytochrome P450 and non P450 metabolism impact anesthetic effects on proximal tubule homeostasis. The basis for this will be explored to: a) define underlying mechanism for these actions; b) to ascertain ways to pharmacologically enhance the expression of anesthetic "cytoprotective" vs. "injurious" effects 2)Define the mechanistic link between anesthetic "toxicity" and "cytoresistance". A plethora of information indicates that sub lethal injury can initiate adaptive responses that culminate in a cytoresistant state. Thus, "injury" and ~protection~ can be two points on a spectrum. The role of 3 specific anesthetic effects on tubule homeostasis (mitochondrial injury, NaK-ATPase inhibition, PLA2/activation-depletion) as "triggers" for anesthetic cytoresistance will be tested; and 3: Define mechanisms by which fluorinated anesthetics mitigate a specific model of ARF. These studies will test how fluorinated anesthetics specifically interact with specific subcellular pathways of a clinically relevant form of injury (myohemoglobin toxicity,) thereby protecting against ARF. In particular, the hypothesis will be tested that fluoride-induced alterations in PLA2 expression, mitochondrial free radical generation and NaK-ATPase activity act in concert to abrogate critical induction pathways of myohemoglobinuric ARF.

尽管对急性肾功能衰竭的发病机制有了新的见解 (ARF)，这种疾病的发病率和死亡率都没有 在过去的30年里下降了。这可能是因为大多数新的 规定的药物治疗必须在 肾损害的诱导期。由于ARF患者通常 只有在肾损害发生后才能看到，可能已经太晚了 启动肾脏保护性治疗。其中一个值得注意的例外是5月 成为接受手术的高危患者。由于此设置可赋予 ARF的高风险(在某些系列中=30%)，术中 这一时期可能是开始肾脏“预防”的理想时机 心理治疗。我们最近的研究(细胞培养、分离的大鼠 小管、整个大鼠、外科患者)表明当前使用的 含氟麻醉剂(e.E.异氟醚、七氟醚、地氟烷) 以及它们的一些降解产物(例如无机氟， 氟乙烯基醚)可显著影响近曲小管细胞 动态平衡。在高剂量下，会导致明显的肾毒性。 相反，在低剂量下，一些迅速(=3小时)会引发强烈的 一种细胞保护状态，能够减轻叠加的ATP 肾功能衰竭/肾毒素所致的肾小管坏死和ARF。建议数 研究试图确定这种情况的决定因素和机制。 细胞保护状态，从而优化其表达 潜在地降低了术后ARF的风险。朝向这些 最后，提出了三个具体目标：1)确定 麻醉新陈代谢是麻醉毒性的决定因素 细胞保护。现有的数据表明，细胞色素P450和 非P450代谢对近端小管麻醉效应的影响 动态平衡。将探讨这方面的基础：a)界定 这些行动的基本机制；b)确定如何 药理作用促进麻醉剂的表达 “细胞保护”与“伤害”效应2)定义了 麻醉剂“毒性”和“细胞抵抗力”之间的联系。太多了 信息表明亚致命性损伤可以启动适应性 最终达到细胞抵抗状态的反应。因此，“伤害” 和~保护~可以是频谱上的两个点。3的作用 特异性麻醉对肾小管内稳态(线粒体)的影响 损伤、NAK-ATPase抑制、PLA2/激活-耗竭)AS 将测试麻醉剂细胞耐药性的“触发物”；以及3： 明确氟化麻醉剂缓解高血压的机制 ARF的特定模型。这些研究将测试氟化程度 麻醉药与特定的亚细胞通路特异地相互作用 临床上相关的损伤形式(肌红蛋白中毒) 从而防止ARF。特别是，这一假说将 被测试为氟化物诱导PLA2表达的改变， 线粒体自由基生成和NAK-ATPase活性在脑损伤中的作用 协议会废除肌红蛋白尿酸的关键诱导途径 啊哈。