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: 2906254
• 负责人: Richard A. Zager
• 金额: $ 24.85万
• 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/2906254
• 关键词: acute renal failure; anesthetics; cysteine; cytochrome P450; cytoprotection; 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.

尽管对急性肾衰竭的发病机制有了新的认识 （ARF），这种疾病的发病率和死亡率都没有 30多年来不断下降。 这可能是由于最近 必须在治疗期间进行明确的药物治疗 肾损伤的诱导期。 由于 ARF 患者通常 仅在肾损害发生后才发现，可能为时已晚 开始肾脏保护治疗。 一个值得注意的例外可能是 是接受手术的高危患者。 由于此设置赋予 ARF 风险较高（某些系列中>= 30%），术中 这段时期可能是开始肾脏“预防”的理想时间 治疗 。 我们最近的研究（细胞培养、离体大鼠 肾小管、整只大鼠、手术患者）表明目前使用 氟化麻醉剂（例如异氟烷、七氟烷、地氟烷） 及其一些降解产物（例如无机氟化物， 氟化乙烯基醚）可显着影响近端小管细胞 体内平衡。 高剂量时会产生明显的肾毒性。 相反，在低剂量下，一些药物会迅速（<=3小时）引发强效 能够减轻叠加 ATP 的细胞保护状态 耗竭/肾毒素诱导的肾小管坏死和 ARF。 拟议的 研究旨在确定这一现象的决定因素和机制 细胞保护状态，从而优化其表达 可能降低术后 ARF 的风险。 朝着这些 最后，提出了三个具体目标 1) 定义角色 麻醉代谢作为麻醉毒性的决定因素 细胞保护。 现有数据表明细胞色素 P450 和 非P450代谢影响近曲小管麻醉效果 体内平衡。 将探讨其基础：a) 定义 这些行动的基本机制； b) 确定方法 药理学上增强麻醉剂的表达 “细胞保护”与“有害”作用 2) 定义机制 麻醉剂“毒性”和“细胞抗性”之间的联系。 过多 的信息表明亚致死性损伤可以启动适应性 最终形成细胞抗性状态的反应。 于是，“受伤” 和~保护~可以是频谱上的两个点。 3的角色 对肾小管稳态（线粒体 损伤、NaK-ATP酶抑制、PLA2/激活-耗竭） 将测试麻醉细胞抵抗的“触发因素”；和 3： 定义氟化麻醉剂减轻疼痛的机制 ARF的具体模型。 这些研究将测试如何氟化 麻醉剂与特定的亚细胞途径发生特异性相互作用 临床相关形式的损伤（肌血红蛋白毒性） 从而预防 ARF。 特别是，该假设将 测试氟化物诱导的 PLA2 表达变化， 线粒体自由基的产生和 NaK-ATP 酶活性作用于 消除肌血红蛋白尿关键诱导途径的音乐会 ARF。