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: 6381176
• 负责人: Richard A. Zager
• 金额: $ 26.36万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381176
• 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 下降了30多年。 这可能是因为大多数新的 必须在治疗期间给予规定的药物治疗。 肾损害的诱导期。 由于ARF患者通常 只有在肾损害发作后才能看到，可能为时已晚， 启动肾脏保护治疗。 一个值得注意的例外是， 接受手术的高危患者。 由于这种设置赋予了 ARF的高风险（在某些系列中>= 30%）， 月经周期可能是启动肾脏“预防性”治疗的理想时间 疗法 我们最近的研究（细胞培养，离体大鼠 小管、整个大鼠、手术患者）表明，目前使用的 氟化麻醉剂（e.e.异氟烷、七氟烷、地氟烷） 以及它们的一些降解产物（例如无机氟化物， 氟化乙烯基醚）可显著影响近曲小管细胞 体内平衡 在高剂量下，会产生明显的肾毒性。 相反，在低剂量下，一些快速（<=3小时）触发有效的 能够减轻叠加ATP的细胞保护状态 消耗/肾毒素诱导的肾小管坏死和ARF。 拟议 研究试图确定这一点的决定因素和机制， 从而优化其表达 可能降低术后ARF的风险。 对这些 为此，提出了三个具体目标：（1）确定 麻醉剂代谢是麻醉剂毒性的决定因素， 细胞保护 现有数据表明，细胞色素P450和 非P450代谢对近曲小管麻醉作用的影响 体内平衡 将探讨这一点的基础，以：a）界定 这些行动的基本机制; B）确定如何 增强麻醉药的表达 “细胞保护”与“伤害”效应2）定义机制 麻醉剂“毒性”和“细胞抗性”之间的联系。 大量 信息表明，亚致死性损伤可以启动适应性损伤， 最终导致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 对肾小管稳态（线粒体）的特异性麻醉作用 损伤、NaK-ATP酶抑制、PLA 2/活化-耗竭）， 将测试麻醉剂细胞抗性的“触发物”;和3： 定义氟化麻醉剂减轻 ARF的具体模式。 这些研究将测试氟化 麻醉剂与特定的亚细胞通路特异性相互作用 临床相关形式的损伤（肌血红蛋白毒性，） 从而防止ARF。 特别是，该假设将 可以测试氟化物诱导的PLA 2表达的改变， 线粒体自由基的产生和NaK-ATP酶活性在 共同消除肌血红蛋白尿的关键诱导途径 ARF。

项目成果

Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.

脓毒症综合征刺激近曲小管胆固醇合成并抑制 SR-B1 胆固醇转运蛋白。

• DOI: 10.1046/j.1523-1755.2003.00735.x
• 发表时间: 2003
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Zager,RichardA;Johnson,AliCM;Hanson,SherryY
• 通讯作者: Hanson,SherryY