MECHANISMS AND TREATMENT OF PHOSGENE POISONING

光气中毒的机制和治疗

• 批准号: 3420492
• 负责人: THOMAS P KENNEDY
• 金额: $ 16.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-30 至 1990-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3420492
• 关键词: acute disease /disorder; ammonia; arachidonate; bronchoconstrictors; chlorine; gas poisoning; laboratory rabbit; leukotrienes; lung disorder; occupational hazard; oxidizing agents; pulmonary hypertension; sulfur oxides; thromboxanes

Acute massive toxic gas exposure continues to be a problem facing occupational medicine and critical care medicine, not only due to isolated accidents involving workers in the manufacturing and use of chlorine, phosgene, nitrogen dioxide, ammonia, and sulfer dioxide, but also from exposure of larger bystander populations resulting from accidental toxic gas release during transportation. Much research exists on chronic low level exposure to these agents, but there is little work on pathophysiology and therapy of acute lung damage and respiratory distress from toxic gas inhalation. The proposed research will use inhaled phosgene exposure of an isolated perfused rabbit lung as a laboratory model for acute toxic gas inhalation. The pathophysiology of acute phosgene lung damage will be investigated, including whether acute broncho-constriction and pulmonary hypertension are due to lung production of arachidonic acid metabolites such as thomboxane and leukotrienes, and whether oxidant lung damage from phosgene causes depletion of lung glutathione. Several pharmacologic agents (corticosteroids, nosteroidal anti-inflammatory agents blocking cyclooxygenase and lipoxygenase pathways, protease inhibitors, beta-adrenergic agonists, and prostaglandin El) will be studied to determine their usefulness in attentuating lung edema formation. N-acetyl cysteine, a precursor of glutathione effective in treating oxidant liver damage from toxic doses of acetaminophen, will be evaluated as therapy for phosgene poisoning by insuring a sufficient supply of lung glutathione to react with phosgene and prevent its combination with membranes and cellular enzymes. Drugs such as the food additive antioxidant butylated hydroxy anisol (BHA) which elevate lung glutathione will be studied to determine whether chemoprophylaxis of phosgene poisoning is possible. The results of this research can provide a foundation for recommending physiologically sound therapy of oxidant lung damage from acute toxic gas inhalation in man.

急性大量有毒气体暴露仍然是一个问题， 职业医学和重症医学，不仅由于孤立的 涉及制造和使用氯的工人的事故， 光气、二氧化氮、氨和二氧化硫，但也可以从 意外中毒导致的较大旁观者群体的暴露 在运输过程中释放气体。 许多研究表明，慢性低 水平暴露于这些代理，但很少有工作的病理生理学 毒气致急性肺损伤和呼吸窘迫的治疗 吸入。 拟议的研究将使用吸入光气暴露的 离体兔肺灌流急性毒气实验模型的建立 吸入。 急性光气肺损伤的病理生理学将是 研究，包括是否急性支气管收缩和肺 高血压是由于肺产生花生四烯酸代谢物 如thomoxane和白三烯，以及是否氧化剂肺损伤， 光气引起肺谷胱甘肽的消耗。 几种药理学 药物（皮质类固醇、类固醇抗炎药、阻断剂） 环氧合酶和脂氧合酶途径，蛋白酶抑制剂， β-肾上腺素能激动剂和前列腺素E1）将被研究， 确定它们在减弱肺水肿形成中的有用性。 n乙酰 半胱氨酸，谷胱甘肽的前体，有效治疗氧化性肝 对乙酰氨基酚的毒性剂量的损害，将被评估为治疗 光气中毒，通过确保足够的肺谷胱甘肽供应， 与光气反应并防止其与膜和细胞结合 内切酶 药物如食品添加剂抗氧化剂丁羟 苯甲醚（BHA），提高肺谷胱甘肽将进行研究，以确定 光气中毒的化学预防是否可行。 的结果 这项研究可以为生理学推荐提供依据。 急性有毒气体吸入性氧化性肺损伤声治疗