Alleviation of methyl isocyanate−induced airway obstruction and mortality by tissue plasminogen activator,Annals of the New York Academy of Sciences

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Alleviation of methyl isocyanate−induced airway obstruction and mortality by tissue plasminogen activator
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2020-03-31 , DOI: 10.1111/nyas.14344
Heidi J Nick ₁ , Jacqueline S Rioux ₁ , Livia A Veress ₁ , Preston E Bratcher _{1,

2} , Leslie A Bloomquist ₁ , Poojya Anantharam ₃ , Claire R Croutch ₃ , Richard S Tuttle ₃ , Eric Peters ₃ , William Sosna ₃ , Carl W White ₁

Affiliation

Methyl isocyanate (MIC, “Bhopal agent”) is a highly reactive, toxic industrial chemical. Inhalation of high levels (500–1000 ppm) of MIC vapor is almost uniformly fatal. No therapeutic interventions other than supportive care have been described that can delay the onset of illness or death due to MIC. Recently, we found that inhalation of MIC caused the appearance of activated tissue factor in circulation with subsequent activation of the coagulation cascade. Herein, we report that MIC exposure (500 ppm for 30 min, nose‐only) caused deposition of fibrin‐rich casts in the conducting airways resulting in respiratory failure and death within 24 h in a rat model (LC90−100). We thus investigated the effect of airway delivery of the fibrinolytic agent tissue plasminogen activator (tPA) on mortality and morbidity in this model. Intratracheal administration of tPA was initiated 11 h post MIC exposure and repeated every 4 h for the duration of the study. Treatment with tPA afforded nearly 60% survival at 24 h post MIC exposure and was associated with decreased airway fibrin casts, stabilization of hypoxemia and respiratory distress, and improved acidosis. This work supports the potential of airway‐delivered tPA therapy as a useful countermeasure in stabilizing victims of high‐level MIC exposure.

中文翻译：

组织纤溶酶原激活剂减轻异氰酸甲酯引起的气道阻塞和死亡率

异氰酸甲酯（MIC，“Bhopal 试剂”）是一种高反应性、有毒的工业化学品。吸入高浓度（500-1000 ppm）的 MIC 蒸气几乎都是致命的。除了支持性护理外，没有描述过可以延迟 MIC 引起的疾病或死亡的发生的治疗干预措施。最近，我们发现吸入 MIC 会导致循环中出现激活的组织因子，随后激活凝血级联。在此，我们报告了 MIC 暴露（500 ppm 持续 30 分钟，仅鼻子）导致富含纤维蛋白的管型在传导气道中沉积，导致大鼠模型（LC90-100）在 24 小时内呼吸衰竭和死亡。因此，我们研究了纤溶剂组织纤溶酶原激活剂 (tPA) 的气道递送对该模型中死亡率和发病率的影响。tPA 的气管内给药在 MIC 暴露后 11 小时开始，并在研究期间每 4 小时重复一次。tPA 治疗在 MIC 暴露后 24 小时提供近 60% 的存活率，并且与气道纤维蛋白管型减少、低氧血症和呼吸窘迫稳定以及酸中毒改善有关。这项工作支持气道输送 tPA 疗法作为稳定高水平 MIC 暴露受害者的有用对策的潜力。

更新日期：2020-03-31

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