Alleviation of methyl isocyanate-induced airway obstruction and mortality by tissue plasminogen activator.
Alleviation of methyl isocyanate-induced airway obstruction and mortality by tissue plasminogen activator.
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DOI：
10.1111/nyas.14344
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发表时间：
2020-11
影响因子：
5.2
通讯作者：
White CW
中科院分区：
文献类型：
--
作者：
Nick HJ;Rioux JS;Veress LA;Bratcher PE;Bloomquist LA;Anantharam P;Croutch CR;Tuttle RS;Peters E;Sosna W;White CW
异氰酸甲酯（MIC，“博帕尔剂”）是一种高活性、有毒的工业化学品。吸入高浓度（500 - 1000ppm）的MIC蒸气几乎都是致命的。除支持性护理外，没有其他治疗干预措施可延迟因MIC引起的发病或死亡。最近，我们发现吸入MIC引起循环中出现活化组织因子，随后激活凝血级联。在本研究中，我们报告了MIC暴露（500 ppm，仅鼻子暴露30分钟）导致导气管中富含纤维蛋白的铸型沉积，导致大鼠模型（LC90 - 100） 24小时内呼吸衰竭和死亡。因此，我们在该模型中研究了气道输送纤维蛋白溶解剂组织纤溶酶原激活剂（tPA）对死亡率和发病率的影响。在mic暴露后11小时开始气管内给药tPA，在研究期间每4小时重复一次。在mic暴露后24小时，tPA治疗提供了近60%的生存率，并与气道纤维蛋白铸型减少、低氧血症和呼吸窘迫的稳定以及酸中毒的改善有关。这项工作支持了气道输送tPA治疗作为稳定高水平MIC暴露受害者的有用对策的潜力。我们的研究表明，在MIC吸入暴露的急性致死模型中，气道输送的tPA提供了部分预防死亡率的保护，并显著降低了气道阻塞。在MIC吸入引起的呼吸窘迫的急性治疗中，该方法可用于气道清除。此外，类似的治疗方案可能潜在地减轻由其他异氰酸酯或二异氰酸酯引起的肺损伤，从而扩大其临床重要性。
Methyl isocyanate (MIC, “Bhopal agent”) is a highly reactive, toxic industrial chemical. Inhalation of high levels (500–1000 ppm) of MIC vapor are almost uniformly fatal. No therapeutic interventions other than supportive care have been described that can delay the onset of illness or death owing 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. Our study demonstrates that airway-delivered tPA provided partial protection against mortality, and substantially decreased airway obstruction in an acutely lethal model of MIC inhalation exposure. This approach could be useful for airway clearance in acute therapy of MIC inhalation–induced respiratory distress. Furthermore, a similar therapeutic regimen may potentially alleviate lung injuries owing to other isocyanates or diisocyanates, thereby expanding its clinical importance.
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DOI：
10.1164/ajrccm/140.4.1104
发表时间：
1989-10-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
BROWN, LF;DVORAK, AM;DVORAK, HF
通讯作者：
DVORAK, HF
DOI：
10.1513/pats.201001-004sm
发表时间：
2010-07-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Bessac, Bret F;Jordt, Sven-Eric
通讯作者：
Jordt, Sven-Eric
影响因子：
3.7
作者：
Hohlbaum, Katharina;Bert, Bettina;Thoene-Reineke, Christa
通讯作者：
Thoene-Reineke, Christa
影响因子：
9.8
作者：
Groeben, H;Meier, S;Brown, RH
通讯作者：
Brown, RH
DOI：
10.1016/0272-0590(86)90188-0
发表时间：
1986-05-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
FOWLER, EH;DODD, DE
通讯作者：
DODD, DE