Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide
Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide
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DOI：
10.1152/ajplung.00306.2010
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发表时间：
2012-01-01
影响因子：
4.9
通讯作者：
White, Carl W.
中科院分区：
文献类型：
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作者：
Rancourt, Raymond C.;Veress, Livia A.;White, Carl W.
Rancourt RC，Veress LA，Guo X，Jones TN，Hendry-Hampton T，白色CW.对硫芥类似物2-氯乙基乙基硫醚反应的气道组织因子依赖性凝血活性。Am J Physiol Lung Cell Mol Physiol 302：L82-L92，2012.首次发表于2011年9月30日; doi：10.1152/ajplung.00306.2010.-急性肺损伤是芥子气（SM）吸入后发病和死亡的主要原因。阻塞性，含纤维蛋白的气道管型最近已报告在大鼠吸入模型采用SM类似物2-氯乙基乙基硫醚（CEES）。本研究旨在确定CEES诱导的气道损伤后引起凝血级联激活的机制。在这里，我们报告，CEES吸入升高组织因子（TF）的活性和脱落的上皮细胞的数量存在于灌洗液（BALF）暴露后（18小时）的大鼠。使用16 HBE细胞或大鼠BALF的体外研究表明，当与因子VII孵育时，分离的上皮细胞可将因子X（FX）转化为活性形式FXa，并可引起血浆快速凝固。此外，免疫细胞化学分析表明CEES暴露的16 HBE细胞上的细胞表面（TF）表达升高作为时间的函数。然而，总细胞TF表达没有增加。由于携带TF的膜表面是凝块起始的重要决定因素，因此检测了针对这些实体的抗凝剂限制BALF或培养基的血浆凝血或FX活化能力的能力。添加替法古金（TF途径抑制剂）可有效阻断任一活性，表明CEES的促凝血作用是TF途径依赖性的。Lactadherin是一种能够与凝血因子竞争磷脂结合位点的蛋白质，在限制这些促凝血作用方面部分有效。这些结果表明，TF途径抑制可能是一种有效的策略，以防止气道阻塞后SM或CEES吸入。
Rancourt RC, Veress LA, Guo X, Jones TN, Hendry-Hofer T, White CW. Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide. Am J Physiol Lung Cell Mol Physiol 302: L82-L92, 2012. First published September 30, 2011; doi: 10.1152/ajplung.00306.2010.-Acute lung injury is a principal cause of morbidity and mortality in response to mustard gas (SM) inhalation. Obstructive, fibrin-containing airway casts have recently been reported in a rat inhalation model employing the SM analog 2-chloroethyl ethyl sulfide (CEES). The present study was designed to identify the mechanism(s) causing activation of the coagulation cascade after CEES-induced airway injury. Here we report that CEES inhalation elevates tissue factor (TF) activity and numbers of detached epithelial cells present in lavage fluid (BALF) from rats after exposure (18 h). In vitro studies using 16HBE cells, or with rat BALF, indicated that detached epithelial cells could convert factor X (FX) to the active form FXa when incubated with factor VII and could elicit rapid clotting of plasma. In addition, immunocytochemical analysis demonstrated elevated cell surface (TF) expression on CEES-exposed 16HBE cells as a function of time. However, total cell TF expression did not increase. Since membrane surfaces bearing TF are important determinants of clot initiation, anticoagulants directed against these entities were tested for ability to limit plasma clotting or FX activation capacity of BALF or culture media. Addition of tifacogin, a TF pathway inhibitor, effectively blocked either activity, demonstrating that the procoagulant actions of CEES were TF pathway dependent. Lactadherin, a protein capable of competing with clotting factors for phospholipid-binding sites, was partially effective in limiting these procoagulant actions. These findings indicate that TF pathway inhibition could be an effective strategy to prevent airway obstruction after SM or CEES inhalation.