Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortality and lacks any effective therapy. Rats exposed to aerosolized CEES (2-chloroethyl ethyl sulfide; 10% in ethanol), an analog of SM, developed acute respiratory distress syndrome (ARDS), which is characterized by increased inflammation, hypoxemia and impaired gas exchange. We observed elevated levels of extracellular nucleic acids (eNA) in the bronchoalveolar lavage fluid (BALF) of CEES-exposed animals. eNA can induce inflammation, coagulation and barrier dysfunction. Treatment with hexadimethrine bromide (HDMBr; 10 mg/kg), an eNA neutralizing agent, 2 h post-exposure, reduced lung injury, inhibited disruption of alveolar-capillary barrier, improved blood oxygenation (PaO2/FiO2 ratio), thus reversing ARDS symptoms. HDMBr treatment also reduced lung inflammation in the CEES-exposed animals by decreasing IL-6, IL-1A, CXCL-1 and CCL-2 mRNA levels in lung tissues and HMGB1 protein in BALF. Furthermore, HDMBr treatment also reduced levels of lung tissue factor and plasminogen activator inhibitor-1 indicating reduction in clot formation and increased fibrinolysis. Fibrin was reduced in BALF of the HDMBr-treated animals. This was further confirmed by histology that revealed diminished airway fibrin, epithelial sloughing and hyaline membrane in the lungs of HDMBr-treated animals. HDMBr completely rescued the CEES-associated mortality 12 h post-exposure when the survival rate in CEES-only group was just 50%. Experimental eNA treatment of cells caused increased inflammation that was reversed by HDMBr. These results demonstrate a role of eNA in the pathogenesis of CEES/SM-induced injury and that its neutralization can serve as a potential therapeutic approach in treating SM toxicity.

中文翻译：

---

细胞外核酸清除使大鼠免于硫芥类似物引起的肺损伤和死亡。

硫芥 (SM) 是一种剧毒的战争化学品，会导致严重的发病率和死亡率，并且缺乏任何有效的治疗方法。暴露于 SM 类似物雾化 CEES（2-氯乙基乙基硫醚；10% 乙醇溶液）的大鼠出现急性呼吸窘迫综合征 (ARDS)，其特征是炎症增加、低氧血症和气体交换受损。我们观察到 CEES 暴露动物的支气管肺泡灌洗液 (BALF) 中细胞外核酸 (eNA) 水平升高。eNA 可诱导炎症、凝血和屏障功能障碍。暴露后 2 小时使用 eNA 中和剂溴化己二甲胺 (HDMBr；10 mg/kg) 治疗，减少肺损伤，抑制肺泡-毛细血管屏障破坏，改善血氧合（PaO2/FiO2 比率），从而逆转 ARDS 症状. HDMBr 治疗还通过降低肺组织中的 IL-6、IL-1A、CXCL-1 和 CCL-2 mRNA 水平以及 BALF 中的 HMGB1 蛋白来减少 CEES 暴露动物的肺部炎症。此外，HDMBr 治疗还降低了肺组织因子和纤溶酶原激活物抑制剂 1 的水平，表明凝块形成减少和纤维蛋白溶解增加。HDMBr 治疗动物的 BALF 中的纤维蛋白减少。组织学进一步证实了这一点，组织学显示 HDMBr 治疗动物肺中的气道纤维蛋白减少、上皮脱落和透明膜。当仅 CEES 组的存活率仅为 50% 时，HDMBr 完全挽救了暴露后 12 小时与 CEES 相关的死亡率。细胞的实验性 eNA 处理引起了 HDMBr 逆转的炎症增加。