Vascular injury and repair predict divergent late onset cardiovascular morbidities after chlorine and sulfur mustard exposure

项目总结-R 01（Veress） 吸入高剂量硫芥（SM）可导致高凝状态的急性心肺衰竭。 在肺内的状态，表现为纤维蛋白气道管型引起的急性气道阻塞。急性和早期全身性 还发生高凝状态，导致至少在肺内的大血管和微血管血栓形成。 血管，可能还有其他器官。然而，大多数接触SM的人吸入的剂量较低， SM，导致轻微急性症状和急性死亡。然而，他们的SM吸入暴露 导致发生显著的肺部疾病，包括迟发性、长期性（通常为进行性） 急性暴露事件发生后数月至数年出现心血管后遗症。SM的这些迟发性疾病 吸入性疾病包括慢性肺病和慢性进行性心血管疾病，例如肺 高血压（PH）、动脉高血压（HTN）和心功能不全/衰竭。这些疾病减少 生存者的生活质量，没有治愈方法，其发病机制知之甚少。与SM相反，高 氯（Cl 2）吸入剂量仅在暴露后几小时内致命，因为严重的上皮和气道 水肿、严重急性神经系统功能障碍、钙储存/释放异常和急性 血管收缩性肺动脉高压（PH）。没有急性纤维蛋白管型形成的气道与氯气，和有趣的是， 暴露于Cl 2后的恢复不会导致任何长期的心血管疾病。保护机制 从发展中国家的慢性心肺疾病后，氯气是高度关注。我们开发了， 在Sprague道利大鼠中表征并验证SM和Cl 2吸入的两种相关恢复模型（LD 50- 28 d），两者都模仿这些损伤后的人类恢复综合征。初步数据显示， 吸入低剂量SM不仅可发生迟发性肺纤维化， （随时间恶化）PH、RV功能障碍、心力衰竭和晚期全身动脉阻力增加（>14- 21天）-通过大鼠超声心动图和血液动力学技术测量。此外，本发明还 我们发现，在从暴露于Cl 2吸入中急性恢复后，发生了完全的心血管恢复 29天（或更早）。SM吸入后29天的蛋白质组学途径分析和组织病理学研究 表明显著进行性内皮细胞途径功能障碍、心肌细胞/肌细胞途径功能障碍 并在急性恢复期后持续凝血异常。我们假设， 在SM而不是Cl 2吸入后恢复期间的内皮细胞功能障碍将触发持续的促内皮细胞增殖。 凝血和促重塑途径在肺，心脏和全身血管系统，这将导致 在慢性血栓形成和肌原纤维肥大的发展中， 肺动脉功能障碍（PH）、全身血管功能障碍（HTN）和心室功能障碍 和失败该提案将为未来针对慢性心血管疾病的治疗开发提供支持 SM吸入后遗症。

PROJECT SUMMARY - R01 (Veress) Inhalation of sulfur mustard (SM) at high doses causes acute cardiopulmonary failure from a hypercoagulable state within the lungs, presenting as acute airway obstruction by fibrin airway casts. Acute and early systemic hypercoagulability also occurs, resulting in macro- and microvascular thrombosis within at least the pulmonary vessels, and likely other organs as well. However, most people who are exposed to SM inhale a lower dose of SM, resulting in minimal acute symptoms and acute fatalities. Nevertheless, their SM inhalation exposures results in the development of significant pulmonary morbidities, including delayed, long-term (often progressive) cardiovascular sequelae months to years after the acute exposure event. These late-onset morbidities from SM inhalation include chronic lung diseases, and chronic progressive cardiovascular diseases, such as pulmonary hypertension (PH), arterial hypertension (HTN) and cardiac dysfunction/failure. These disorders decrease quality of life for survivors, have no cure, and their pathogenesis are poorly understood. Conversely to SM, high dose chlorine (Cl2) inhalation is only fatal within a few hours after exposure, due to severe epithelial and airway edema, severe acute nervous system dysfunction, abnormal calcium storage/release, and acute vasoconstrictive pulmonary hypertension (PH). No acute fibrin casts form in the airways with Cl2, and intriguingly, recovery after Cl2 exposure does not result in any long-term cardiovascular morbidities. Mechanisms that protect from development of chronic cardiopulmonary diseases after Cl2 gas is of high interest. We developed, characterized and validated two relevant recovery models of SM and Cl2 inhalation in Sprague Dawley rats (LD50- 28d), both of which mimic the human recovery syndrome after these injuries. Preliminary data show that rats exposed to low dose SM inhalation develop not only late pulmonary fibrosis, but also significant progressive (worsening over time) PH, RV dysfunction, cardiac failure, and increased systemic arterial resistance late (>14- 21 days) after exposure – as measured by rat echocardiography and hemodynamics techniques. Additionally, we found that after acute recovery from exposure to Cl2 inhalation, a complete cardiovascular recovery occurs by 29 days (or earlier). Proteomics pathway analysis and histopathologic studies from 29 days after SM inhalation indicate significant ongoing endothelial cell pathway dysfunction, cardiomyocyte/myocyte pathway dysfunction, and continued coagulation abnormalities past the acute recovery phase. We hypothesize, that continued endothelial cell dysfunction during recovery following SM but not Cl2 inhalation will trigger persistent pro- coagulant and pro-remodeling pathways within the lungs, heart and systemic vasculature, and that this will result in the development of chronic thrombosis and myofibrillar hypertrophy, leading to late-onset chronic progressive pulmonary arterial dysfunction (PH), systemic vascular dysfunction (HTN), and cardiac ventricular dysfunction and failure. This proposal will develop hits for future therapeutic development against chronic cardiovascular sequelae of SM inhalation.