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

项目摘要 - R01 (Veress) 吸入高剂量的硫芥（SM）会导致高凝状态导致急性心肺衰竭 肺部状态，表现为纤维蛋白气道管型引起的急性气道阻塞。急性和早期系统性 还会发生高凝状态，导致至少肺内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 SM 剂量较低。 SM，导致轻微的急性症状和急性死亡。尽管如此，他们的 SM 吸入暴露 导致严重肺部疾病的发生，包括延迟性、长期性（通常是进行性） 急性暴露事件后数月至数年的心血管后遗症。这些由 SM 引起的迟发性疾病 吸入包括慢性肺部疾病和慢性进行性心血管疾病，例如肺病 高血压（PH）、动脉高血压（HTN）和心脏功能障碍/衰竭。这些疾病减少 幸存者的生活质量下降，无法治愈，其发病机制也知之甚少。与 SM 相反，高 由于严重的上皮和气道损伤，吸入剂量氯 (Cl2) 仅在接触后几小时内致命 水肿、严重急性神经系统功能障碍、钙储存/释放异常以及急性 血管收缩性肺动脉高压（PH）。 Cl2 不会在气道中形成急性纤维蛋白管型，有趣的是， Cl2 暴露后的恢复不会导致任何长期心血管疾病。保护机制 Cl2气体后慢性心肺疾病的发展引起了高度关注。我们开发了， 表征并验证了 Sprague Dawley 大鼠吸入 SM 和 Cl2 的两种相关恢复模型（LD50- 28d），两者都模仿了这些伤害后的人类恢复综合症。初步数据表明，大鼠 暴露于低剂量 SM 吸入不仅会发生晚期肺纤维化，而且会出现显着的进展性肺纤维化。 （随着时间的推移而恶化）PH、右心室功能障碍、心力衰竭和晚期全身动脉阻力增加（>14- 21 天）暴露后——通过大鼠超声心动图和血流动力学技术测量。另外， 我们发现，从吸入 Cl2 中急性恢复后，心血管会完全恢复 29 天（或更早）之前。 SM吸入后29天的蛋白质组学通路分析和组织病理学研究 表明显着的持续内皮细胞途径功能障碍、心肌细胞/肌细胞途径功能障碍、 以及急性恢复期后持续的凝血异常。我们假设，继续 SM 后恢复期间的内皮细胞功能障碍而非 Cl2 吸入将引发持续的促 肺、心脏和全身脉管系统内的凝血和促重塑途径，这将导致 慢性血栓形成和肌原纤维肥大的发展，导致迟发性慢性进行性 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。该提案将为未来慢性心血管疾病的治疗开发带来成功 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.