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

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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.