Editor’s Highlight: Pulmonary Vascular Thrombosis in Rats Exposed to Inhaled Sulfur Mustard

Abstract

Sulfur mustard (SM) is a chemical warfare agent. When inhaled, SM causes significant injury to the respiratory tract. Although the mechanism involved in acute airway injury after SM inhalation has been well described previously, the mechanism of SM's contribution to distal lung vascular injury is not well understood. We hypothesized that acute inhalation of vaporized SM causes activated systemic coagulation with subsequent pulmonary vascular thrombi formation after SM inhalation exposure. Sprague Dawley rats inhaled SM ethanolic vapor (3.8 mg/kg). Barium/gelatin CT pulmonary angiograms were performed to assess for pulmonary vascular thrombi burden. Lung immunohistochemistry was performed for common procoagulant markers including fibrin(ogen), von Willebrand factor, and CD42d in control and SM-exposed lungs. Additionally, systemic levels of d-dimer and platelet aggregometry after adenosine diphosphate- and thrombin-stimulation were measured in plasma after SM exposure. In SM-exposed lungs, chest CT angiography demonstrated a significant decrease in the distal pulmonary vessel density assessed at 6 h postexposure. Immunohistochemistry also demonstrated increased intravascular fibrin(ogen), vascular von Willebrand factor, and platelet CD42d in the distal pulmonary vessels (<200 µm diameter). Circulating d-dimer levels were significantly increased (p < .001) at 6, 9, and 12 h after SM inhalation versus controls. Platelet aggregation was also increased in both adenosine diphosphate - (p < .01) and thrombin- (p < .001) stimulated platelet-rich plasma after SM inhalation. Significant pulmonary vascular thrombi formation was evident in distal pulmonary arterioles following SM inhalation in rats assessed by CT angiography and immunohistochemistry. Enhanced systemic platelet aggregation and activated systemic coagulation with subsequent thrombi formation likely contributed to pulmonary vessel occlusion.

Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure

“…The current study is novel in its use of the coculture model of primary HAECs and primary human endothelial cells exposed to pure NM vapor. This in vitro coculture system was developed to model the known in vivo pulmonary complications of high-concentration mustard vapor exposure with AEC death, 7,8 adjacent pulmonary vasculature injury, 11,15,17 and subsequent vascular leak. 16 Different from prior in vitro mustard exposure studies, 18,[23][24][25][26] the model system uses vaporized NM in place of topical mustard exposure for exposures.…”

“…Following high-dose mustard inhalation exposure, doi: 10.1111/nyas.14367 injury to both the airway epithelial and adjacent endothelial cell layers occurs. 15 This acute airway injury results in bronchial vascular leak and subsequent bronchial cast formation. 11,16,17 Fibrin-rich bronchial casts cause significant airway obstruction, and ultimately, death.…”

“…Although airway obstruction is the main cause of acute mortality after mustard exposure, limited understanding remains with regard to both acute and chronic mustard‐induced lung pathogenesis. Following high‐dose mustard inhalation exposure, injury to both the airway epithelial and adjacent endothelial cell layers occurs 15 . This acute airway injury results in bronchial vascular leak and subsequent bronchial cast formation 11,16,17 .…”

The clinical efficacy of using autologous platelet-rich plasma in total hip arthroplasty

“…[ 6 , 7 , 13 ] Studies have shown that the effect of multiple growth factors is better than that of single growth factor, which may be related to a variety of factors, which are related to multiple stages of the healing process. [ 14 , 15 ]…”

Fibrinolytic therapy for refractory COVID‐19 acute respiratory distress syndrome: Scientific rationale and review

“…Both nebulized and direct instillation of t‐PA into the airways via bronchoscopy have been used off‐label to treat fibrin airway casts 61 . In a lethal animal model of both severe pulmonary microvascular thrombi and severe bronchial fibrin casts, treatment with airway t‐PA resulted in improved survival, dissolved airway casts, and normalized pO 2 and pCO 2 62,63 . However, the mounting evidence specific to COVID‐19 that shows pulmonary microvascular thrombosis as a predominant finding 26–28 combined with normal lung compliance and high alveolar‐arterial oxygen gradients 64 suggests intravascular delivery may be the more appropriate delivery route, with concern that intra‐airway delivery via intratracheal instillation or nebulized solutions may increase the risk to health care workers by exposing them to infectious airway secretions.…”