Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

Abstract

Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway-capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot-degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and α2-antiplasmin. Measurement of tissue-specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide-induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and α2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM.

Mustard vesicant-induced lung injury: Advances in therapy

“…At the same time, functionally active reservoirs of plasminogen activator-inhibitor-1, thrombin-activated fibrinolysis inhibitor, and α2 anti-plasmin appear in the airways, which inhibit thrombin-mediated fibrinolysis (Rancourt et al, 2014). SM exposure has been reported to lead to plastic bronchitis, characterized by the formation of branching bronchial casts which can obstruct the airway and lead to segmental lung collapse, patchy infiltrates, and significant respiratory distress.…”

Emerging targets for treating sulfur mustard–induced injuries

“…Autopsy of one patient who died of airway obstruction indicated formation of bronchial casts, in conjunction with formation of fibrin‐rich pseudomembranes and inflammation of the trachea and bronchial tubes . These findings have also been reproduced in animal experiments with CEES or SM …”

“…In addition to TF activation, SM/CEES exposure causes increases in fibrinogen, prothrombin, and thrombin–antithrombin complexes in the bronchoalveolar lavage fluid (BALF) of CEES‐exposed rats . These exposures cause an increase in TF activity and an increase in factor X (FX) expression . SM/CEES exposure also causes a parallel inhibition of the fibrinolytic pathway by increasing plasminogen activator inhibitor‐1 (PAI‐1), thrombin‐activatable fibrinolysis inhibitor, and α 2 ‐antiplasmin .…”

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

“…Evidence supporting one or all of these mechanisms of action include findings of increased lipid peroxidation, depletion of GSH, and increases in 8-hydroxy-2-deoxyguanosine (8-OHdG)[7,10]. Lethal SM exposures produce bronchial airway casts that are associated with restrictive airflow and obstruction and can be lethal within 48 hours[13,14]. Animals that survive the airway obstruction go on to die with lung fibrosis and bronchiolitis obliterans at 4 to 6 weeks post exposure[15,16].…”

“…CEES has been reported to increase cellular ROS and RNS, produce oxidative DNA damage, increase mitochondrial ROS formation, and mitochondrial dysfunction [20]. CEES exposures also result in the formation of obstructive airway casts that has been observed with SM[13,14,21]. …”