Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog

Abstract

Summary Background Inhalation of sulfur mustard (SM) and SM analog, 2-chloroethyl ethyl sulfide (CEES), cause fibrinous cast formation that occludes the conducting airways, similar to children with Fontan physiology-induced plastic bronchitis. These airway casts cause significant mortality and morbidity, including hypoxemia and respiratory distress. Our hypothesis was that intratracheal heparin, a highly cost effective and easily preserved rescue therapy, could reverse morbidity and mortality induced by bronchial cast formation. Methods Sprague-Dawley rats were exposed to 7.5% CEES via nose-only aerosol inhalation to produce extensive cast formation and mortality. The rats were distributed into three groups: non-treated, phosphate-buffered saline (PBS)-treated, and heparin-treated groups. Morbidity was assessed with oxygen saturations and clinical distress. Blood and bronchoalveolar lavage fluid (BALF) were obtained for analysis, and lungs were fixed for airway microdissection to quantify the extent of airway cast formation. Results Heparin, given intratracheally improved survival (100%) when compared to non-treated (75%) and PBS-treated (90%) controls. Heparin-treated rats also had improved oxygen saturations, clinical distress and airway cast scores. Heparin-treated rats had increased thrombin clotting times, factor Xa inhibition and activated partial thromboplastin times, indicating systemic absorption of heparin. There were also increased red blood cells (RBCs) in the BALF in 2/6 heparin-treated rats compared to PBS-treated control rats. Conclusions Intratracheal heparin 1 hr after CEES inhalation improved survival, oxygenation, airway obstruction, and clinical distress. There was systemic absorption of heparin in rats treated intratracheally. Some rats had increased RBCs in BALF, suggesting a potential for intrapulmonary bleeding if used chronically after SM inhalation.

Computational study on the interactions of mustard gas with cucurbituril macrocycles

“…Hence, there is considerable interest in the development of materials that can selectively absorb and recognize mustard gas. However, due to the toxic nature of HD, oxygen mustard (OM), has been used as a surrogate for HD in diffusion and sorption studies . However, there exists conformational and reactivity difference between HD and OM …”

Emerging targets for treating sulfur mustard–induced injuries

“…In rats, treatment with tissue plasminogen activator (TPA) after SM inhalation prevented cast formation and mortality . Similarly, treatment with heparin and tissue factor pathway inhibitor also prevented mortality . These studies underscore the importance of coagulation in SM/CEES‐induced injuries.…”

“…35 Similarly, treatment with heparin and tissue factor pathway inhibitor also prevented mortality. 34,36 These studies underscore the importance of coagulation in SM/CEES-induced injuries. Our studies suggest a significant contribution of airway epithelium to TF and other components of the clotting cascade.…”

Sulfur mustard inhalation: mechanisms of injury, alteration of coagulation, and fibrinolytic therapy

“…Also noteworthy was the observation that TFPI did not appreciably correct protein leak, an indication that mustard‐induced hypoxemia is not simply a manifestation of lung edema, but is instead caused by fibrin‐dependent airway obstruction. Airway delivery of other anticoagulants, including heparin, has been shown to limit mortality in response to half‐mustard (CEES), but these had to be given early (1 h) and caused occasional microhemorrhage . Following mustard inhalation, plasmin‐dependent fibrinolysis is the physiologic mechanism for removal of airway casts and restoration of airway patency.…”

“…Airway delivery of other anticoagulants, including heparin, has been shown to limit mortality in response to half-mustard (CEES), but these had to be given early (1 h) and caused occasional microhemorrhage. 45 Following mustard inhalation, plasmin-dependent fibrinolysis is the physiologic mechanism for removal of airway casts and restoration of airway patency. Elevated airway levels of several antifibrinolytic molecules also occur, which collectively inhibit the plasminogen activation pathway.…”