title: 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.
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, Colorado.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Rancourt
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.forename: Livia A
authors.initials: LA
authors.lastname: Veress
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Rioux
authors.forename: Rhonda B
authors.initials: RB
authors.lastname: Garlick
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000402:Airway Obstruction / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000933:Antifibrinolytic Agents / Q000633:toxicity*; D015824:Blood-Air Barrier / Q000187:drug effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects; D025901:Carboxypeptidase B2 / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D005342:Fibrinolysis / Q000187:drug effects*; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D000933:Antifibrinolytic Agents; D002619:Chemical Warfare Agents; D017395:Plasminogen Activator Inhibitor 1; D000979:alpha-2-Antiplasmin; C031278:2-chloroethyl ethyl sulfide; D025901:Carboxypeptidase B2; D009151:Mustard Gas
keywords: lung injury; plasminogen activator inhibitor-1; sulfur mustard; thrombin activatable fibrinolysis inhibitor; α2-antiplasmin