title: Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide.
abstract: Acute lung injury is a principal cause of morbidity and mortality in response to mustard gas (SM) inhalation. Obstructive, fibrin-containing airway casts have recently been reported in a rat inhalation model employing the SM analog 2-chloroethyl ethyl sulfide (CEES). The present study was designed to identify the mechanism(s) causing activation of the coagulation cascade after CEES-induced airway injury. Here we report that CEES inhalation elevates tissue factor (TF) activity and numbers of detached epithelial cells present in lavage fluid (BALF) from rats after exposure (18 h). In vitro studies using 16HBE cells, or with rat BALF, indicated that detached epithelial cells could convert factor X (FX) to the active form FXa when incubated with factor VII and could elicit rapid clotting of plasma. In addition, immunocytochemical analysis demonstrated elevated cell surface (TF) expression on CEES-exposed 16HBE cells as a function of time. However, total cell TF expression did not increase. Since membrane surfaces bearing TF are important determinants of clot initiation, anticoagulants directed against these entities were tested for ability to limit plasma clotting or FX activation capacity of BALF or culture media. Addition of tifacogin, a TF pathway inhibitor, effectively blocked either activity, demonstrating that the procoagulant actions of CEES were TF pathway dependent. Lactadherin, a protein capable of competing with clotting factors for phospholipid-binding sites, was partially effective in limiting these procoagulant actions. These findings indicate that TF pathway inhibition could be an effective strategy to prevent airway obstruction after SM or CEES inhalation.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Rancourt
authors.forename: Livia A
authors.initials: LA
authors.lastname: Veress
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Guo
authors.forename: Tara N
authors.initials: TN
authors.lastname: Jones
authors.forename: Tara B
authors.initials: TB
authors.lastname: Hendry-Hofer
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000402:Airway Obstruction / Q000139:chemically induced*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002461:Cell Line, Transformed; D002619:Chemical Warfare Agents / Q000633:toxicity; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005167:Factor VII / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008894:Milk Proteins / Q000378:metabolism; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000954:Antigens, Surface; D002619:Chemical Warfare Agents; C499941:MFGE8 protein, rat; D008894:Milk Proteins; D011506:Proteins; C400709:Tifacogin; C031278:2-chloroethyl ethyl sulfide; D005167:Factor VII; D013925:Thromboplastin; D015951:Factor Xa; D009151:Mustard Gas