title: Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation.
abstract: BACKGROUND
  Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, which can lead to respiratory failure and death. Mortality in those requiring intubation is more than 80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress, L. A., Hendry-Hofer, T. B., Loader, J. E., Rioux, J. S., Garlick, R. B., and White, C. W. (2013). Tissue plasminogen activator prevents mortality from sulfur mustard analog-induced airway obstruction. Am. J. Respir. Cell Mol. Biol. 48, 439-447). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome.
  
  
  METHODS
  Adult rats were exposed to SM, and when oxygen saturation reached less than 85% (median: 6.5 h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4 h for 48 h. Oxygen saturation, clinical distress, and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts.
  
  
  RESULTS
  Intratracheal tPA treatment eliminated mortality (0% at 48 h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction.
  
  
  CONCLUSIONS
  tPA given via airway more than 6 h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life-saving rescue therapy after a significant SM inhalation exposure incident.
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland Livia.Veress@ucdenver.edu.
authors.forename: Livia A
authors.initials: LA
authors.lastname: Veress
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Anderson
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Tara B
authors.initials: TB
authors.lastname: Hendry-Hofer
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Houin
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Rioux
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Rhonda B
authors.initials: RB
authors.lastname: Garlick
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Loader
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Paradiso
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Smith
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Rancourt
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Wesley W
authors.initials: WW
authors.lastname: Holmes
authors.affiliation: *Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045 and Medical Toxicology Branch/Analytical Toxicology Division U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, Maryland.
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000138:Acidosis / Q000139:chemically induced / Q000517:prevention & control; D000280:Administration, Inhalation; D000402:Airway Obstruction / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002619:Chemical Warfare Agents; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009151:Mustard Gas; D010100:Oxygen / Q000097:blood; D012123:Pulmonary Ventilation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D002619:Chemical Warfare Agents; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D010100:Oxygen; D009151:Mustard Gas
keywords: airway fibrin; fibrinolysis; plastic bronchitis; sulfur mustard; tPA