Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation.

Autor:	Veress LA; 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., Anderson DR; 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., Hendry-Hofer TB; 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., Houin PR; 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., Rioux JS; 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., Garlick RB; 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., Loader JE; 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., Paradiso DC; 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., Smith RW; 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., Rancourt RC; 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., Holmes WW; 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., White CW; 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.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2015 Jan; Vol. 143 (1), pp. 178-84. Date of Electronic Publication: 2014 Oct 20.
DOI:	10.1093/toxsci/kfu225
Abstrakt:	Rationale: 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. (© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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