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Title: Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

Abstract

To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m{sup 3} of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicatingmore » less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [4];  [2];  [3]
  1. Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500 (United States) and Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States). E-mail: Madhusoodana.nambiar@na.amedd.army.mil
  2. Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500 (United States)
  3. Medical Toxicology Branch /Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Edgewood, MD 21010-5400 (United States)
  4. Department of Pathology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500 (United States)
Publication Date:
OSTI Identifier:
20976879
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 219; Journal Issue: 2-3; Other Information: DOI: 10.1016/j.taap.2006.11.002; PII: S0041-008X(06)00413-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; ATROPINE; BLOOD-BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; CHEMICAL WARFARE; DEXAMETHASONE; ESTERS; FLUIDS; GUINEA PIGS; INHALATION; INJURIES; LAVAGE; LUNGS; METHYL BROMIDE; OLIGONUCLEOTIDES; PROTEINS; SECRETION; TOXICITY

Citation Formats

Nambiar, Madhusoodana P., Gordon, Richard K., Rezk, Peter E., Katos, Alexander M., Wajda, Nikolai A., Moran, Theodore S., Steele, Keith E., Doctor, Bhupendra P., and Sciuto, Alfred M. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.11.002.
Nambiar, Madhusoodana P., Gordon, Richard K., Rezk, Peter E., Katos, Alexander M., Wajda, Nikolai A., Moran, Theodore S., Steele, Keith E., Doctor, Bhupendra P., & Sciuto, Alfred M. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX. United States. doi:10.1016/j.taap.2006.11.002.
Nambiar, Madhusoodana P., Gordon, Richard K., Rezk, Peter E., Katos, Alexander M., Wajda, Nikolai A., Moran, Theodore S., Steele, Keith E., Doctor, Bhupendra P., and Sciuto, Alfred M. Thu . "Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX". United States. doi:10.1016/j.taap.2006.11.002.
@article{osti_20976879,
title = {Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX},
author = {Nambiar, Madhusoodana P. and Gordon, Richard K. and Rezk, Peter E. and Katos, Alexander M. and Wajda, Nikolai A. and Moran, Theodore S. and Steele, Keith E. and Doctor, Bhupendra P. and Sciuto, Alfred M.},
abstractNote = {To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m{sup 3} of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.},
doi = {10.1016/j.taap.2006.11.002},
journal = {Toxicology and Applied Pharmacology},
number = 2-3,
volume = 219,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}