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(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.
authors.affiliation: Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA. Madhusoodana.nambiar@na.amedd.army.mil <Madhusoodana.nambiar@na.amedd.army.mil>
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gordon
authors.forename: Peter E
authors.initials: PE
authors.lastname: Rezk
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Katos
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Wajda
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Moran
authors.forename: Keith E
authors.initials: KE
authors.lastname: Steele
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000208:Acute Disease; D000818:Animals; D001286:Atropine Derivatives / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D006168:Guinea Pigs; D019570:Inhalation Exposure / Q000009:adverse effects*; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011506:Proteins / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000627:therapeutic use; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000111:Acetylcysteine; D001286:Atropine Derivatives; D002619:Chemical Warfare Agents; D009946:Organothiophosphorus Compounds; D011506:Proteins; D011663:Pulmonary Surfactants; C006649:methylatropine; C009680:VX-agent