Acute massive toxic gas exposure continues to be a problem facing occupational medicine and critical care medicine, not only due to isolated accidents involving workers in the manufacturing and use of chlorine, phosgene, nitrogen dioxide, ammonia, and sulfer dioxide, but also from exposure of larger bystander populations resulting from accidental toxic gas release during transportation. Much research exists on chronic low level exposure to these agents, but there is little work on pathophysiology and therapy of acute lung damage and respiratory distress from toxic gas inhalation. The proposed research will use inhaled phosgene exposure of an isolated perfused rabbit lung as a laboratory model for acute toxic gas inhalation. The pathophysiology of acute phosgene lung damage will be investigated, including whether acute broncho-constriction and pulmonary hypertension are due to lung production of arachidonic acid metabolites such as thomboxane and leukotrienes, and whether oxidant lung damage from phosgene causes depletion of lung glutathione. Several pharmacologic agents (corticosteroids, nosteroidal anti-inflammatory agents blocking cyclooxygenase and lipoxygenase pathways, protease inhibitors, beta-adrenergic agonists, and prostaglandin El) will be studied to determine their usefulness in attentuating lung edema formation. N-acetyl cysteine, a precursor of glutathione effective in treating oxidant liver damage from toxic doses of acetaminophen, will be evaluated as therapy for phosgene poisoning by insuring a sufficient supply of lung glutathione to react with phosgene and prevent its combination with membranes and cellular enzymes. Drugs such as the food additive antioxidant butylated hydroxy anisol (BHA) which elevate lung glutathione will be studied to determine whether chemoprophylaxis of phosgene poisoning is possible. The results of this research can provide a foundation for recommending physiologically sound therapy of oxidant lung damage from acute toxic gas inhalation in man.

National Institute of Health (NIH)
National Institute for Occupational Safety and Health (NIOSH)
Research Project (R01)
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Safety and Occupational Health Study Section (SOH)
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University of Tennessee Health Science Center
Schools of Medicine
United States
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Kennedy, T P; Rao, N V; Hopkins, C et al. (1989) Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest 83:1326-35