Journal
TOXICOLOGICAL SCIENCES
Volume 131, Issue 2, Pages 612-628Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfs317
Keywords
pulmonary irritation; lung function; exhaled nitric oxide; nitric oxidase synthetase inhibition
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Phosgene gas is a lower respiratory tract irritant. As such, it stimulates nociceptive vagal C-fiberrelated reflexes in a dose-rate and concentration exposure duration (C t)dependent manner. In rats, this reflex is characterized by extended apnea time periods, bradycardia, and hypothermia. Although inhalation exposures at nonlethal C t products show rapid reversibility of reflexively induced changes in respiratory patterns, lethal C t products seem to cause prolonged stimulation after discontinued exposure to phosgene. This observation has been taken as indirect evidence that phosgene-induced lethal lung edema is likely to be associated with a dysfunctional neurogenic control of cardiopulmonary and microvascular physiology. In order to verify this hypothesis, data from respiratory function measurements during and after the inhalation exposure to phosgene gas were compared with time-course measurements of cardiac function over 20h post-phosgene exposure. These data were complemented by time-course analyses of nitric oxide (NOe) and carbon dioxide in exhaled breath, including time-dependent changes of extravasated protein in bronchoalveolar lavage fluid and hemoglobin in blood. The nitric oxidase synthetase inhibitors L-NAME and L-NIL were used to further elucidate the role of NOe in this type of acute lung injury and whether its analysis can serve as an early biomarker of pulmonary injury. Collectively, the sequence and time course of pathological events in phosgene-induced lung edema appear to suggest that overstimulated, continued sensorimotor vagal reflexes affect cardiopulmonary hemodynamics. A continued parasympathetic tone appears to be involved in this etiopathology.
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