Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation.
Phosgene inhalation causes a severe noncardiogenic pulmonary edema characterized by an influx of neutrophils into the lung. To study the role of neutrophils in lung injury and mortality after phosgene, we investigated the effects of leukocyte depletion with cyclophosphamide, inhibiting the generation of the chemotaxin leukotriene B4 with the 5-lipoxygenase inhibitor AA861 and impairing neutrophil migration with the microtubular poison colchicine. Cyclophosphamide, AA861, and colchicine injected before exposure significantly reduced percent neutrophils, protein, and thiobarbituric acid-reactive products in bronchoalveolar lavage fluid of rats exposed to phosgene (0.5 ppm X 60 min). Cyclophosphamide, AA861, and colchicine also significantly decreased mortality from phosgene (2.0 ppm X 90 min) in mice. Colchicine significantly reduced neutrophil influx, lung injury, and mortality even when given 30 min after phosgene exposure. We conclude that lung injury and mortality after phosgene exposure are associated with an influx of neutrophils into the lung. Prevention of neutrophil migration with colchicine may hold therapeutic potential in phosgene poisoning.
Ghio
A J
AJ
Department of Medicine, Duke University School of Medicine, Durham 27710.
Kennedy
T P
TP
Hatch
G E
GE
Tepper
J S
JS
D000280:Administration, Inhalation; D000818:Animals; D003078:Colchicine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D007975:Leukotriene B4 / Q000378:metabolism / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D010705:Phosgene / Q000008:administration & dosage / Q000633:toxicity*; D011506:Proteins / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D012129:Respiratory Function Tests
D016859:Lipoxygenase Inhibitors; D011506:Proteins; D010705:Phosgene; D007975:Leukotriene B4; D003520:Cyclophosphamide; D003078:Colchicine