Intratracheal administration of dibutyryl camp attenuates edema
formation in phosgene-induced acute lung injury.
Sciuto, Alfred M., Paul T. Strickland, Thomas P. Kennedy, Yue-Liang
Guo, and Gail H. Gurtner.
Physiology Branch, Pathophysiology Division, US Army Medical
Research Institute of Chemical Defense, Aberdeen Proving Ground, MD
21010; Department of Environmental Health Sciences, Division of
Occupational Health, The Johns Hopkins University School of Hygiene
and Public Health, Baltimore, Maryland 21205; and Department of
Pulmonary and Critical Care Medicine, New York Medical College,
Valhalla, New York 10595
APStracts 2:0396A, 1995.
Phosgene, a toxic gas widely used as an industrial chemical
intermediate, is known to cause life-threatening latent non
-cardiogenic pulmonary edema. Mechanisms related to its toxicity
appear to involve lipoxygenase mediators of arachidonic acid (AA) and
can be inhibited by pretreatment with drugs that increase cAMP. In
the present study, we used the isolated buffer-perfused rabbit lung
model to investigate the mechanisms by which cAMP protect against
phosgene-induced lung injury. Posttreatment with Dibutyryl-cAMP
(DbcAMP) was given 60-85 minutes after exposure by intravascular (IV)
or intratracheal (IT) route. Lung weight gain (lwg) was measured
continuously. AA metabolites LTC4/D4/E4 and 6 Keto PGF1[alpha] were
measured in the perfusate at 70, 90,110, 130, and 150 min after
exposure. Tissue malondialdehyde (MDA) and reduced and oxidized
glutathione were analyzed at 150 minutes postexposure. Compared to
measurements in lungs of rabbits exposed to phosgene alone,
posttreatment with DbcAMP significantly reduced lwg, pulmonary artery
pressure, and inhibited the release of LTC4/D4/E4. IT administration
of DbcAMP was more effective than IV administration in reducing lwg.
Post-treatment also decreased MDA and protected against glutathione
oxidation observed with phosgene exposure. We conclude that phosgene
causes marked glutathione oxidation, lipid peroxidation, release of
AA mediators, and increases lwg. Posttreatment with DbcAMP attenuates
these effects, not only by previously described inhibition of
pulmonary endothelial or epithelial cell contraction, but also by
inhibition of AA mediator production and a novel antioxidant effect.
Received 5 June 1995; accepted in final form 1 September 1995
APS Manuscript Number A584-4.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.