A1 adenosine receptor antagonists block endotoxin-induced lung
injury.
Neely, Constance F., Jie Jin, and Ingegerd M. Keith.
Departments of Anesthesia, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104 and Comparative
Biosciences, University of Wisconsin School of Veterinary Medicine,
Madison, Wisconsin 53706
APStracts 2:0108L, 1995.
Endotoxin produces a variety of biological effects on different cell
types, for example, priming of neutrophils and macrophages, which
then release a number of important mediators of endotoxin-induced
lung injury. However, the specific mechanism by which endotoxin
initiates its cascade of pathophysiological events in the lung has
not been described. Both A1 adenosine receptor activation and
endotoxin induce the release of TXA2 from the lung and inhibit
adenylate cyclase. By acting on A1 adenosine receptors, adenosine
promotes neutrophil chemotaxis and adherence to endothelial cells. We
hypothesized that A1 adenosine receptor activation is essential to
endotoxin-induced lung injury, and used the highly selective A1
adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX) and 8-benzyl-7,[2-(ethyl (2-hydroxyethyl) amino) - ethyl]
theophylline (Bamiphylline), to investigate whether selective
blocking of the A1 adenosine receptor would prevent endotoxin-induced
acute lung injury. An intralobar arterial (i.a.) infusion of
endotoxin (15 mg/kg) into the left lower lobe of the lung in intact
-chest, spontaneously breathing cats, produced lung injury
characterized by the presence of neutrophils, macrophages, and red
blood cells in alveoli, and alveolar edema and necrosis. Lower doses
of endotoxin (5 or 10 mg/kg) produced less severe and dose-dependent
lung injury. Endotoxin (15 mg/kg)-induced alveolar injury was blocked
in a highly significant manner by A1 adenosine receptor antagonists,
DPCPX and bamiphylline. An intravenous bolus of DPCPX 30 minutes
prior to endotoxin infusion or a continuous intravenous infusion of
bamiphylline 30 minutes prior to, during, and 30 minutes after
endotoxin reduced the % injured alveoli (defined as the presence of
two or more inflammatory cells or RBCs, or edematous fluid) from 57
+/- 31 % (endotoxin 15 mg/kg) to 9 +/- 1 % (DPCPX) or 21 +/- 14%
(bamiphylline) which were not significantly different from control (1
hour perfusion only) (4 +/- 1 %) (p < .05). These data represent
the first evidence that A1 adenosine receptor antagonism blocks the
capacity of endotoxin to cause lung injury. A1 adenosine receptor
antagonists may be useful in preventing ARDS associated with
septicemia.
Received 9 March 1995; accepted in final form 19 June 1995.
APS Manuscript Number L76-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.