A1 adenosine receptor antagonists block ischemia-reperfusion injury
of the lung.
Neely, Constance F., M. D. and Ingegerd M. Keith, Ph. D.
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 2:0028L, 1995.
Ischemia-reperfusion injury of the lung occurs following lung
transplantation, pulmonary thromboembolectomy, or cardiopulmonary
bypass. In the heart, adenosine, A1 adenosine receptor agonists, and
a brief period of ischemia (preconditioning ischemia), attenuate
ischemia-reperfusion injury. Moreover, in the lung, thromboxane is
released during ischemia and is an important mediator of ischemia
-reperfusion injury. We have previously reported that adenosine
produces vasoconstriction in the feline pulmonary vascular bed by
acting on A1 adenosine receptors to induce the release of thromboxane
and that these vasoconstrictor responses are desensitized by low
doses of A1 adenosine receptor agonists. Because A1 adenosine
receptor agonists mimic the effect of preconditioning ischemia, we
hypothesized, in contrast to previously proposed mechanisms, that
small amounts of adenosine released during preconditioning ischemia
desensitize A1 adenosine receptors. Also, we hypothesized that
greater amounts of adenosine are released following longer periods of
ischemia which activate A1 adenosine receptors. Thus, if
desensitization of A1 adenosine receptors is the mechanism by which
preconditioning attenuates ischemia-reperfusion injury of the heart
and A1 adenosine receptor activation during ischemia plays an
important role in ischemia-reperfusion injury of the lung, A1
adenosine receptor antagonists should provide a protective effect in
ischemia-reperfusion injury of the lung. In the present study, 2
hours of ischemia and 2 hours of reperfusion of the left lower lobe
(LLL) in intact-chest, spontaneously breathing cats, caused lung
injury characterized by the presence of neutrophils, macrophages, and
red blood cells in alveoli, and alveolar edema. This was blocked in a
highly significant manner by the A1 adenosine receptor antagonists -
xanthine amine congener (XAC) and 1,3 dipropyl 8-cyclopentylxanthine
(DPCPX). Reperfusion for 1 hour following 2 hours of ischemia
resulted in lung injury that was less severe than that seen after 2
hours of reperfusion. DPCPX administered to these cats after 1 hour
reperfusion reduced the % injured alveoli (defined as the presence of
two or more inflammatory cells or RBCs, or edematous fluid) from 22
+/- 3 % to 6 +/- 2 %, not significantly different from controls (2
hours of perfusion only)(5 +/- 1 %) (p < .001). When administered 30
minutes prior to 2 hours of ischemia and 2 hours reperfusion, an
intralobar arterial infusion of XAC or intravenous DPCPX reduced the
% injured alveoli from 60 +/- 10 % to 7 +/- 2 % or 13 +/- 7 %,
respectively, which were not significantly different from controls (5
+/- 1 %) (p < .0001). Preconditioning ischemia (10 min ischemia plus
10 min reperfusion) prior to 2 h ischemia and 2 h reperfusion also
reduced the % injured alveoli from 60 +/- 10% to 23 +/- 13 % (p <
.001). These data support the hypothesis that A1 adenosine receptor
antagonists block ischemia-reperfusion injury of the lung. A1
adenosine receptor antagonists may be useful in preventing ischemia
-reperfusion injury of organs following transplant surgery and during
surgical procedures associated with ischemia-reperfusion injury of
the heart, brain, kidney, and spinal cord.
Received 5 August 1994; accepted in final form 17 February 1994.
APS Manuscript Number L224-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 1 March 1995.