Short-term "preconditioning" with inhaled nitric oxide protects rabbit lungs against ischemia-reperfusion injury.
BACKGROUND
Pulmonary edema, owing to an impairment of microvascular barrier function, is an important feature in lung ischemia/reperfusion (IR) injury. Inhalation of nitric oxide (NO) during the period of reperfusion has previously been shown to reduce this leakage response.


METHODS
We investigated the impact of short-term (30 min) low-dose (10 ppm) pre-ischemic NO inhalation on IR injury in buffer-perfused rabbit lungs, subsequently undergoing 210 min of warm, anoxic-ventilated ischemia.


RESULTS
Far-reaching suppression of the leakage response, reflected by manifold increased capillary filtration coefficients and edema formation, was noted in lungs with pre-ischemic NO administration, corresponding to the beneficial effect of NO inhalation during reperfusion. The effect of NO pre-exposure was not related to vasodilation, because microvascular pressures were unchanged, and was mimicked by pre-ischemic intravascular administration of sodium nitroprusside with subsequent washout of this agent. NO inhalation during reperfusion, but not pre-ischemic, short-term NO administration, provoked a manifold increase in the accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) in the perfusate. The cGMP-analogue, 8-Br-cGMP, mimicked the anti-edematous effect of NO when present during reperfusion, but pre-ischemic, short-term administration of 8-Br-cGMP provided only limited protection. The guanylate cyclase-inhibitor, 1H-[1, 2, 4]-Oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), largely antagonized the beneficial effects of NO inhalation during reperfusion but had only minor influence on the effect of NO pre-exposure.


CONCLUSIONS
"Preconditioning" of the lung vasculature with short-term NO administration maintains endothelial integrity in a subsequent ischemia/reperfusion maneuver, with nonvasodilatory and non-cGMP-related mechanisms suggested to be largely responsible. This finding may offer interesting perspectives for donor management in clinical lung transplantation.
Schütte
H
H
Department of Internal Medicine, Justus-Liebig University, Klinikstrasse 36, 35385 Giessen, Germany. hartwig.schuette@innere.med.uni-giessen.de
Witzenrath
M
M
Mayer
K
K
Rosseau
S
S
Seeger
W
W
Grimminger
F
F
D000280:Administration, Inhalation; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D005260:Female; D019194:Ischemic Preconditioning; D008168:Lung / Q000098:blood supply*; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage*; D011651:Pulmonary Artery / Q000502:physiology; D011817:Rabbits; D015427:Reperfusion Injury / Q000517:prevention & control*; D015430:Weight Gain
D009569:Nitric Oxide; D006152:Cyclic GMP