Subthreshold doses of nebulized prostacyclin and rolipram synergistaically protect against lung ischemia-reperfusion.
BACKGROUND
Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury.


METHODS
We investigated the impact of co-aerosolized prostaglandin (PG)I(2) and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained.


RESULTS
On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 microg) or PGI(2) (2.6 microg) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI(2) showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI(2)-rolipram administration but depended on the mode of delivery of these agents.


CONCLUSIONS
Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.
Schütte
Hartwig
H
Charité, Department of Internal Medicine and Infectious Diseases, Humboldt University, Berlin, Germany. hartwig.schuette@charite.de.
Schell
Alexander
A
Schäfer
Christoph
C
Ghofrani
Ardeschir
A
Theo Schermuly
Ralph
R
Seeger
Werner
W
Grimminger
Friedrich
F
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D016040:Lung Transplantation; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009330:Nebulizers and Vaporizers; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011817:Rabbits; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control; D020889:Rolipram / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011464:Epoprostenol; D000242:Cyclic AMP; D020889:Rolipram