CAMP-MEDIATED VASCULAR PROTECTION IN AN ORTHOTOPIC RAT LUNG-TRANSPLANT MODEL - INSIGHTS INTO THE MECHANISM OF ACTION OF PROSTAGLANDIN E(1) TO IMPROVE LUNG PRESERVATION

Prostaglandin E(1) (PGE(1)) is often added to the donor pulmonary flus h solution to enhance clinical lung preservation for transplantation. Although PGE(1) is thought to act as a pulmonary vasodilator during th e harvest period, the precise mechanism(s) of action whereby PGE(1) en hances lung preservation is unknown. Because cAMP levels decline in en dothelial and vascular smooth muscle cells exposed to hypoxia, we hypo thesized that a PGE(1)-mediated increase in cAMP levels within the pre served lungs might improve pulmonary vascular homeostasis following lu ng transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantl y increased by PGE(1) supplementation (approximate to 2-fold by 6 hour s, P<.0005). To test whether augmenting cAMP levels may enhance lung p reservation, experiments were performed using an orthotopic rat left l ung transplant model. Compared with controls, supplementing the preser vation solution with the membrane-permeable cAMP analogue dibutyryl-cA MP resulted in dose-dependent preservation enhancement, marked by redu ced pulmonary vascular resistance (6.0-fold, P<.01), improved arterial oxygenation (3.0-fold, P<.01), reduced graft neutrophil infiltration (1.5-fold, P<.05), and improved recipient survival (7.0-fold, P<.005). Similar preservation enhancement was observed with another cAMP analo gue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimu lating the cAMP second messenger system by PGE(1) supplementation resu lted in marked hemodynamic benefits and improved recipient survival, i n parallel with reduced graft neutrophil infiltration, vascular permea bility, and platelet deposition. These beneficial effects of PGE(1) we re abrogated by simultaneous administration of the cAMP-dependent prot ein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (mino xidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE(1) and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE(1) enhances lun g preservation by stimulating the cAMP-dependent protein kinase and pr omoting nonvasodilatory mechanisms of pulmonary protection.