Normal gas exchange after 30-h ischemia and treatment with phosphodiesterase inhibitor PDI747.
OBJECTIVE
Phosphodiesterases (PDEs) negatively regulate the concentrations of cAMP and/or cGMP, which act as downstream second messengers to the prostaglandins. PDE type-4 (PDE4) is selective for cAMP and is found in high concentrations in endothelial, epithelial, and different blood cells. The aim of this study was to evaluate if PDI747, a novel selective inhibitor of PDE4, can restore pretransplant cAMP levels and thereby posttransplant organ function after prolonged cold ischemia.


METHODS
Left lung transplantation was performed in pigs (25-31 kg). Donor lungs were flushed with low potassium dextran glucose (LPDG) solution only (control, n=5)or, in addition with 1 micromol of PDI747 (PDI747, n=5) and stored for 30 h at 1 degrees C. PDI747 animals further received a bolus of PDI747 (0.3 mg/kg) 15 min prior to reperfusion and a continuous infusion (0.3 mg/kg per hour) during the 5 h after reperfusion. After occlusion of the right pulmonary arteries and the right main bronchus, hemodynamic and gas exchange parameters and extravascular lung water (EVLW) levels of the transplanted lung were assessed.


RESULTS
Two control animals died of severe lung edema leading to heart failure (control, n=3). One animal in the treatment group was excluded due to a patent ductus arteriosus (PDI747, n=4). Gas exchange at the end of the experiment was restored to normal levels in the PDI747 group (Pa, O(2) 47.6+/-11.2 kPa, Pa,CO(2) 6.4+/-1.8 kPa) but not in the control group (Pa, O(2) 7.7+/-2.9 kPa, Pa, CO(2) 11.9+/-3.0 kPa, P(PaO2)<0.0001, P(Pa, CO2)=0.06). Extravascular lung water (EVLW) was normal in the PDI747 group (8.5+/-1.1 ml/kg) and clearly elevated in the control group (16.2+/-5.6 ml/kg, P=0.007). Airway pressure in the PDI747 group was significantly lower than in the control group (7.8+/-0.5 cm H(2)O vs. 11.3+/-0.6 cm H(2)O, respectively, P<0.0001). The free radical mediated tissue injury measured by lipid peroxidation (TBARS) was significantly reduced (P=0.001) in the PDI747 group.


CONCLUSIONS
With the inhibition of PDE4 with PDI747 we achieved normal gas exchange, no posttransplant lung edema, normal airway pressures, and a reduced free radical injury after 30 h of cold ischemia.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015633:Extravascular Lung Water / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D016040:Lung Transplantation / Q000009:adverse effects / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011654:Pulmonary Edema / Q000517:prevention & control; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine
D010726:Phosphodiesterase Inhibitors; D002245:Carbon Dioxide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010100:Oxygen