8-Br-cyclic GMP given during reperfusion improves post-transplant lung edema and free radical injury.
Substitution of the NO-pathway reduces ischemia/reperfusion injury following lung transplantation. 8-Br-cGMP is a membrane permeable analogue of cGMP, the second messenger of NO. In this study the effect of continuous administration of 8-Br-cGMP on early graft function was evaluated.


METHODS
Unilateral left lung transplantation was performed in 10 weight-matched pigs (23-30 kg). Donor lungs were flushed with 1.51 cold (1 degree C) LPD solution and preserved for 20 hours. In Group I (n = 5), 8-Br-cGMP (0.2 mg/kg/h) was given continuously over the entire observation time starting 15 min before reperfusion. Group II served as control, no 8-Br-cGMP was administered. In both groups, 250 microg PGE1 was injected into the pulmonary artery (PA) before flush. One hour after reperfusion the recipients contralateral right PA and bronchus were ligated to assess isolated graft function only. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, mean systemic arterial pressure and gas exchange were assessed during a 5-hour observation period. Lipid peroxidation as indicator for free radical mediated injury and neutrophil migration to the allograft were measured at the end of the assessment.


RESULTS
EVLWI was significantly reduced in animals treated with 8-Br-cGMP (overall difference P = 0.024) with a peak 2 hours after reperfusion (Group I, 8.2+/-0.3 mg/ml vs Group II, 10.1+/-0.6 mg/ml; P = 0.039). Also in Group I the free radical mediated tissue injury was significantly lower when compared to Group II (Group I, 61.8+/-12.3 pmol/g vs Group II, 120.7+/-7.2 pmol/g; P = 0.006). A tendency towards a reduced neutrophil migration after 8-Br-cGMP infusion was shown; however, the changes in comparison to the control animals were not statistically significant (Group I, 1.0+/-0.2 deltaOD/mg/min vs Group II, 1.7+/-0.3 deltaOD/mg/min; P = 0.13). Pulmonary- and systemic hemodynamics, and allograft gas exchange did not differ between groups.


CONCLUSIONS
The results indicate that substitution of the NO pathway by administration of the second messenger cGMP at the time of reperfusion improves post-transplant lung allograft function.
Sandera
P
P
Department of Internal Medicine, University Hospital, Zürich, Switzerland.
Hillinger
S
S
Stammberger
U
U
Schoedon
G
G
Zalunardo
M
M
Weder
W
W
Schmid
R A
RA
D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D015633:Extravascular Lung Water; D005609:Free Radicals; D015227:Lipid Peroxidation; D016040:Lung Transplantation; D011184:Postoperative Period; D011654:Pulmonary Edema / Q000188:drug therapy*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances; D014184:Transplantation, Homologous
D005609:Free Radicals; D017392:Thiobarbituric Acid Reactive Substances; C016276:8-bromocyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP