Survival and graft function in a large animal lung transplant model after 30 h preservation and substitution of the nitric oxide pathway.
OBJECTIVE
Substitution of the nitric oxide- (NO-) pathway improves early graft function following lung transplantation. We previously demonstrated that 8-Br-cGMP (second messenger of NO) to the flush solution and tetrahydrobiopterin (BH4, coenzyme of NO synthase) given as additive during reperfusion improve post-transplant graft function. In the present study, the combined treatment with 8-Br-cGMP and BH4 was evaluated.


METHODS
Unilateral left lung transplantation was performed in weight matched outbred pigs (24-31 kg). In group I, grafts were preserved for 30 h (n=5). 8-Br-cGMP (1mg/kg) was added to the flush solution (Perfadex, 1.5l, 1 degrees C) and BH4 (10mg/kg/h) was given to the recipient for 5h after reperfusion. In group II, lungs were transplanted after a preservation time of 30 h (n=3) and prostaglandin E(1) (250 g) was given into the pulmonary artery (PA) prior to flush. In all recipients 1h after reperfusion the contralateral right PA and bronchus were ligated to assess graft function only. Survival time after reperfusion, extravascular lung water index (EVLWI), hemodynamic variables, and gas exchange (PaO(2)) were assessed during a 12h observation period.


RESULTS
All recipients in group I survived the 12h assessment, whereas none of the group II animals survived more than 4h after reperfusion with a rapid increase of EVLWI up to 24.8+/-6.7 ml/kg. In contrast, in group I EVLWI reached up to 8.9+/-1.5 ml/kg and returned to nearly normal levels at 12h (6.1+/-0.8 ml/kg). In two animals of group I the gas exchange deteriorated slightly. The other three animals showed normal arterial oxygenation over the entire observation time.


CONCLUSIONS
Our data indicate that the combined substitution of the NO pathway during preservation and reperfusion reduces ischemia/reperfusion injury substantially and that this treatment even allows lung transplantation after 30 h preservation in this model.
Hillinger
S
S
Division of General Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland.
Sandera
P
P
Carboni
G L
GL
Stammberger
U
U
Zalunardo
M
M
Schoedon
G
G
Schmid
R A
RA
D000818:Animals; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002465:Cell Movement; D003067:Coenzymes / Q000008:administration & dosage / Q000494:pharmacology; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D015633:Extravascular Lung Water / Q000502:physiology; D006085:Graft Survival; D006439:Hemodynamics; D007262:Infusions, Intravenous; D015227:Lipid Peroxidation; D008168:Lung / Q000378:metabolism; D016040:Lung Transplantation; D009504:Neutrophils / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D009926:Organ Preservation; D019188:Organ Preservation Solutions; D009195:Peroxidase / Q000032:analysis; D011659:Pulmonary Gas Exchange; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D013997:Time Factors
D003067:Coenzymes; D019188:Organ Preservation Solutions; D017392:Thiobarbituric Acid Reactive Substances; D001708:Biopterins; C016276:8-bromocyclic GMP; D009195:Peroxidase; D019001:Nitric Oxide Synthase; C003402:sapropterin; D006152:Cyclic GMP