The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation.
OBJECTIVE
Exogenous nitric oxide reduces ischemia-reperfusion injury after solid organ transplantation. Tetrahydrobiopterin, an essential cofactor for nitric oxide synthases, may restore impaired endothelium-dependent nitric oxide synthesis. We evaluated whether tetrahydrobiopterin administration to the recipient attenuates lung reperfusion injury after transplantation in swine.


METHODS
Unilateral left lung transplantation was performed in 15 weight-matched pigs (24-31 kg). Donor lungs were flushed with 1.5 L cold (1 degrees C) low-potassium-dextran solution and preserved for 20 hours. Group I animals served as controls. Group II and III animals were treated with a bolus of tetrahydrobiopterin (20 mg/kg). In addition, in group III a continuous infusion of tetrahydrobiopterin (10 mg/kg per hour over 5 hours) was given. One hour after reperfusion, the recipient right lung was occluded. Cyclic guanosine monophosphate levels were measured in the pulmonary venous and central venous blood. Extravascular lung water index, hemodynamic variables, lipid peroxidation, and neutrophil migration to the allograft were assessed.


RESULTS
In group III a significant reduction of extravascular lung water was noted in comparison with the controls (P =.0047). Lipid peroxidation in lung allograft tissue was significantly reduced in group II (P =.0021) and group III ( P =. 0077) in comparison with group I. Pulmonary venous levels of cyclic guanosine monophosphate increased up to 23 +/- 1 pmol/mL at 5 hours in group II and up to 40 +/- 1 pmol/mL in group III (group I, 4.1 +/- 0.5 pmol/mL [I vs III]; P <.001), whereas central venous levels of cyclic guanosine monophosphate were unchanged in all groups.


CONCLUSIONS
Tetrahydrobiopterin administration during lung allograft reperfusion may reduce posttransplantation lung edema and oxygen-derived free radical injury in the graft. This effect is mediated by local enhancement of the nitric oxide/cyclic guanosine monophosphate pathway.
Schmid
R A
RA
Department of Surgery, Division of Thoracic Surgery, University Hospital, Zürich, Switzerland.
Hillinger
S
S
Walter
R
R
Zollinger
A
A
Stammberger
U
U
Speich
R
R
Schaffner
A
A
Weder
W
W
Schoedon
G
G
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015925:Cryopreservation; D006152:Cyclic GMP / Q000097:blood; D003911:Dextrans / Q000627:therapeutic use; D004195:Disease Models, Animal; D004487:Edema / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000201:enzymology; D015633:Extravascular Lung Water / Q000737:chemistry; D016166:Free Radical Scavengers / Q000627:therapeutic use; D006439:Hemodynamics / Q000502:physiology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D015227:Lipid Peroxidation / Q000502:physiology; D008171:Lung Diseases / Q000517:prevention & control; D016040:Lung Transplantation; D020556:Neutrophil Infiltration / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010952:Plasma Substitutes / Q000627:therapeutic use; D011188:Potassium / Q000627:therapeutic use; D011667:Pulmonary Veins; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine
D000975:Antioxidants; D003911:Dextrans; D016166:Free Radical Scavengers; D010952:Plasma Substitutes; D017382:Reactive Oxygen Species; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin; D006152:Cyclic GMP; D011188:Potassium