Extended lung preservation with platelet-activating factor-antagonist TCV-309 in combination with prostaglandin E1.
BACKGROUND
Ischemia-reperfusion injury is one of the major problems in organ transplantation. The role of platelet-activating factor (PAF) in the pathophysiology of ischemia-reperfusion injury and the protective effect of a novel phospholipid PAF analog (TCV-309) alone and combined with prostaglandin E1 (PGE1) is investigated in an extended (20 hours) ex vivo lung preservation.


METHODS
Forty-two swine were divided into three groups. Group A was the control. In groups B and C, the effect of PAF was blocked with TCV-309 administered 1 hour before cross-clamping for donor and recipient. Group C received PGE1 50 micrograms bolus in the donor pulmonary plegia, and the recipients received a 50 micrograms bolus plus 0.003 microgram/kg/min infusion at the time of implantation. Donor lungs were perfused with cold modified Collins solution and maintained in hypothermic storage (4 degrees C) for 20 hours. Hemodynamics, lung mechanics, gas exchange, and biochemistry were assessed before transplantation (donor) and at 30 minutes and 24 hours after reperfusion (recipient). At 24 hours after reperfusion, the histopathologic condition of transplanted lungs was evaluated.


RESULTS
Radioimmunoassay demonstrated a significant (p < 0.001) increase in the production of PAF and TXB2 in transplanted lungs at 24 hours after transplantation for group A only. Hemodynamics, gas-exchange parameters, and lung compliance were significantly (p < 0.05) better after transplantation for groups B and C. Wet lung weight was significantly less (p < 0.05) for group C. Semiquantitative morphometric analysis demonstrated the highest degree of damage for group A compared with groups B and C. A strong correlation (r2 = 70) between lung weight and histologic injury scores was observed among groups.


CONCLUSIONS
This study suggests that PAF is responsible in part for the deleterious effects of ischemia and reperfusion, that PAF-antagonist TCV-309 protects lungs from extended (20 hours) ischemic injury, and that PGE1 seems to have an additional beneficial effect.
Qayumi
A K
AK
Department of Surgery, University of British Columbia, Vancouver Hospital, Vancouver, Canada.
English
J E
JE
Duncan
S
S
Ansley
D M
DM
Pearson
B
B
Nikbakht-Sangari
M
M
Sammartino
C
C
Fradet
G
G
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000473:pathology; D016040:Lung Transplantation / Q000473:pathology / Q000502:physiology*; D009926:Organ Preservation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011659:Pulmonary Gas Exchange / Q000502:physiology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D015656:Respiratory Mechanics / Q000502:physiology; D013552:Swine; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; D000527:Alprostadil; C067430:TCV 309