Carbohydrate selectin inhibitor CY-1503 reduces neutrophil migration and reperfusion injury in canine pulmonary allografts.
BACKGROUND
Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration.


METHODS
We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) and preserved for 21 hours at 1 degree C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO2 = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503.


RESULTS
Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 x 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 +/- 0.06 compared with 0.40 +/- 0.02 delta OD/mg/ min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis.


CONCLUSIONS
Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.
Schmid
R A
RA
Department of Surgery, Barnes Hospital, Washington University School of Medicine, St. Louis, Mo., USA.
Yamashita
M
M
Boasquevisque
C H
CH
Ando
K
K
Fujino
S
S
Phillips
L
L
Cooper
J D
JD
Patterson
G A
GA
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002423:Cause of Death; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006085:Graft Survival; D006439:Hemodynamics / Q000502:physiology; D006982:Hypertonic Solutions / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008168:Lung / Q000201:enzymology; D016040:Lung Transplantation / Q000473:pathology / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects*; D009844:Oligosaccharides / Q000627:therapeutic use*; D009926:Organ Preservation; D019188:Organ Preservation Solutions / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D011659:Pulmonary Gas Exchange / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*; D019087:Selectins / Q000187:drug effects*; D014184:Transplantation, Homologous
C090410:CY 1503; C037096:Euro-Collins' solution; D006982:Hypertonic Solutions; D009844:Oligosaccharides; D019188:Organ Preservation Solutions; D019087:Selectins; D009195:Peroxidase