FAILURE TO EXPRESS THE P-SELECTIN GENE OR P-SELECTIN BLOCKADE CONFERSEARLY PULMONARY PROTECTION AFTER LUNG ISCHEMIA OR TRANSPLANTATION

Endothelial P-selectin expression contributes to the first wave of neu trophil (polymorphonuclear leukocyte; PMN) influx in several inflammat ory conditions, Although remote tissue ischemia, such as a crush injur y to the hindlimb, may result in p-selectin-mediated pulmonary leukose questration, it is not known whether the lungs exhibit a similar respo nse after hypothermic preservation or when subjected to a direct ische mic insult, To determine if P-selectin may mediate early primary graft failure, left lungs harvested from male Lewis rats were preserved for 6 hr at 4 degrees C and transplanted orthotopically into isogeneic re cipients, Recipients immunodepleted of PMNs before transplantation dem onstrated improved graft function; pulmonary vascular resistance was r educed approximate to 6-fold, arterial oxygenation was increased appro ximate to 3-fold, and recipient survival was increased approximate to 4-fold (P < 0.05, 0.05, and 0.005, respectively), Administration of a blocking anti-P-selectin IgG 10 min before reperfusion diminished graf t PMN infiltration and resulted in improved graft function and recipie nt survival compared with controls, To establish the role of P-selecti n in normothermic pulmonary ischemia, mice were subjected to temporary left pulmonary artery ligation, After functional removal of the nonis chemic right lung, mice deletionally mutant for the P-selectin gene (P -selectin -/-) exhibited reduced PMN infiltration (approximate to 2-fo ld), improved arterial oxygenation (approximate to 2-fold), and improv ed survival (approximate to-3-fold) compared with P-selectin +/+ contr ol mice (P < 0.05, 0.01, and 0.05, respectively), These studies isolat e and identify the central role of a single gene product (P-selectin) in early PMN recruitment and tissue injury after frank pulmonary ische mia and in the setting of lung transplantation after hypothermic prese rvation.