Failure to express the P-selectin gene or P-selectin blockade confers early pulmonary protection after lung ischemia or transplantation.
Endothelial P-selectin expression contributes to the first wave of neutrophil (polymorphonuclear leukocyte: PMN) influx in several inflammatory conditions. Although remote tissue ischemia, such as a crush injury to the hindlimb, may result in P-selectin-mediated pulmonary leukosequestration, it is not known whether the lungs exhibit a similar response after hypothermic preservation or when subjected to a direct ischemic 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 recipients. Recipients immunodepleted of PMNs before transplantation demonstrated improved graft function; pulmonary vascular resistance was reduced approximately 6-fold, arterial oxygenation was increased approximately 3-fold, and recipient survival was increased approximately 4-fold (P < 0.05, 0.05, and 0.005, respectively). Administration of a blocking anti-P-selectin IgG 10 min before reperfusion diminished graft PMN infiltration and resulted in improved graft function and recipient survival compared with controls. To establish the role of P-selectin in normothermic pulmonary ischemia, mice were subjected to temporary left pulmonary artery ligation. After functional removal of the nonischemic right lung, mice deletionally mutant for the P-selectin gene (P-selectin-/-) exhibited reduced PMN infiltration (approximately 2-fold), improved arterial oxygenation (approximately 2-fold), and improved survival (approximately 3-fold) compared with P-selectin +/+ control mice (P < 0.05, 0.01, and 0.05, respectively). These studies isolate and identify the central role of a single gene product (P-selectin) in early PMN recruitment and tissue injury after frank pulmonary ischemia and in the setting of lung transplantation after hypothermic preservation.
Naka
Y
Y
Department of Physiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Toda
K
K
Kayano
K
K
Oz
M C
MC
Pinsky
D J
DJ
D000818:Animals; D002448:Cell Adhesion; D015870:Gene Expression; D007511:Ischemia / Q000503:physiopathology; D008168:Lung / Q000098:blood supply; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009926:Organ Preservation / Q000379:methods; D019007:P-Selectin / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000503:physiopathology*; D013997:Time Factors
D019007:P-Selectin