Failure to express the P-selectin gene or P-selectin blockade confers early pulmonary protection after lung ischemia or transplantation

Abstract

Endothelial P-selectin expression contributes to the first wave of neutrophil (polymorphonuclear leukocyte; PMN) inf lux in several inf lammatory 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؇C and transplanted orthotopically into isogeneic recipients. Recipients immunodepleted of PMNs before transplantation demonstrated improved graft function; pulmonary vascular resistance was reduced Ϸ6-fold, arterial oxygenation was increased Ϸ3-fold, and recipient survival was increased Ϸ4-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 (Pselectin ؊͞؊) exhibited reduced PMN infiltration (Ϸ2-fold), improved arterial oxygenation (Ϸ2-fold), and improved survival (Ϸ3-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 (Pselectin) in early PMN recruitment and tissue injury after frank pulmonary ischemia and in the setting of lung transplantation after hypothermic preservation.

sCR1sLeX reduces lung allograft ischemia–reperfusion injury but does not ameliorate acute rejection

“…Blockade of both leukocyte integrin adhesion molecule and its counterpart, intercellular adhesion molecule-1 (ICAM-1), has been shown to be efficient in a rat lung transplant model, as combined administration of monoclonal antibodies against ICAM-1, CD11a and CD18 resulted in superior gas exchange 24 h after reperfusion and reduced neutrophil accumulation in lung tissue [20]. In addition, blockade of P-selectin by a monoclonal anti-P-selectin antibody or a selectin inhibitor improved graft function and reduced PMN infiltration after syngeneic rat lung transplantation [21].…”

Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries

“…Evidence against this role includes findings that P-selectin-inhibitory mAb does not block leukocyte rolling in venules (26) and that bacteria-induced leukocyte migration is not inhibited in P/E-selectin-knockout mice (27). Evidence supporting a role for P-selectin includes findings that P-selectin-blocking mAbs inhibit ALI induced by cobra venom (28) or ischemia-reperfusion (29) and that P-selectin-knockout mice are protected from ALI due to ischemia-reperfusion (30). We reported that P-selectin accounts for the pressure-induced leukocyte accumulation (6), thereby implying a role for P-selectin in the proinflammatory phenotype induced by pulmonary venous hypertension.…”

Prevention of Neutrophil Migration Ameliorates Rat Lung Allograft Rejection

“…Ischemia-reperfusion injury increases activation of vascular endothelial cells and releases a variety of chemoattractants, which help the activated neutrophils influx into the lung parenchyma with the coordination of adhesion molecules that are upregulated during ischemia-reperfusion injury (5). During this nonspecific insult, it has been thought that neutrophils play a key role through a number of mechanisms including release of reactive oxygen species and proteolytic enzymes (6).…”