Essential role of P-selectin in the initiation of the inflammatory response induced by hemorrhage and reinfusion

Resuscitation from hemorrhage induces profound pathophysiologic alterations and activates inflammatory cascades able to initiate neutrophil accumulati on in a variety of tissues. This process is accompanied by acute organ dama ge (e.g., lungs and liver). We have previously demonstrated that significan t leukocyte-endothelium interactions occur very early in other form of isch emia/reperfusion (i.e., splanchnic ischemia/reperfusion and traumatic shock ) which are largely mediated by increased expression of the adhesion molecu le, P-selectin, on the vascular endothelium. Here we postulated that increa sed endothelial expression of P-selectin in the microvasculature would play an essential role in initiating the inflammatory signaling of hemorrhagic shock. Using intravital microscopy, we found that hemorrhagic shock signifi cantly increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. In contrast, mice genetically deficient in P- selectin, or wild-type mice given either an anti-P-selectin monoclonal anti body or a recombinant soluble P-selectin glycoprotein ligand (PSGL)-1 immun oglobulin, exhibited markedly attenuated leukocyte-endothelium interaction after hemorrhagic shock. Thus, activation of P-selectin protein on the micr ovascular endothelium is essential for the initial upregulation of the infl ammatory response occurring in hemorrhagic shock. Moreover, endogenous leve ls of PSGL-1 mRNA were significantly increased in the lung, liver, and smal l intestine of wild-type mice subjected to hemorrhagic shock. Since PSGL-1 promotes adhesive interactions largely through P-selectin expressed on the vascular endothelium, this result further supports the crucial role played by P-selectin in the recruitment of leukocytes during hemorrhagic shock.