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J. Exp. Med.,
Volume 189, Number 6, March 15, 1999 931-938
By
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
Resuscitation from hemorrhage induces profound pathophysiologic alterations and activates inflammatory cascades able to initiate neutrophil accumulation in a variety of tissues. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that significant leukocyte-endothelium interactions occur very early in other forms of
ischemia/reperfusion (i.e., splanchnic ischemia/reperfusion and traumatic shock) which are
largely mediated by increased expression of the adhesion molecule, P-selectin, on the vascular
endothelium. Here we postulated that increased 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 significantly
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 antibody or a recombinant soluble P-selectin glycoprotein ligand
(PSGL)-1 immunoglobulin, exhibited markedly attenuated leukocyte-endothelium interaction after hemorrhagic shock. Thus, activation of P-selectin protein on the microvascular endothelium is essential for the initial upregulation of the inflammatory response occurring in hemorrhagic shock. Moreover, endogenous levels of PSGL-1 mRNA were significantly increased in
the lung, liver, and small 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.
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