Effect of recombinant soluble P-selectin glycoprotein ligand-1 on leukocyte-endothelium interaction in vivo - Role in rat traumatic shock

Traumatic shock induces profound pathophysiological alterations and initiat es inflammatory reactions in many tissues, thus resulting in acute multiple organ damage (eg, intestine, pancreas, and liver). In the rat, Noble-Colli p drum trauma increases P-selectin expression on the vascular endothelium a s a result of loss of endothelium-derived NO. Here we postulated that block ade of the earliest steps in leukocyte adhesion (ie, leukocyte rolling) via administration of a recombinant soluble form of P-selectin glycoprotein li gand-1 (PSGL-1; the recombinant soluble form is rsPSGL.Ig) would attenuate selectin-mediated events observed in the rat during traumatic shock. Using intravital microscopy of the rat mesenteric microvasculature, we found that intravenous infusion of rsPSGL.Ig significantly inhibited leukocyte-endoth elium interaction (ie, leukocyte rolling, adherence, and transmigration) in duced by traumatic shock as well as by activation of the microvascular endo thelium with 50 mu mol/L N-G-nitro-L-arginine methyl eater. Immunohistochem ical detection of P-selectin on the mesenteric venular endothelial surface demonstrated that rsPSGL.Ig functionally neutralizes effects of P-selectin on the endothelial cell surface rather than attenuating P-selectin expressi on. Systemic administration of rsPSGL.Ig to traumatized rats prolonged surv ival time and survival rate, significantly attenuating ileal myeloperoxidas e activity and significantly preserving mesenteric endothelial function. Fu rthermore, PSGL-1 mRNA levels were significantly increased in the blood of traumatized rats and were reduced after systemic administration of rsPSGL.I g. Thus, soluble recombinant forms of PSGL-1 are able to ameliorate acute s hock states by suppressing selectin-mediated leukocyte-endothelium interact ion at both the functional and molecular levels.