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Circulation Research. 1999;84:93-102

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(Circulation Research. 1999;84:93-102.)
© 1999 American Heart Association, Inc.

Original Contribution

Effect of Recombinant Soluble P-Selectin Glycoprotein Ligand-1 on Leukocyte-Endothelium Interaction In Vivo

Role in Rat Traumatic Shock

Rosario Scalia, Reid Hayward, Valerie E. Armstead, Alexander G. Minchenko, Allan M. Lefer

From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Allan M. Lefer, PhD, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799. E-mail allan.m.lefer{at}mail.tju.edu

Abstract—Traumatic shock induces profound pathophysiological alterations and initiates inflammatory reactions in many tissues, thus resulting in acute multiple organ damage (eg, intestine, pancreas, and liver). In the rat, Noble-Collip drum trauma increases P-selectin expression on the vascular endothelium as a result of loss of endothelium-derived NO. Here we postulated that blockade of the earliest steps in leukocyte adhesion (ie, leukocyte rolling) via administration of a recombinant soluble form of P-selectin glycoprotein ligand-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-endothelium interaction (ie, leukocyte rolling, adherence, and transmigration) induced by traumatic shock as well as by activation of the microvascular endothelium with 50 µmol/L NG-nitro-L-arginine methyl ester. Immunohistochemical 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 expression. Systemic administration of rsPSGL.Ig to traumatized rats prolonged survival time and survival rate, significantly attenuating ileal myeloperoxidase activity and significantly preserving mesenteric endothelial function. Furthermore, PSGL-1 mRNA levels were significantly increased in the blood of traumatized rats and were reduced after systemic administration of rsPSGL.Ig. Thus, soluble recombinant forms of PSGL-1 are able to ameliorate acute shock states by suppressing selectin-mediated leukocyte-endothelium interaction at both the functional and molecular levels.


Key Words: endothelial dysfunction • myeloperoxidase activity • mRNA • P-selectin • intravital microscopy




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