Abstract
Selectin-dependent leukocyte rolling is one of the earliest steps of an acute inflammatory response and, as such, contributes to many inflammatory diseases. Although inhibiting leukocyte rolling with selectin antagonists is a strategy that promises far-reaching clinical benefit, the perceived value of this strategy has been limited by studies using inactive, weak, or poorly characterized antagonists. Recombinant P-selectin glycoprotein ligand-1-immunoglobulin (rPSGL-Ig) is a recombinant form of the best-characterized selectin ligand (PSGL-1) fused to IgG, and is one of the best prospects in the search for effective selectin antagonists. We have used intravital microscopy to investigate the ability of rPSGL-Ig to influence leukocyte rolling in living blood vessels and find that it can reduce rolling dependent on each of the selectins in vivo. Interestingly, doses of rPSGL-Ig required to reverse pre-existing leukocyte rolling are 30-fold higher than those required to limit inflammation, suggesting additional properties of this molecule. In support of this, we find that rPSGL-Ig can bind the murine chemokine KC and inhibit neutrophil migration toward this chemoattractant in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antibodies, Monoclonal / pharmacology
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Aortic Valve Stenosis / complications
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Aortic Valve Stenosis / pathology
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Chemokine CXCL1
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Chemokines / antagonists & inhibitors*
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Chemokines, CXC*
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Chemotactic Factors / antagonists & inhibitors*
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Chemotaxis, Leukocyte
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Disease Models, Animal
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E-Selectin / genetics
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E-Selectin / physiology*
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Endothelium, Vascular / drug effects
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Intercellular Signaling Peptides and Proteins
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Ischemia / etiology
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Ischemia / pathology
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L-Selectin / physiology*
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Leukocyte Rolling / drug effects*
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Male
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / drug effects
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P-Selectin / physiology*
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Peritonitis / chemically induced
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Peritonitis / pathology
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Recombinant Fusion Proteins / pharmacology
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Reperfusion Injury / pathology
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Thioglycolates / toxicity
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antibodies, Monoclonal
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Chemokine CXCL1
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Chemokines
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Chemokines, CXC
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Chemotactic Factors
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Cxcl1 protein, mouse
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E-Selectin
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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P-Selectin
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P-selectin ligand protein
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Recombinant Fusion Proteins
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Thioglycolates
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Tumor Necrosis Factor-alpha
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L-Selectin