Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium

Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo. E-selectin-deficient (E-/-) mice were produced by gen...

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Published in:Microcirculation (New York, N.Y. 1994) N.Y. 1994), 1998, Vol.5 (2-3), p.153-171
Main Authors: Milstone, D S, Fukumura, D, Padgett, R C, O'Donnell, P E, Davis, V M, Benavidez, O J, Monsky, W L, Melder, R J, Jain, R K, Gimbrone, Jr, M A
Format: Article
Language:English
Subjects:
Animals
Cell Adhesion - physiology
Cell Movement - physiology
Cytokines - physiology
E-Selectin - genetics
E-Selectin - physiology
Endothelium, Vascular - physiology
Female
Gene Expression
Leukocytes - physiology
Lipopolysaccharides - toxicity
Male
Mice
Mice, Knockout
Microcirculation - physiology
Skin - blood supply
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo. E-selectin-deficient (E-/-) mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) in dermal microvessels with low blood flow (dorsal skin-fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow. E-/- mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E-/- mice without inflammatory stimulation. After local administration of TNF alpha, rolling increased modestly and equivalently in both genotypes. The main effect of TNF alpha was a dramatic increase in leukocyte stable adhesion and, unlike rolling, this manifestation of endothelial activation was significantly reduced in E-/- animals. This reflected fewer dermal microvessels supporting higher adhesion densities in E-/- mice, and a similar trend was observed in mesenteric microvessels. E-selectin plays a previously unappreciated role in facilitating and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.
ISSN:1073-9688
1549-8719
1073-9688
DOI:10.1038/sj.mn.7300023