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Published online before print June 26, 2007

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(Journal of Leukocyte Biology. 2007;82:519-531.)
© 2007 by Society for Leukocyte Biology

Endothelial selectins regulate skin wound healing in cooperation with L-selectin and ICAM-1

Toru Yukami^*, Minoru Hasegawa^*,1, Yukiyo Matsushita^*, Tomoyuki Fujita^*, Takashi Matsushita^*, Mayuka Horikawa^*, Kazuhiro Komura^*, Koichi Yanaba^*, Yasuhito Hamaguchi^*, Tetsuya Nagaoka^*, Fumihide Ogawa, Manabu Fujimoto^*, Douglas A. Steeber, Thomas F. Tedder, Kazuhiko Takehara^* and Shinichi Sato

^* Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan;
Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA; and
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA

¹ Correspondence: Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8641, Japan. E-mail: minoruha{at}derma.m.kanazawa-u.ac.jp

ABSTRACT

Skin wound healing is mediated by inflammatory cell infiltration that is highly regulated by various adhesion molecules. Mice lacking intercellular adhesion molecule-1 (ICAM-1) delayed skin wound healing and mice lacking both L-selectin and ICAM-1 (L-selectin/ICAM-1^–/–) show more delayed wound healing. Deficiency of both endothelial selectins (E-selectin or P-selectin) also delays wound healing. However, the relative contribution and interaction of selectins and ICAM-1 to the wound healing remain unknown. To clarify them, repair of excisional wounds was examined in L-selectin/ICAM-1^–/– mice, wild-type mice with both E- and P-selectin blockade, and L-selectin/ICAM-1^–/– mice with both E- and P-selectin blockade. Wild-type mice with both E- and P-selectin blockade showed delayed wound healing that was comparable with that in L-selectin/ICAM-1^–/– mice. Combined E- and P-selectin blockade in L-selectin/ICAM-1^–/– mice resulted in more significant delay. Mice lacking or blocked for adhesion molecules also showed suppressed keratinocyte migration, angiogenesis, granulation tissue formation, leukocyte infiltration, and cytokine expression, including transforming growth factor-ß and interleukin-6. Application of basic fibroblast growth factor (bFGF) but not platelet-derived growth factor to the wounds significantly improved wound healing in L-selectin/ICAM-1^–/– mice with both E- and P-selectin blockade. bFGF significantly increased the leukocyte infiltration and subsequent fibrogenic cytokine production, as well as keratinocyte migration, angiogenesis, and collagen synthesis despite the loss of four kinds of adhesion molecules. These results indicate that skin wound healing is regulated cooperatively by all selectins and ICAM-1 and may provide critical information for the therapy of skin wounds.

Key Words: adhesion molecule • cytokine • animal model