Yukami Toru, Hasegawa Minoru, Matsushita Yukiyo, Fujita Tomoyuki, Matsushita Takashi, Horikawa Mayuka, Komura Kazuhiro, Yanaba Koichi, Hamaguchi Yasuhito, Nagaoka Tetsuya, Ogawa Fumihide, Fujimoto Manabu, Steeber Douglas A, Tedder Thomas F, Takehara Kazuhiko, Sato Shinichi
Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8641, Japan.
J Leukoc Biol. 2007 Sep;82(3):519-31. doi: 10.1189/jlb.0307152. Epub 2007 Jun 26.
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-beta 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.
皮肤伤口愈合由炎症细胞浸润介导，而炎症细胞浸润受到多种黏附分子的高度调控。缺乏细胞间黏附分子-1（ICAM-1）的小鼠皮肤伤口愈合延迟，而同时缺乏L-选择素和ICAM-1（L-选择素/ICAM-1(-/-)）的小鼠伤口愈合延迟更明显。内皮选择素（E-选择素或P-选择素）缺乏也会延迟伤口愈合。然而，选择素和ICAM-1对伤口愈合的相对贡献及相互作用仍不清楚。为阐明这些问题，对L-选择素/ICAM-1(-/-)小鼠、E-和P-选择素均被阻断的野生型小鼠以及E-和P-选择素均被阻断的L-选择素/ICAM-1(-/-)小鼠的切除伤口修复情况进行了研究。E-和P-选择素均被阻断的野生型小鼠伤口愈合延迟，与L-选择素/ICAM-1(-/-)小鼠相当。L-选择素/ICAM-1(-/-)小鼠联合阻断E-和P-选择素导致伤口愈合延迟更显著。缺乏或被阻断黏附分子的小鼠还表现出角质形成细胞迁移、血管生成、肉芽组织形成、白细胞浸润及细胞因子表达受抑制，包括转化生长因子-β和白细胞介素-6。对E-和P-选择素均被阻断的L-选择素/ICAM-1(-/-)小鼠伤口应用碱性成纤维细胞生长因子（bFGF）而非血小板衍生生长因子可显著改善伤口愈合。尽管缺乏四种黏附分子，bFGF仍显著增加白细胞浸润及随后的促纤维化细胞因子产生，以及角质形成细胞迁移、血管生成和胶原蛋白合成。这些结果表明，皮肤伤口愈合由所有选择素和ICAM-1协同调节，可能为皮肤伤口治疗提供关键信息。
