Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing
Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing
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DOI：
10.2353/ajpath.2007.060018
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发表时间：
2007-04-01
影响因子：
6
通讯作者：
D'Amore, Patricia A.
中科院分区：
文献类型：
--
作者：
Maruyama, Kazuichi;Asai, Jun;D'Amore, Patricia A.
伤口愈合不良是糖尿病的常见并发症。尽管巨噬细胞和血管对伤口修复都是至关重要的，但伤口相关淋巴管的作用尚未得到充分研究。我们报告说，活化的巨噬细胞和淋巴管的形成都是糖尿病伤口愈合的限速因素。我们先前已经表明，巨噬细胞有助于在角膜伤口愈合的急性期形成的淋巴管。我们现在证明这是一种普遍现象;巨噬细胞标志物F4/80和淋巴标志物LYVE-1（淋巴管内皮透明质酸受体）和podoplanin共染色的细胞有助于全层伤口中的淋巴管。与对照组（db/+）小鼠相比，糖尿病小鼠（db/db）角膜伤口愈合中LYVE-1阳性淋巴管和CD 31阳性血管显著减少（P < 0.02）。对照巨噬细胞的葡萄糖处理导致细胞特异性受体VEGFR 3及其配体，血管内皮生长因子-C和-D（VEGF-C，-D）的下调。白细胞介素-1 β刺激挽救了糖尿病巨噬细胞功能;将白细胞介素-1 β处理的db/db衍生的巨噬细胞应用于dbldb小鼠的伤口诱导淋巴管形成并加速伤口愈合。这些观察结果表明，糖尿病患者伤口愈合的潜在治疗方法。
Impaired wound healing is a common complication of diabetes. Although it is well known that both macrophages and blood vessels are critical to wound repair, the role of wound-associated lymphatic vessels has not been well investigated. We report that both the presence of activated macrophages and the formation of lymphatic vessels are rate-limiting to the healing of diabetic wounds. We have previously shown that macrophages contribute to the lymphatic vessels that form during the acute phase of corneal wound healing. We now demonstrate that this is a general phenomenon; cells that co-stain for the macrophage marker F4/80 and the lymphatic markers LYVE-1 (lymphatic vascular endothelium hyaluronate receptor) and podoplanin contribute to lymphatic vessels in full-thickness wounds. LYVE-1-positive lymphatic vessels and CD31-positive blood vessels were significantly reduced in corneal wound healing in diabetic mice (db/db) (P < 0.02) compared with control (db/+) mice. Glucose treatment of control macrophages led to the down-regulation of the lymphatic-specific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1 beta stimulation rescued diabetic macrophage function; application of interleukin-1 beta-treated db/db-derived macrophages to wounds in dbldb mice induced lymphatic vessel formation and accelerated wound healing. These observations suggest a potential therapeutic approach for healing wounds in diabetic patients.