Harada Kazuhiko, Yamahara Kenichi, Ohnishi Shunsuke, Otani Kentaro, Kanoh Hirohisa, Ishibashi-Ueda Hatsue, Minamino Naoto, Kangawa Kenji, Nagaya Noritoshi, Ikeda Tomoaki
Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Regul Pept. 2011 Jun 7;168(1-3):21-6. doi: 10.1016/j.regpep.2011.02.014. Epub 2011 Feb 26.
Pressure ulcers are one of the most common complications in elderly, incontinent or paralyzed patients. For the healing of pressure ulcers, the development of granulation tissue and reepithelialization is required. Adrenomedullin (AM), an endogenous vasodilator peptide, is reported to stimulate the proliferation and migration of various cells including endothelial cells, fibroblasts and keratinocytes. Therefore, we hypothesized that AM might accelerate the healing process of pressure ulcers in which these cells were involved. We developed a sustained-release ointment containing human recombinant AM, and applied it in a mouse model of pressure ulcer twice a day for 14 days. Human AM was efficiently absorbed in wound area, but its blood concentration was negligible. AM ointment significantly reduced the wound area on day 5 to 7 after injury. In addition, AM ointment accelerated the formation of granulation tissue and angiogenesis as well as lymphangiogenesis after 7 days of treatment. Immunological analysis revealed that Ki-67-positive proliferating cells in granulation tissue expressed AM receptors. In summary, sustained-release AM significantly improved wound healing of pressure ulcers through acceleration of granulation and induction of angiogenesis and lymphangiogenesis. Therefore, sustained-release AM ointment may be a novel therapeutic agent for pressure ulcers.
压疮是老年人、大小便失禁或瘫痪患者最常见的并发症之一。压疮愈合需要肉芽组织的形成和上皮再形成。肾上腺髓质素（AM）是一种内源性血管舒张肽，据报道可刺激包括内皮细胞、成纤维细胞和角质形成细胞在内的各种细胞的增殖和迁移。因此，我们推测AM可能会加速涉及这些细胞的压疮愈合过程。我们研制了一种含有人重组AM的缓释软膏，并将其每天两次应用于压疮小鼠模型，持续14天。人AM在伤口部位被有效吸收，但其血药浓度可忽略不计。AM软膏在损伤后第5至7天显著减小了伤口面积。此外，治疗7天后，AM软膏加速了肉芽组织的形成、血管生成以及淋巴管生成。免疫分析显示，肉芽组织中Ki-67阳性增殖细胞表达AM受体。总之，缓释AM通过加速肉芽形成以及诱导血管生成和淋巴管生成，显著改善了压疮的伤口愈合。因此，缓释AM软膏可能是一种治疗压疮的新型药物。
