title: Sustained-release adrenomedullin ointment accelerates wound healing of pressure ulcers.
abstract: 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.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Harada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Otani
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kanoh
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D053607:Adrenomedullin / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009824:Ointments / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D003668:Pressure Ulcer / Q000188:drug therapy* / Q000473:pathology; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D058286:Calcitonin Receptor-Like Protein; D009824:Ointments; C545505:Ramp1 protein, mouse; C545506:Ramp2 protein, mouse; C545507:Ramp3 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D053607:Adrenomedullin