title: Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing.
abstract: Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.
authors.affiliation: The Sutton Arthritis Research Laboratories, Institute of Bone and Joint Research, University of Sydney, Sydney, New South Wales, Australia. cjackson@med.usyd.edu.au
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: Meilang
authors.initials: M
authors.lastname: Xue
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Ross A
authors.initials: RA
authors.lastname: Davey
authors.forename: Kaley
authors.initials: K
authors.lastname: Whitmont
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
authors.forename: Nathalie
authors.initials: N
authors.lastname: Buisson-Legendre
authors.forename: Tamara
authors.initials: T
authors.lastname: Sztynda
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Furphy
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.forename: Philip
authors.initials: P
authors.lastname: Sambrook
authors.forename: Lyn
authors.initials: L
authors.lastname: March
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D006801:Humans; D007249:Inflammation / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D014945:Wound Healing / Q000187:drug effects* / Q000276:immunology
chemical_list: D011486:Protein C; D020778:Matrix Metalloproteinase 2