The heme-heme oxygenase system in wound healing; implications for scar formation.
Wound healing is an intricate process requiring the concerted action of keratinocytes, fibroblasts, endothelial cells, and macrophages. Here, we review the literature on normal wound healing and the pathological forms of wound healing, such as hypertrophic or excessive scar formation, with special emphasis on the heme-heme oxygenase (HO) system and the versatile effector molecules that are formed after HO-mediated heme degradation. Excessive scar formation following wounding is thought to relate to prolonged oxidative and inflammatory stress in the skin. Evidence is accumulating that the heme-HO system forms a novel and important target in the control of wound healing. Heme-protein derived heme can act as a potent oxidative and inflammatory stress inducer, and excess levels of heme may thus contribute to delayed resolution of oxidative and inflammatory insults in the skin. This emphasizes the need for a timely reduction of the levels of heme. Heme-binding proteins, heme transporters, and the heme degrading protein, HO, form therefore a necessary defense. Deficiencies in these defense proteins or a disturbed redox status, as in diabetic patients, may render individuals more prone to heme-induced deleterious effects. A better understanding of the heme-heme oxygenase system as target during wound healing may result in novel strategies to reduce scar formation.
Wagener
Frank A D T G
FA
Department of Orthodontics and Oral Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. f.wagener@dent.umcn.nl
Scharstuhl
Alwin
A
Tyrrell
Rex M
RM
Von den Hoff
Johannes W
JW
Jozkowicz
Alicja
A
Dulak
Jozef
J
Russel
Frans G M
FG
Kuijpers-Jagtman
Anne Marie
AM
D000818:Animals; D017209:Apoptosis; D002921:Cicatrix / Q000378:metabolism / Q000503:physiopathology; D017439:Cicatrix, Hypertrophic / Q000378:metabolism / Q000503:physiopathology; D004790:Enzyme Induction; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D012867:Skin / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D014945:Wound Healing / Q000502:physiology*
D006420:Hemeproteins; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1