The Heme-Heme Oxygenase System in Wound Healing; Implications for Scar Formation

Frank      A.D.T.G. Wagener; Alwin      Scharstuhl; Rex      M. Tyrrell; Johannes      W. Von den Hoff; Alicja      Jozkowicz; Jozef      Dulak; Frans      G.M. Russel; Anne      Marie Kuijpers-Jagtman

Abstract

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.

Keywords: Heme, wound healing, scar formation, inflammation, heme oxygenase, (myo)-fibroblasts, keratinocytes, fibroblasts, endothelial cells, macrophages, heme-heme oxygenase (HO), inflammatory stress, angiogenesis, homeostatic mechanisms, hemorrhage, hemolysis, microenvironment, plasma proteins, leukocyte-adhesion cascade, coagulation cascade, chemokine, granulocytes, proliferative phase, neovascularization, extracellular matrix (ECM), remodeling phase, hypertrophic scar, alveolar bone, matrix metalloproteinase (MMPs), reactive oxygen species (ROS), iron protoporphyrin IX, aminolevulinate synthase (ALA-S), hemoglobin, myoglobin, electron transport, cyclo-oxygenase (COX), nitric oxide synthase (NOS), molecular switch, pathogenesis, Toll-like receptor molecule-4 (TLR-4), rheumatoid arthritis, Heme Binding Proteins, hemoglobin (Hb), hemopexin, haptoglobin-hemopexin (HpHx), splenectomized, Microglobulin, lipophilic heme, anionic carboxylate, heme/porphyrin transport proteins, heme carrier protein 1 (HCP1), feline leukemia virus receptor C (FLVCR), breast cancer resistance protein (ABCG2/BCRP), carbon monoxide (CO), biliverdin, biliverdin reductas, atherosclerosis, haptoglobin, guanine-thymidine (GT), stromal cell derived factor-1 (SDF-1), glutathione-Stransferase, cyclo oxygenase (COX), holo-enzyme, arachidonic acid (AA), Ornithine, hypertrophic scars, tumor necrosis factor (TNF), death-inducing signaling complex (DISC), mitochondrial outer membrane permeabilization (MOMP), apoptosis inducing factor (AIF), hypertrophy, systemic sclerosis patients (SSC), transforming growth factor-β (TGFβ), bleomycin, alpha-smooth muscle actin (aSMA), fibronectin, iron chelators, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), keratinocyte growth factor (KGF), insulin-like growth factor (IGF), myocardium, adenoviral gene transfer, angiopoietin-1, hyperbilirubinemic rats, amelioration