Comment on Hoffman et al, page 3053
Hoffman and colleagues provide evidence for the link between the coagulation process, wound healing, and angiogenesis. Compared with wild-type mice, those with Christmas disease lacking coagulation factor IX (FIX) developed subcutaneous hematomas and exhibited delayed monocyte infiltration and impaired wound healing after 3-mm punch biopsies were placed in the skin. Surprisingly, the wounds of hemophilic mice contained twice as many blood vessels as those in wild-type animals
Wounds are a part of life, and wound healing affects everyone at some time. Nonhealing, chronic wounds impair the quality of life for millions of Americans, costing billions of health care dollars. In this issue of Blood, Hoffman and colleagues provide evidence for the link between the coagulation process, wound healing, and angiogenesis. Compared with wild-type mice, those with Christmas disease lacking coagulation factor IX (FIX) developed subcutaneous hematomas and exhibited delayed monocyte infiltration and impaired wound healing after 3-mm punch biopsies were placed in the skin. Surprisingly, the wounds of hemophilic mice contained twice as many blood vessels as those in wild-type animals.
Wound healing1 is divided into 4 phases. The first includes triggering of the coagulation mechanism following injury to vessels with exposure of tissue factor and activation of a cascade of enzymes and cofactors that leads to thrombin generation, platelet activation, and fibrin deposition—the provisional wound matrix upon which platelets adhere and aggregate in the wound base. Growth factors, including basic fibroblast growth factor and platelet derived growth factor, are released from activated platelets and are the precursor to the inflammatory phase marked by the appearance of monocytes. Cytokines and other immunoeffector molecules result in rubor, calor, tumor, and dolor, and functio laesa—cardinal manifestations of wounds. The proliferation phase begins with the appearance of fibroblasts and is followed by the maturation phase in which collagen is deposited and then remodeled to enhance tensile strength. Vessel formation is critical to each phase of wound healing.2 The mediators of this process are not known, but Hoffman and colleagues hypothesize that Fe may play a role. The formation of subcutaneous hematomas in hemophilic but not wild-type mice results in the deposition of Fe in the wound base that is released from erythrocyte heme by the action of heme-oxygenase, an enzyme from monocytes.
The multiple functions of Fe in cell metabolism were recently reviewed by Le and Richardson.3 Fe is an obligate requirement for life and its depletion leads to G1/S arrest and apoptosis. Fe deprivation inhibits the growth of tumors such as neuroblastoma, a highly vascular and aggressive malignancy, and reduces the activity of the R2 subunit of ribonucleotide reductase necessary for DNA synthesis, decreases the expression of cyclins A, B, and D, and results in hypophosphorylation of the retinoblastoma protein. The levels of p53 increase following Fe chelation via the ability of hypoxia-inducible factor to bind to and stabilize p53 and by phosphorylation at serine 15 and serine 37 that prevents the interaction of p53 with murine double minute-2 (mdm-2) leading to p53 degradation. Chelating Fe also increases the mRNA levels of the p53-inducible cyclin-dependent kinase (cdk) inhibitor, p21 (WAS1/CIP1). In contrast to the precious metals such as silver, the most abundant element on earth, iron (35% by mass), may be the key to healing wounds. ▪
