The Role Of MMPs In Chronic Wound Edema
Fibrin plugs formed during coagulation also block lymphatic drainage and localize the inflammatory reaction to support healing. Inflammatory mediators stimulate MMP transcription and activation. Presumably, the inflammatory mediators vary with differing wound types, the type and extent of colonization and the capability of host modulation. Postoperative surgical wounds provide a source for acute wound fluid. One can obtain chronic wound fluid from a variety of lower extremity ulcers. Growth factors, MMPs, immune factors, and cytokines are measured. Functional assessments include the ability of the fluids to influence the growth of fibroblasts, endothelial cells and keratinocytes. Acute wound fluid activates growth factors such as platelet-derived growth factor (PDGF) necessary for fibroblast proliferation, collagen secretion and matrix formation. On the other hand, chronic wound fluid activates MMP-8, -2, and -9 with subsequent degradation of growth factor, reduction of ECM, interference with collagen cross-bridging and decreased deposition of vital stromal structures. In chronic wound fluid samples, epidermal growth factor (EGF) degradation is associated with elevated MMP protease activity. On the other hand, degradation of recombinant vascular endothelial growth factor (rVEGF165) stimulated by chronic leg wound fluid is associated with plasmin. What The Literature Reveals For chronic venous leg ulcers, studies show a 30-fold elevation in MMP activity when compared to acute wounds. MMP-9 activity exceeds MMP-2 activity. In a pressure ulcer model (decubitus ulcers), the levels of MMP-2 and MMP-9 are elevated more than 10-fold and 25-fold respectively. In pressure ulcers, MMP-8 collagenase activity is also elevated. The diabetic foot ulcer model shows a 65-fold increase in MMP-1 collagenase activity, a three-fold increase in MMP-2 proenzyme activity, a six-fold increase in activated MMP-2, a two-fold increase in MMP-8 activity and a 14-fold increase in MMP-9 activity. The MMP proteolytic activity in acute wounds is not as pronounced. Acute mastectomy wound fluid shows an increased gelatinase activity for MMP-9 and MMP-2. However, these increases were only five to ten-fold. It is also important to note that the inactive zymogen forms tended to persist in acute wound fluid. These results suggest that the pro-inflammatory environment of non-healing ulcers supports high levels of gelatinase activation. TIMP activity appears to be inversely related to the chronicity of the wound. In the diabetic foot model, TIMP-2 activity is decreased. In the venous ulcer model, TIMP-1 activity is depressed. Likewise, the pressure ulcer model shows lower TIMP activity secondary to complexes of TIMP and activated MMP. Proteolytic activity normalizes as the wound healing progresses. Studies comparing protease activity in venous leg ulcers showed a reduction in MMP-2 and MMP-9 levels as the wounds healed over a two-week period following treatment with bed rest and leg elevation. Pro-inflammatory cytokines IL-1, IL-6 and TNF-alpha in wound fluid from previously non-healing lower extremity wounds also decrease during healing. Platelet derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-basic) and transforming growth factor-beta (TGF-ß) did not significantly change as wounds healed. These results suggest that the impaired healing response seen in chronic wounds may be more dependent upon inflammatory mediators and MMP activation than upon a deficit in growth factors. Controlled proteolysis is needed for cell migration, angiogenesis and matrix remodeling. Collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) are expressed in keratinocytes bordering both acute and chronic wounds. Differential collagenase expression suggests various MMPs serve different functions during the wound healing process. The presence of collagenase-1 (MMP-1) in keratinocytes appears to be important for cellular migration whereas collagenase-3 (MMP-13), which present exclusively in fibroblasts embedded deep within the chronic ulcer wound bed, probably functions more in matrix remodelling. TIMP-1 associated with keratinocytes bordering healing wounds at the basement membrane is not expressed in the epidermis of chronic wounds. TIMP-3 expression is conserved in both acute and chronic wounds, localized in the stromal fibroblast and macrophage-like cells surrounding vessels and sweat glands.