Proteases and the Chronic Wound
The process of wound healing is a complex physiological event designed to restore skin integrity. In general, it is divided into three phases: an initial inflammatory phase necessary to debride the wound of foreign material and damaged tissue and to control bioburden, a reconstructive phase characterized by the deposition of granulation tissue, reepithelialization and wound contraction, and finally the remodeling phase and scar formation. These wound healing phases involve complex successions of overlapping chemical events at a cellular level.
Proteases are a family of proteolytic enzymes that play a critical role in each of these physiological phases of wound repair at the cellular level. Proteases are associated with the early inflammatory stage of wound healing in several ways. During angiogenesis, proteases are expressed ephemerally at the growing tip of blood vessels to facilitate vascular invasion. Proteases also assist in debridement and cleansing of the wound of necrotic tissue, foreign bodies and bacteria. In normally healing wounds, during the reconstructive and remodeling phase, proteases digest the extracellular matrix and assists in tissue remodeling. In fact, one of the proteases main functions throughout the wound repair process is to regulate the balance between tissue synthesis and tissue degradation.
Research shows that the biochemical environment of the non-healing wound is different from that of a healing wound. A chronic non-healing wound has a biochemical environment that shows evidence of excessive inflammatory cytokines and proteases and low levels of growth factors. Wounds that have a high level of bioburden are prone to increase levels of proteases. Bacterial endotoxins released when bacteria are destroyed, or lipopolysaccharides from Gram-negative cell walls cause the release of inflammatory cytokines that stimulate production of proteases. In addition, there is a change in the balance of proteases and TIMPs in the aged, with higher protease activity level in older patients. Abnormal elevated protease levels are a concern in wound care because their uncontrolled activity destroys growth factors and their receptors, inhibits angiogenesis, and breaks down granulation tissue resulting in tissue damage. Growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-B), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), are essential in normal wound repair playing a significant role in cell migration, proliferation, protein synthesis, and extracellular matrix formation. The degradation of growth factors by proteases therefore results in delayed wound healing caused by an increase in tissue destruction.
There are numerous types of proteases involved in tissue remodeling and wound repair. Neutrophil-derived elastase, plasmin, and MMP’s are major proteases present in chronic wounds that have a role in delaying healing. The most predominant protease activity in chronic wounds is the neutrophil- derived elastase. Its presence supports the theory that healing is delayed in chronic wounds because the wound is trapped in the inflammatory phase of repair.
Matrix metalloproteases or MMP’s are another type of proteases that have elevated levels in chronic wounds impairing healing. Multiple cell types, including macrophages, fibroblasts, neutrophils, epithelial cells, and endothelial cells, synthesize MMP’s in the presence of specific biochemical signals such as inflammatory cytokines. MMP’s are capable of digesting almost all of the components of the extracellular matrix. For wound healing to occur, a balance is needed between the protein degrading activities of MMP’s and other cellular activity that synthesizes and deposits protein components of granulation tissue. In normal wound healing, this proteolytic activity of MMP’s is controlled by various mechanisms including gene transcription, production of the enzyme in an inactive form (zymogen) that requires extracellular activation, and by local secretion of endogenous enzyme inhibitors called tissue inhibitors of metalloproteases (TIMPs). During wound repair, a balance exists between the activities of the MMP’s and the TIMPs. Another endogenous chemical agent that will inhibit proteases is alpha-2-macroglobin (A2M). When chronic wounds are surgically debrided, local bleeding creates an influx of A2M that acts as a protease inhibitor.
In chronic wounds when the excess of proteases is not balanced by the normal physiological mechanisms, the control of these protease activities becomes a crucial component of wound management. In fact, research related to the cellular activities of wound healing has changed chronic wound management from processes that facilitated passive healing and/or prevention of wound deterioration (e.g. moisture retentive wound dressings, wound cleansers, and topical and systemic antibiotics) to newer advance modalities that control the molecular mediators of healing. One such advance modality that controls proteases activity is ORC/Collagen.
ORC/Collagen is a medical device composed of freezed- dried oxidized regenerated cellulose (ORC) and bovine collagen. This bioactive dressing binds to and neutralizes destructive proteases in chronic wound fluid. Bound proteases undergo an alteration of their protein configuration, rendering them inactive. The lowered protease enzymatic activity decreases destruction of growth factors, and actually isolate and protect wound growth factors and promote cellular chemotaxis and proliferation. ORC/Collagen is used whenever it is expected that there is excessive protease activity contributing to delayed wound healing and/or when protection of growth factor activity is necessary for the healing process.
In summary, chronic wounds exhibit an imbalance between tissue deposition stimulated by growth factors, and tissue destruction mediated by proteases, with the imbalance favoring the destructive processes. High protease levels in chronic wound fluid delay wound healing by degrading newly formed granulation tissue and proteins, such as growth factors and extracellular matrix protein. ORC/collagen inactivates proteases and protects growth factors from enzymatic degradation. The result is an overall increase in granulation tissue and wound repair.
This article was written by Jane Ellen Barr RN, MSN, CWOCN, ANP
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