Practical context of enzymatic treatment for wound healing: A secreted protease approach (Review)

Abstract

Skin wounds have been extensively studied as their healing represents a critical step towards achieving homeostasis following a traumatic event. Dependent on the severity of the damage, wounds are categorized as either acute or chronic. To date, chronic wounds have the highest economic impact as long term increases wound care costs. Chronic wounds affect 6.5 million patients in the United States with an annual estimated expense of $25 billion for the health care system. Among wound treatment categories, active wound care represents the fastest-growing category due to its specific actions and lower costs. Within this category, proteases from various sources have been used as successful agents in debridement wound care. The wound healing process is predominantly mediated by matrix metalloproteinases (MMPs) that, when dysregulated, result in defective wound healing. Therapeutic activity has been described for animal secretions including fish epithelial mucus, maggot secretory products and snake venom, which contain secreted proteases (SPs). No further alternatives for use, sources or types of proteases used for wound healing have been found in the literature to date. Through the present review, the context of enzymatic wound care alternatives will be discussed. In addition, substrate homology of SPs and human MMPs will be compared and contrasted. The purpose of these discussions is to identify and propose the stages of wound healing in which SPs may be used as therapeutic agents to improve the wound healing process.

Keywords: enzymatic wound treatment; fish epithelial mucus; maggot secretory products; matrix metalloproteases; snake venom proteases.

Figure 1

Simplified diagram of the interactions between different cell types during wound healing, the contribution of MMPs and proposed wound healing mechanisms of SPs. Skin injury repair begins with hemostasis, a process which stops blood loss and provides a temporary matrix facilitating further steps in wound healing. Fibrin-rich ECM formation stimulates neutrophil-activated monocyte recruitment through TNF-α and PDGF. Both neutrophils and monocytes produce several growth factors, such as TNF-α, TGF-α, TGF-β, EGF and FGF, to enhance migration and proliferation of fibroblasts, endothelial cells, and keratinocytes to the site of injury. Fibroblasts stimulate other cells to produce collagen deposits in the ECM, wound contraction, angiogenesis and re-epithelization. Studies suggest that SPs, such as FMC, FMMP, FMM, FMSP, MaP, SVMP and SVSP, may behave similarly to endogenous MMPs during these stages. Ang, angiopoietin; CTGF, connective tissue growth factor; Col, collagen; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; FMC, fish mucus cathepsin; FMMP, fish mucus matrix metalloprotease; FMM, fish mucus meprin; FMSP, fish mucus serine protease; FN, fibronectin; Hy, hyaluronan; IL-1, interleukin-1; MaP, maggot protease; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PG, proteoglycan; SVMP, snake venom metalloprotease; SVSP, snake proteinase; TGF, transforming growth factor; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.