Proteases and Delayed Wound Healing

Abstract

Significance: Proteases and their inhibitors contribute to the balance between extracellular matrix (ECM) degradation and deposition, creating an equilibrium that is essential for the timely and coordinated healing of cutaneous wounds. However, when this balance is disrupted, wounds are led into a state of chronicity characterized by abundant levels of proteases and decreased levels of protease inhibitors.

Recent advances: Researchers have sought to investigate the roles of proteases within both acute and chronic wounds and how the manipulation of protease activity may aid healing. Indeed, numerous wound dressings have been developed that target such proteases in an attempt to promote wound healing.

Critical issues: The normal tissue response to injury involves a complex interaction between cells and cellular mediators. In particular, the inflammatory response is augmented in chronic wounds which are characterized by elevated levels of proinflammatory cytokines and proteases. While controlling levels of inflammation and protease expression is a critical part of normal wound healing, elevated and prolonged expression of proteases produced during the inflammatory phase of healing can lead to excessive ECM degradation associated with impaired healing.

Future directions: It seems plausible that future research should aim to investigate the ways in which proteases may be targeted as an alternative therapeutic approach to wound management and to assess the benefits and draw-backs of utilizing wound fluids to assess wound progression in terms of proteolytic activity.

Steven L. Percival, PhD

Figure 1.

Stages involved in normal cutaneous wound repair. Following initial tissue injury, hemostasis commences, the end product of which is fibrin clot formation. Inflammation then proceeds, leading to the debridement and cleansing of the wound area before cellular proliferation and migration. Cytokines and growth factors play a pivotal role in the wound-healing process, mediating cellular signaling, and healing pathways. Macrophages and neutrophils act to debride and cleanse the wound area via the clearance of contaminating microorganisms and foreign material. Proteases, including matrix metalloproteinases (MMPs) are secreted, which aid in the remodeling of the extracellular matrix (ECM). A balance between ECM degradation and deposition is maintained via the secretion of both MMPs and tissue inhibitors of metalloproteinases (TIMPs).

Figure 2.

Stages involved in the development of a chronic cutaneous wound. Following the initial tissue injury, external stimuli, including bacterial contamination and infection cause a prolonged and augmented inflammatory response. This in turn leads to an elevated level of inflammatory cytokines and proteases. An imbalance in the deposition and degradation of the ECM is created, leading the wound into a state of chronicity.

Figure 3.

Simple domain structure of the MMPs important in cutaneous wound healing. The upper image represents the simple hemopexin domain-containing MMPs (including collagenases and stromeolysins). The lower image represents the gelatinases, MMP-2 and MMP-9. MMPs consist of a signal peptide (SP), a propeptide (light gray), which prevent enzyme activity, a catalytic domain, which contains the zinc binding site (dark gray), and a hemopexin-like c-terminal domain, which is made up of 4 repeat units joined by a disulfide bridge. The hemopexin-like c-terminal domain and the catalytic domain are connected by a hinge region (H). The gelatinases (MMP-2 and MMP-9) have an insert in the catalytic domain consisting of three fibronectin type II repeats (FN).

Figure 4.

Effects of bacterial colonization and infection on cutaneous wound healing. Invading bacteria release proteases, which augment the host's inflammatory response, in turn contributing to the proteolytic nature of a chronic wound.