Zinc in Wound Healing Modulation

Abstract

Wound care is a major healthcare expenditure. Treatment of burns, surgical and trauma wounds, diabetic lower limb ulcers and skin wounds is a major medical challenge with current therapies largely focused on supportive care measures. Successful wound repair requires a series of tightly coordinated steps including coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodelling. Zinc is an essential trace element (micronutrient) which plays important roles in human physiology. Zinc is a cofactor for many metalloenzymes required for cell membrane repair, cell proliferation, growth and immune system function. The pathological effects of zinc deficiency include the occurrence of skin lesions, growth retardation, impaired immune function and compromised would healing. Here, we discuss investigations on the cellular and molecular mechanisms of zinc in modulating the wound healing process. Knowledge gained from this body of research will help to translate these findings into future clinical management of wound healing.

Keywords: TRIM family proteins; anti-oxidant; immune response; inflammation; matrix metalloproteinase; matrix remodelling; tissue proliferation.

Figure 1

The function of zinc throughout the stages of wound healing. Zinc has a significant function in many cells over the entire process of wound repair. After injury wounded tissue must establish haemostasis via coagulation and clot formation. Injury is quickly followed by immune infiltration and inflammation as a means to clear the wound of damaged tissue and microbes, thus preventing infection and allowing room for granulation. Fibroblast, epithelial cells, keratinocytes and endothelial cells, will proliferate and migrate into wounds to deposit ECM and re-populate the injury site, facilitating wound closure. Finally, matrix deposition and clearance regulates the development of scar formation. PMN—polymorphonuclear leukocytes; NETosis—a novel form of programed neutrophil death that resulted in the formation of neutrophil extracellular traps (NETs); ECM—extracellular matrix.

Figure 2

Proposed roles of zinc in MG53 mediated wound healing process. MG53 exists as intrinsic intracellular vesicles which could be secreted into blood circulation as a myokine to mediate wound healing. In response to dermal injury, MG53 could exert the following functions. (a) MG53-containing vesicles nucleate the cell membrane repair machinery and trafficking to damaged cell membrane to protect against acute membrane injury of keratinocytes and fibroblasts; (b) MG53 mediates cytoskeletal stress fibre remodelling to promote fibroblasts migration to the wound sites; and (c) MG53 regulates TGFβ signalling to modulate trans-differentiation of fibroblasts into myofibroblasts and suppresses deposition of ECM proteins during tissue remodelling stage of wound healing. Zinc is proposed to bind to MG53 on its two zinc-binding sites and modulates MG53-mediated wound healing process (Modified from JBC 290(40): 24592). MG53: Mitsugumin 53; ECM: extracellular matrix; TGFβ: transforming growth factor-β.