Davis, NG; (2015) Privileged and Staphylococcus aureus Impaired Healing: Is there a Connexin Connection? Doctoral thesis , UCL (University College London).

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Abstract

Wound healing is a vital process, ensuring re-establishment of homeostasis and protection from pathogens. A few regions exhibit privileged healing, such as buccal mucosa, repairing very rapidly. In contrast, wound healing can be impaired, creating chronic wounds. Connexins (Cx) are a group of proteins that form gap junctions, enabling direct communication between the cytoplasm of connected cells. They play a pivotal role in normal skin wound healing. Cx43 is involved in cell proliferation and migration, but the roles of Cx26 and Cx30 are less well understood. Connexin expression changes in the privileged healing of buccal mucosa have not previously been determined. Cx26, Cx30 and Cx43 were highly expressed throughout the mucosa epithelium, but became rapidly down-regulated at the wound edge. This is in contrast to skin, where Cx26 and Cx30 are expressed at low levels, but increase at the wound edge, showing that the connexin dynamics differ between the tissues. Cx26, Cx30 and Cx43 expression also differs in chronic wounds compared to normal skin. They are expressed at abnormally high levels throughout the epidermis, and Cx43 is highly expressed in the dermis. It is thought that bacterial infection is involved in chronic wound development and healing impairment. Staphylococcus aureus is found in 90% of chronic wounds, where it forms a biofilm. I found that in vitro S.aureus biofilm exotoxins caused senescence in fibroblasts, impaired migration, and reduced Cx43 expression. The bacteria themselves reduced Cx43 expression, which increased their internalisation into fibroblasts. Furthermore, loss of Cx43 expression resulted in increased toxicity of S.aureus infection. In vivo S.aureus infection impaired healing, and resulted in epidermal hyperplasia and connexin up-regulation, mimicking the aetiology of chronic wounds. Connexin expression differs in buccal mucosa and S.aureus infected wounds compared to normal skin during healing, but their role in the healing status of these tissues is still poorly understood.

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