Wang, CM; (2008) The role of gap junctions in diabetic wound healing. Doctoral thesis , UCL (University College London).

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Abstract

The process of wound healing is slow in diabetes, often resulting in infection or chronic wounds that can lead to amputation. Cell-cell communication through the gap junction protein connexin 43 (Cx43) and the dynamic regulation of Cx43 expression play pivotal roles in the wound healing process. Acute streptozotocin-induced diabetes in rats altered connexin expression in uninjured back skin, decreasing Cx26, Cx30 and Cx43 protein and gap junctional communication in the epidermis and increasing Cx43 protein and communication in the dermis. Diabetes was also found to alter the dynamic changes of connexins associated with the wound healing response. Within 24 hours, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated, as in controls which formed a thin process of migratory cells). Cx43 protein reduction was delayed until 48 hours when re-epithelialisation then began. Although Cx26 protein was upregulated as usual in diabetes, its distribution at the wound edge was abnormal, being more widespread. Preventing the abnormal upregulation of Cx43 expression in wound edge keratinocytes with Cx43 specific antisense oligodeoxynucleotides doubled the rate of re-epithelialisation to control levels and above. Other subsequent events of wound healing including the inflammatory response and granulation tissue maturation were also greatly improved. These results imply that diabetes-induced changes in connexin expression dynamics contribute to delayed wound healing and that targeting Cx43 expression is of potential therapeutic value in diabetic wound healing. A pilot study showed that Cx43 plays a role in the early activation of endothelial cells during inflammation. The data in this thesis provide further evidence for the central roles of connexins in the homeostasis of skin and response to injury. In particular, its role in the coordination of inflammatory response can have a pivotal impact on the quality of cutaneous wound repair.

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