Apoptosis down-regulates inflammation under the advancing epithelial wound edge: delayed patterns in diabetes and improvement with topical growth factors.

Wound healing is involved in many aspects of care, ranging from anastomoses and skin incisions to foot ulcers and decubitus. Clinical healing failures are a major challenge to the physician and cause significant morbidity and mortality in select patient populations. As we are starting to understand more fully the mechanisms of impaired wound healing, the diabetic mouse (C57BL/KsJ-db/db) has been a good model for research. The diabetic wound exhibits significant delays in healing, previously identified as impaired cellular infiltration and granulation tissue formation. Apoptosis, or programmed cell death, is intimately involved in the regulation of inflammation and ultimately should play a role in the inflammatory phase of wound healing. To examine its role in wound healing, patterns of apoptosis in large, full-thickness cutaneous wounds were compared between groups of diabetic and nondiabetic mice. Initially apoptosis was mainly limited to the wound edge and followed the advancing epithelial edge toward the center of the wound as healing progressed. Significant delays in the appearance of the apoptotic pattern were noted in the diabetic mice. Wounds in diabetic mice were then treated with topical application of growth factors. The delay in apoptotic pattern was reversed after treatment with the combination of insulin-like growth factor-II and platelet-derived growth factor, approaching levels in nondiabetic animals. Apoptosis appears concurrently with reepithelialization of the wound and may signal the end of the inflammatory phase of healing at that site in the wound. One can speculate that a signal for apoptosis and down-regulation of inflammation in the wound is derived from the epithelium.