Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Pathology & Laboratory Medicine, 2009.
Impaired wound healing, including acute wounds and chronic ulcers, has imposed multi-billion dollar costs on US health service. Especially, it often associates with aging and other pathological conditions, such as diabetes mellitus. More and more evidence shows gender differences in cutaneous wound healing, especially in elderly population. Clinically, cutaneous wounds heal more slowly in elderly men than women, accompanied with more inflammatory cell infiltration and reduced collagen deposition. In other studies, male gender has also been known as a risk factor for impaired wound healing, suggesting that sexual hormones, including androgens, might regulate the repair process. Nevertheless, the underlying mechanisms remain poorly understood. In this thesis, we used conditional androgen receptor (AR) knockout mouse models to dissect AR function in different types of cells involved in the healing process and studied the detailed mechanisms how androgens/AR involves cutaneous wound healing. Interestingly, compared to wild type (WT) controls, we found cutaneous wound healing was accelerated in AR knockout (ARKO) mice, accompanied by faster re-epithelialization and accelerated collagen deposition. The acceleration of healing was due to loss of AR function instead of decreased androgen levels in ARKO mice. By using reciprocal bone marrow transplantation and conditional ARKO mice, we demonstrated that AR in monocytes/macrophages rather than in mesenchymal cells played a critical role in suppressing healing, as well as collagen deposition in granulation tissues. Further analysis of the mRNA and protein expression of inflammatory mediators involved in wound repair, we found the overall inflammation was attenuated in ARKO compared to WT wounds. Among these mediators, we demonstrated that TNF? is critical to mediate the suppressive effect of AR in wound healing regulation. Mechanistic dissection further suggested that monocyte/macrophage AR might utilize distinct mechanisms to enhance the local TNF? expression, including (a) increasing macrophages in the wound area via increasing the inflammatory monocyte population and augmenting recruitment of monocytes via enhancing their chemotaxis into the wound areas, and (b) increasing TNF? expression in macrophages via transcriptional modulation. Further using mesenchymal-specific ARKO mice, the results confirm that although mesenchymal AR plays a role in re-epithelialization, it is the AR function in monocytes/macrophages that is the most important in suppressing overall cutaneous wound healing. In terms of therapeutic purpose, fascinatingly, we found that topical ASC-J9, a curcumin-derived anti-AR compound, treatment to target AR could accelerate cutaneous wound healing in WT mice. Overall, our studies provide the detailed mechanisms showing that AR in monocytes/macrophages enhances local TNF? expression to suppress cutaneous wound healing, and to demonstrate that targeting AR could be a potential therapeutic approach for enhancing wound healing.