Chronic wounds represent a significant burden to the U.S. health care system, affecting millions of patients and costing billions of dollars. To manage these problems, there is a need to find new factors that facilitate chronic wound healing process. In chronic wounds, oxidative stress is a consequence of an imbalance in the prooxidant-antioxidant homeostasis and thought to drive deleterious events perpetuating a non-healing state. Reactive oxygen species (ROS) are involved in all stages of wound healing process but the regulation of ROS-generating system in fibroblasts still remains poorly understood. In chronic wounds, there are enhanced levels of ROS released from residential fibroblasts and the load of ROS persists over a long period of time with subsequent continuous damage.
Migration, adhesion, proliferation, neovascularization, remodeling and apoptosis are the main processes in wound healing regulated, or at least modulated, by ROS. Major source of these molecules in cells are mitochondria which DNA is sensitive target for oxidative damage and resulting alterations in mitochondrial DNA (mtDNA) might perpetuate and increase oxidative stress and subsequently generate changes in cellular ROS production. Thus, this research will elucidate the role of ROS produced by mtDNA variants in the process of chronic wound healing. Cybrid model system of mtDNA alterations will be used to stimulate varying levels of ROS liberation by fibroblasts. Cybrids are cells created by introducing mtDNAs of interest into the fibroblast ρ0 cells depleted of endogenous mtDNAs. In this way, the nuclear genetic complement is held constant and observed changes in ROS production can be linked to the introduced mtDNA.
This research has broad implications in medicine in that it will help identify potential factors/targets that may influence still poorly understood process of chronic tissue repair and provide insight into the potential mechanisms whereby the modulating of cellular levels of mitochondrial ROS could be a potential natural therapeutic target in the processes of chronic wound healing. Better understanding of how the regulation of intracellular ROS levels generated by mitochondria may influence the chronic wound repair could result in novel redox-based strategies to help treat these non-healing wounds. Moreover, in chronic wounds when increased cellular proliferation and motility is desired, altered mitochondrial function may be advantageous and topical medications modulating the downstream effects of ROS signaling might be natural therapeutic targets in this disease status.