Papers of The 9th Japan Scar Workshop

4. The role of reactive oxygen species in the wound healing process in aged mice

Toshihiro Fujiwara1,2
Geoffrey C. Gurtner2
1:Department of Plastic Surgery, Hyogo College of Medicine, Nishinomiya, Japan
2:Division of Plastic Surgery, Stanford University, California, USA

An excessive stress of superoxide, a reactive oxygen species (ROS), can result in significant impairment of the wound healing process. Intracellular superoxide dismutase (SOD1) is a scavenger enzyme that regulates intracellular superoxide degradation and therefore plays a critical role in homeostasis. While it is well documented that wound healing is significantly impaired with aging, recent studies indicated that expression of SOD1 is reduced with aging. In this study, we evaluated the role of SOD1 in wound healing in aging mice
Materials and Methods
Young (4-month-old) and aged (22-month-old) wild-type mice were used for all experiments. An excisional wound model was created and followed over time to evaluate the wound healing ability, ROS stress, and protein expression of SOD1. Furthermore, dermal fibroblasts were isolated from unwounded skin and assessed for their tolerance to intracellular superoxide stress and their ability to differentiate into myofibroblasts under intracellular superoxide stress conditions using a collagen gel contraction assay.
The wound healing rate was decreased in the in vivo model of aged mice. ROS stress peaked 3 days after injury and was higher in aged mice than in young mice. Expression of SOD1 was also lower in aged mice than in young mice. In an in vitro model, fibroblasts of aged mice had a lower tolerance to intracellular superoxide than those of young mice. The collagen gel contraction rate and expression rate of alpha smooth muscle actin were decreased under intracellular superoxide conditions in aged mice.
Excessive accumulation of ROS after injury causes cell dysfunction and apoptosis, leading to significant impairment of wound healing. However, appropriate intracellular superoxide stress promotes the wound healing process by inducing the differentiation of fibroblasts into myofibroblasts. SOD1 can protect cells from excessive oxidative stress and appropriately regulate intracellular superoxide stress for the differentiation of fibroblasts. Therapeutic strategies that target this pathway may be an interesting alternative for the treatment of chronic wounds in aging people.
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