Controlling levels of reactive oxygen species breaks cycle of wounds that have refused to heal

December 17, 2013

By controlling levels of reactive oxygen species levels within chronic wounds of genetically modified mouse models., Manuela Martins-Green, Ph.D., of the University of California, Riverside (UC Riverside) was able to normalize conditions and heal the wounds, according to research to be presented on Tuesday, Dec. 17, at the American Society for Cell Biology annual meeting in New Orleans.

Two biological activities are out of control in chronic wound infections, said Dr. Martins-Green. They are: reactive oxygen species (ROS), which are chemically reactive molecules formed by the partial reduction of oxygen, and biofilms that are formed by selective invading bacteria.

ROS, the natural byproduct of normal oxygen metabolism, plays a role in cell signaling and homeostasis. The UC Riverside researchers identified the central role of ROS in maintaining chronic wound infection by inhibiting glutathione peroxidase and catalase, antioxidant enzymes that help maintain normal tissue levels of ROS. Because the antioxidant enzymes were inhibited, the amount of ROS in the wounds soared. The scientists also found that the antioxidant inhibitors were more damaging if administered in combination rather than individually.

Wounds that don't heal are a major danger for patients with type 2 diabetics. A small blister on a patient's foot can evolve into a seriously infected wound that refuses to heal and, if gangrene develops, the patient's foot may have to be amputated.

Such "simple" foot blisters and other diabetic ulcers or sores account for the vast majority of foot and leg amputations in the U.S. today. Individuals who are paraplegic or quadriplegic and anyone with severely limited mobility are also highly vulnerable to these chronic skin wounds as well as pressure ulcers and bedsores. Together, chronic wounds affect an estimated 6.5 million Americans at an annual cost of about $25 billion.

Previous studies in Dr. Martins-Green's lab showed that excessive ROS can induce chronic inflammation, a key characteristic of wounds that do not heal. Biofilms are bacterial defense mechanisms. Together ROS and a biofilm create a sealed toxic environment that can resist all efforts to heal and close a chronic wound.

After inhibiting the ROS inhibitors, Dr. Martins-Green and her colleagues then returned ROS to normal levels by applying two strong antioxidant supplements, vitamin E and N-Acetyl cysteine. Vitamin E reduces the levels of the oxygen radicals, and N-Acetyl cysteine stabilizes the antioxidant enzyme pool, which helps decrease the hydrogen peroxide levels, a contributor to oxidative damage.

As a result of the antioxidant treatment, glutathione peroxidase and catalase activities were restored, and the bacterial biofilm disintegrated in the wound, said Dr. Martins-Green. Restoration of glutathione peroxidase and catalase activities and biofilm disintegration lead to development of healthier wound tissue.

These results show for the first time that, by deliberately modulating specific redox parameters, the researchers were able to create chronic wounds and then reverse chronicity by antioxidant treatment.

"Our findings emphasize the importance of maintaining redox balance during healing and will help in unraveling the mechanisms underlying the development of chronic wounds and hence in identifying potential targets for treatment of these wounds in humans," said Dr. Martins-Green.

Manuela Martins-Green, Ph.D.
UC Riverside


John Fleischman

Cathy Yarbrough

Author will present, "Creating and reversing diabetic chronic wounds by manipulation of redox parameters," on Tuesday, Dec. 17, during the 12 noon to 1:30 p.m., poster session, "Defining Therapeutic Targets and New Therapeutics."

Co-authors: S. Dhall, D. C. Do, M. Garcia, N. Schiller and M. M. Green, UC Riverside.

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