It may begin as a "simple" foot blister, but for patients with type 2 diabetes there is nothing simple about wounds that won't heal. That blister 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. Paraplegics, quadriplegics, 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.
Two biological activities are out of control in chronic wound infections, says Manuela Martins-Green of the University of California, Riverside (UC Riverside)—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. However, previous studies have shown that excessive ROS can induce chronic inflammation, a key characteristic of wounds that do not heal. The biofilms are bacterial defense mechanisms. Together they create a sealed toxic environment that can resist all efforts to heal and close a chronic wound. But by controlling ROS levels within the wound, Martins-Green now reports that her UC Riverside lab was able to normalize conditions and heal chronic wounds in genetically modified mouse models. Decreasing ROS to normal levels resulted in significant improvement in wound healing.
The 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.
The researchers then decreased 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, says Martins-Green. This leads 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," says Martins-Green.