Redox dysregulation in the pathogenesis of chronic venous ulceration

In chronic venous ulcers (CVUs), which account for up to 75% of leg ulcers, the inflammatory stage of wound healing fails to down-regulate, preventing progression to proliferation, remodeling and eventual epithelialisation. The roles of reactive oxygen species (ROS) in the oxidative burst and pathogen killing are well known, but ROS also have important functions in extra-cellular and intra-cellular signalling. Iron deposition, resulting from venous reflux, primes macrophages towards a persistent inflammatory response, with ongoing stimulation by bacteria potentially playing a role. Generation of excessive ROS by activated inflammatory cells causes tissue destruction and disintegration of the dermis, and then at later stages, a failure to heal. Here, we review the evidence for ROS in CVU formation and in normal and delayed healing. We also discuss how ROS modulation might be used to influence the healing of these complex wounds, which cause long-term morbidity and are associated with a significant financial burden to healthcare systems.