Abstract
Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone [1]. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re-epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm-forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies.
Highlights
Failure of acute wounds to proceed through the normal regulated repair process results in wounds that have impaired healing and/or become chronic [2,3]
In order to identify parameters in the wounds with impaired healing that, when changed, may lead these wounds to become chronic, we first characterized the state of reactive oxygen species (ROS)/reactive nitrogen species (RNS) in the early stages of impaired healing by examining a variety of components of the oxidative and nitrosative stress cycle as represented schematically in Figure S1 in File S1 Superoxide dismutase (SOD) dismutates superoxide anions (O22) to generate H2O2, which can be detoxified by catalase to H2O+O2 and by glutathione peroxidase (GPx) to H2O
We found that the levels were significantly elevated but that elevation did not occur until 12 hrs and 24 hrs post-wounding, respectively (Figure 2F,G), suggesting that the increase in Nitric oxide (NO) production must be due to activation of other systems/factors occurring very early after wounding
Summary
Failure of acute wounds to proceed through the normal regulated repair process results in wounds that have impaired healing and/or become chronic [2,3]. Great efforts have been made to switch the course of repair from non-healing wounds to healing wounds, success has been limited This is primarily due to the pathophysiological complexity of changing an acute wound into a chronic wound and the lack of good animal models. Even in well-oxygenated wounds [11], when the number of neutrophils is high [13], lactate and ROS become significantly elevated as a result of aerobic glycolysis – the so-called ‘‘Warburg effect’’ [14]. This environment leads to a stagnant inflammatory phase. If the inflammatory cells are not removed from the wound tissue, they can promote further tissue damage through excessive production of inflammatory cytokines, proteases, and reactive oxygen intermediates, and increased cell death that, together, result in abnormal granulation tissue development and lead to wounds with impaired healing [15,16,17]
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