A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity.
A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity.
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DOI：
10.1371/journal.pone.0109848
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Martins-Green M
中科院分区：
文献类型：
--
作者：
Dhall S;Do D;Garcia M;Wijesinghe DS;Brandon A;Kim J;Sanchez A;Lyubovitsky J;Gallagher S;Nothnagel EA;Chalfant CE;Patel RP;Schiller N;Martins-Green M
慢性伤口对健康有很大影响，仅在美国就影响到约650万人，每年造成约250亿美元的损失。我们之前发现，一种转基因小鼠模型显示出与人类问题伤口相似的愈合受损，有时伤口会变成慢性的。在这里，我们展示了这些受损伤口是如何以及为什么会变成慢性的，描述了一种我们可以随意将受损伤口变成慢性的方法，并提出了同样的过程也参与了人类慢性伤口的发展。我们假设氧化应激水平的加剧是慢性开始的关键。我们发现，在受伤后的早期，愈合受损的伤口含有较高水平的活性氧和氮，就像人类一样，这些水平随着年龄的增长而增加。此外，抗氧化酶活性不升高，导致伤口环境中氧化应激的积累。为了诱导慢性，我们通过进一步抑制抗氧化酶和用从这些小鼠的慢性伤口中分离出来的形成生物膜的细菌感染伤口来加剧氧化还原失衡。这些伤口不能再上皮化，肉芽组织缺乏血管化和间质胶原纤维，它们含有具有生物膜形成能力的耐抗生素混合生物菌群，并且它们保持开放数周。这些发现非常重要，因为它们首次表明慢性伤口可以在动物模型中有效和一致地产生。这种模型的可用性将显著推动该领域向前发展，因为它可以用来制定策略，以恢复氧化还原平衡，这可能导致抑制生物膜的形成，并导致健康伤口组织的恢复。此外，该模型可以导致对慢性伤口发展的其他基本机制的理解，这可能会导致新的治疗方法。
Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone. 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.
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