Fernandez Melissa L, Stupar Dario, Croll Tristan, Leavesley David, Upton Zee
Institute of Medical Biology, Agency for Science, Technology and Research, Singapore, Singapore.
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Adv Wound Care (New Rochelle). 2018 Mar 1;7(3):95-104. doi: 10.1089/wound.2016.0724.
Chronic wounds are a major burden to patients and to healthcare systems worldwide. These wounds are difficult to heal and treatment is often lengthy and expensive. This has led to research efforts focussed on the wound environment attempting to understand the underlying pathological mechanisms of impaired wound healing. While some of this research has translated to advancements in wound therapies and implementation of new treatment options, chronic wounds remain a significant challenge to treat. Thus, identification of effective, low-cost, advanced wound therapies that enhance healing rates of these problematic wounds is still essential. Xanthine oxidoreductase (XOR), a molybdoflavin enzyme, is emerging as an important source of reactive oxygen species (ROS) in various pathologies, including diabetes and chronic wounds. XOR has recently been shown to be upregulated in chronic wounds, stimulating the overproduction of ROS during dysfunctional wound healing. XOR-induced ROS can amplify and potentiate inflammation in the wound environment further delaying wound closure. The detrimental role of XOR in impaired healing indicates it may be a therapeutic target. Targeted inhibition of XOR has been shown to reduce the expression and activity of this enzyme in diabetic wound models. In turn, this resulted in a significant decrease in ROS levels in the wound environment and improved wound healing. Therefore, repurposing existing XOR inhibitors that are approved for human use may be able to restore homeostasis at the wound site and enable damaged tissue to return to normal healing.
慢性伤口对全球患者和医疗系统来说都是一项重大负担。这些伤口难以愈合，治疗往往耗时长久且费用高昂。这促使研究工作聚焦于伤口环境，试图了解伤口愈合受损的潜在病理机制。尽管其中一些研究已转化为伤口治疗方面的进展以及新治疗方案的应用，但慢性伤口的治疗仍然是一项重大挑战。因此，识别有效、低成本且先进的伤口治疗方法以提高这些棘手伤口的愈合速度依然至关重要。黄嘌呤氧化还原酶（XOR）是一种钼黄素酶，在包括糖尿病和慢性伤口在内的各种病理状况下，正逐渐成为活性氧（ROS）的重要来源。最近研究表明，XOR在慢性伤口中上调，在功能失调的伤口愈合过程中刺激ROS过度产生。XOR诱导的ROS可放大并增强伤口环境中的炎症，进一步延迟伤口闭合。XOR在愈合受损中的有害作用表明它可能是一个治疗靶点。在糖尿病伤口模型中，对XOR的靶向抑制已显示可降低该酶的表达和活性。相应地，这导致伤口环境中ROS水平显著降低，并改善了伤口愈合。因此，重新利用已获人类使用批准的现有XOR抑制剂或许能够恢复伤口部位的内环境稳定，并使受损组织恢复正常愈合。
