Novel translational model of resolving inflammation triggered by UV-killed E. coli.
Novel translational model of resolving inflammation triggered by UV-killed E. coli.
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DOI：
10.1002/cjp2.43
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Gilroy DW
中科院分区：
文献类型：
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作者：
Motwani MP;Flint JD;De Maeyer RP;Fullerton JN;Smith AM;Marks DJ;Gilroy DW
虽然在啮齿类动物中进行了大量调查炎症性疾病病因学的研究，但这些数据对人类病理生理学的适用性经常引起争议。无论生物医学研究中啮齿动物模型的优点和缺点，都需要开发人类实验性炎症模型。在这里，我们描述了将紫外线灭活的大肠杆菌注射到健康志愿者的前臂中所引发的自消性急性炎症反应。通过在发炎部位施加负压，从发病到消退期间收集细胞和渗出物。发病的特点是高血流量、中性粒细胞增多和促炎细胞因子水平达到峰值，而消退则表现为血流量下降、中性粒细胞减少、单核细胞/巨噬细胞增加以及经典促炎细胞因子水平下降。通过服用萘普生（一种传统的非甾体抗炎药）证明了抗炎作用，定义为抑制发作期事件。总之，这种解决急性炎症的模型是微创的、高度易处理的，并且允许同时研究人类急性炎症的发作和消退阶段的血管反应、细胞运输和化学介质特征。它可以作为一个转化平台，提供机制见解并测试新型抗炎和促消退药物的临床疗效，也可以作为患者探索消退途径固有缺陷的工具。
Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self‐resolving acute inflammatory response triggered by the intradermal injection of UV‐killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro‐inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro‐inflammatory cytokine levels. An anti‐inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non‐steroidal anti‐inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti‐inflammatory and pro‐resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways.