Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation.
Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation.
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DOI：
10.3791/53913
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发表时间：
2016-05-16
期刊：
影响因子：
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通讯作者：
Gilroy DW
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文献类型：
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作者：
Fullerton JN;Segre E;De Maeyer RP;Maini AA;Gilroy DW
炎症通路的激活代表了急性和慢性多种疾病状态的中心机制。通过病原体或组织损伤相关的分子基序触发，常见的生化途径导致保守但可变的生理和免疫学改变。解剖和描绘的决定因素和机制的表型变异的反应，预计将产生新的治疗进展。内毒素（革兰氏阴性细菌脂多糖），一种特异性Toll样受体4激动剂，静脉（IV）给药，代表了人体全身性炎症的体内模型。美国国立卫生研究院临床中心参考内毒素（CCR，大肠杆菌O：113：H10：K阴性）用于可靠和可重复地产生血管，血液学，内分泌，免疫学和器官特异性功能效应，这些效应在不同程度上与病理状态早期阶段所见的效应平行。剂量（0.06 - 4 ng/kg）和暴露时间尺度（推注vs.输注）的改变允许急性或慢性炎症的复制以及引发一系列严重程度，较高剂量（2 - 4 ng/kg）经常用于产生“败血症样”状态。可以在内毒素暴露之前或之后另外施用确定的和新的药用化合物，以评价它们对炎症级联的作用。尽管在范围和普遍性方面存在局限性，但人IV内毒素挑战提供了一个独特的平台，以获得对诱导性生理反应和炎症途径的机制见解。合理地使用它可能有助于将这些知识转化为治疗创新。
Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations.