Low-dose aspirin and the resolution of acute inflammation

小剂量阿司匹林与急性炎症的缓解

• 批准号: G0500017/1
• 负责人: Derek Gilroy
• 金额: $ 35.04万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0500017%2F1
• 关键词: Low; dose; aspirin; resolution; acute

Inflammation is the major driving force behind rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and Crohn s disease, for example. However, such diseases are non-resolving or recurrent in nature. By contrast, there are other inflammatory diseases such as streptococcal-induced pneumonia, which typically resolve without causing lasting tissue injury. Therefore, it is fair to say that some inflammatory responses are under the control of endogenous factors that signal their cessation, which may be dysregulated in others. The idea behind this MRC-funded research project comes from the observation that acute inflammation, elicited, for example, by a finger prick or bee-sting injury has a natural progression from start (swelling, pain and redness) to finish (reduction in swelling and pain and restoration of the tissue to its prior form, collectively called resolution). However, it has remained unappreciated for many years that resolution of inflammation is under the control of factors manufactured by the injured tissue. Our philosophy is that we could use these factors or develop drugs that mimic their action to trick chronic inflammatory diseases into resolving or switching off. This approach would allow the inflammatory response to progress as normal and neutralize the injurious agent, which is the basis and function of the inflammatory response, but bring about resolution of the event in a timely manner with minimal tissue injury. In pursuit of this thinking, there are certain hormones called lipoxins that are preferentially expressed during the resolution phase of acute inflammation. Of the lipoxin family of eicosanoids are a sub-group triggered by aspirin called aspirin-triggered epi-lipoxins. In a series of experiments, including those carried out in man, we found that aspirin at low, cardioprotective doses alters the expression of these protective factors resulting in a significant impact on the innate immune response in man. These findings are particularly important given the widespread use of low-dose aspirin, not alone for its cardio-protective but also potential anti-cancer effects. In which event, we are now uncovering novel properties of low-dose aspirin on the innate immune response in man that will not only change the way we view how inflammation occurs but also how it may be treated more effectively.

例如，炎症是类风湿性关节炎、银屑病关节炎、系统性红斑狼疮和克罗恩病背后的主要驱动力。然而，这些疾病在性质上是不消退的或复发的。相比之下，还有其他炎症性疾病，如链球菌引起的肺炎，通常不会引起持久的组织损伤。因此，可以公平地说，一些炎症反应是在内源性因素的控制下，这些内源性因素发出停止的信号，这可能在其他情况下失调。这个由MRC资助的研究项目背后的想法来自于观察到，例如，由手指刺伤或蜂蜇伤引起的急性炎症从开始（肿胀，疼痛和发红）到结束（肿胀和疼痛减少以及组织恢复到其先前的形式，统称为解决）有一个自然的进展。然而，多年来一直没有认识到炎症的消退是在由受损组织产生的因子的控制下。我们的理念是，我们可以利用这些因素或开发模仿其作用的药物，以诱使慢性炎症性疾病消退或关闭。这种方法将允许炎症反应正常进行并中和有害物质，这是炎症反应的基础和功能，但以最小的组织损伤及时解决事件。在追求这个想法时，有一些称为脂氧素的激素在急性炎症的消退阶段优先表达。类二十烷酸脂氧素家族是由阿司匹林触发的亚组，称为阿司匹林触发的表脂氧素。在一系列的实验中，包括在人体中进行的实验，我们发现，低剂量的阿司匹林，心脏保护剂量改变了这些保护因子的表达，从而对人类的先天免疫反应产生重大影响。这些发现特别重要，因为低剂量阿司匹林的广泛使用，不仅是因为它的心脏保护作用，而且还有潜在的抗癌作用。在这种情况下，我们现在正在发现低剂量阿司匹林对人类先天免疫反应的新特性，这不仅会改变我们对炎症如何发生的看法，而且会改变如何更有效地治疗炎症。