Mechanisms of inflammatory memory in the human respiratory mucosa

我们的肺部经常暴露在细菌和污染物中，因此肺部的衬里起到了物理和免疫屏障的作用，以抵御吸入的威胁。第一道防线是“先天”免疫系统，它最近被证明能够“记住”过去的炎症事件。参与炎症的蛋白质是由基因中编码的指令产生的。环境暴露可以通过留下印记(或“表观遗传”变化)来改变我们基因的工作方式，这在炎症性记忆中起着关键作用。虽然遗传信息在遗传后不能改变，但表观遗传变化可能会被修改以调节未来的反应。人们已经研究了血液中的炎性记忆，但它在人类肺部的作用还没有被很好地了解。炎性记忆在哮喘等疾病中可能特别重要，哮喘导致全球45.5万人死亡，英国每年花费30亿英镑的医疗费用。哮喘发作的常见诱因包括病毒和空气污染物，它们会导致严重的呼吸道炎症。哮喘发作的治疗几十年来没有改变，需要类固醇来减少炎症，这有很大的副作用。迫切需要新的治疗方法，表观遗传变化的可逆性使它们成为吸引人的目标。我的初步研究表明，表观遗传修饰可以用来减少呼吸道炎症。研究呼吸道炎症最相关、最直接的方法是通过研究人。我小心翼翼地让志愿者接触到引起短期和有限炎症的物质，使用含有纯合成化合物(R848)的鼻喷剂来模拟病毒感染，以受控的方式安全地再现现实生活中的情景。我发现，与没有哮喘的人相比，患有哮喘的人经历得更快，鼻炎也更严重。这表明他们的细胞更有可能对导致过度炎症的外部触发因素做出反应。这项提议的目的是找出哮喘患者在控制暴露于R848和空气污染前后的肺部是否有表观遗传学变化。该项目提出了以下问题：1.哮喘患者的肺部细胞对一种类似病毒的物质的反应是否与非哮喘患者不同？2.不同的炎症诱因(如病毒和空气污染)是否会导致肺部的表观遗传变化，这是否会改变肺的运作方式？3.我们能否使用药物来针对表观遗传变化和改变炎症反应？这项研究将与剑桥大学和加拿大温哥华的专家科学合作伙伴一起进行。我将使用尖端分子生物学工具来研究肺部对R848的反应，并比较哮喘患者和非哮喘患者的差异。我将检查哮喘患者的细胞是否有使其更容易发炎的表观遗传变化，以及这种变化在发炎后是否会持续。空气污染是肺部炎症的关键触发因素，温哥华的合作者开发了一种受控的柴油尾气暴露模型，该模型在包括哮喘患者在内的志愿者身上是安全耐受的。我将使用这个模型来研究肺部在应对污染时的表观遗传和免疫变化。最后，为了帮助将这些研究结果转化为潜在的新疗法，我将评估我们是否可以针对这些表观遗传变化来减少实验室中的呼吸道炎症。这项研究的结果将导致开发一种独特的方法来研究模仿病毒感染的人类肺部炎症，这种方法也可以在未来用于开发针对炎症的药物。它将详细了解为什么哮喘患者会有过度的肺部炎症，并提供关于表观遗传变化是否可以通过靶向药物改变的信息，如果成功，这些药物可能会转化为临床试验。

Our lungs are regularly exposed to germs and pollutants, so the lining of the lungs acts as a physical and immune barrier against inhaled threats. The first line of defence is the "innate" immune system which has recently been shown to be able to "remember" past inflammatory events. Proteins involved in inflammation are created from instructions encoded within genes. Environmental exposures can alter the way our genes work by leaving an imprint (or "epigenetic" changes) which plays a key role in inflammatory memory. Although genetic information cannot be altered after it has been inherited, epigenetic changes can potentially be modified to regulate future responses. Inflammatory memory has been studied in blood but its role in human lungs is not well understood.Inflammatory memory may be especially important in conditions such as asthma which contributes to 455,000 deaths globally and UK healthcare costs of £3 billion annually. Common triggers for asthma attacks include viruses and air pollutants which cause serious airway inflammation. Treatment for asthma attacks has not changed in decades and requires steroids to reduce inflammation which has significant side effects. New approaches to treatment are urgently required, and the reversible nature of epigenetic changes makes them attractive targets. My preliminary research suggests that epigenetic modification may be used to reduce airway inflammation.The most relevant and direct way to study inflammation of the airways is by studying people. I carefully exposed volunteers to substances that cause short-term and limited inflammation using a nasal spray containing a pure synthetic compound (R848) to mimic a viral infection, safely recreating real-life scenarios in a controlled manner. I discovered that individuals with asthma experience faster and increased nasal inflammation compared to people without asthma. This suggests their cells are more likely to respond to external triggers resulting in excessive inflammation.The aim of this proposal is to find out whether people with asthma have epigenetic changes in their lungs before and after controlled exposure to R848 and air pollution. The project asks the following questions:1. Do cells in the lungs of people with asthma respond differently to a substance that mimics viruses from those without asthma?2. Do different inflammatory triggers (e.g., viruses and air pollution) cause epigenetic changes in the lungs and does this alter how the lungs work?3. Can we use drugs to target epigenetic changes and modify inflammatory responses?The research will take place with expert scientific partners in the University of Cambridge and in Vancouver, Canada. I will use cutting-edge molecular biology tools to study how the lungs respond to R848 and compare differences in people with and without asthma. I will examine whether cells from people with asthma have epigenetic changes that make them more prone to inflammation and whether this persists after inflammation. Air pollution is a key trigger for lung inflammation and collaborators in Vancouver have developed a controlled diesel exhaust exposure model which is safely tolerated in volunteers including those with asthma. I will use this model to study epigenetic and immune changes in the lungs in response to pollution. Finally, in order to help translate these research findings into potential new therapies, I will assess whether we can target these epigenetic changes to reduce airway inflammation in the lab.The results of the study will lead to the development of a unique approach to studying human lung inflammation that mimics viral infection, which can also be used in future to develop drugs that target inflammation. It will provide a detailed understanding of why people with asthma have excessive lung inflammation, and information on whether epigenetic changes can be modified by targeted drugs, which if successful could be translated into clinical trials.