Mechanisms of inflammatory memory in the human respiratory mucosa

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.