To delineate immune mechanisms for limiting asthma development and severity

There are more than 300 million people worldwide living with asthma, and it causes 250,000 deaths annually, which is responsible for huge healthcare expenditure. Drugs (e.g. corticosteroids) help control both asthma symptoms and asthma exacerbations, yet their effects rapidly disappear when discontinued. It is thus urgent to study the pathogenic mechanisms underlying the development and exacerbation of asthma and the regulatory mechanisms for better understanding of the control of asthma and its exacerbation, which will help for providing new opportunities to prevention and treatment of asthma.

Non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin) are very commonly used at huge amounts as pain killers and reducing fever worldwide. This is because these drugs block the production of a group of lipids called prostaglandins (PGs) that mediate the pain response and fever generation. Like other drugs, however, NSAIDs can also cause adverse effects - e.g., the most well known one is inducing gut bleeding. Our group has recently discovered a previously unknown mechanism as to why use of NSAIDs leads to bleeding in the gut and found an essential role of the lipid mediator prostaglandin E2 in the maintenance of gut barrier homeostasis. But how prostaglandins function in response to aggravating stimuli (e.g. allergen- or pathogen-induced allergic inflammation) are not well understood. Clinical and epidemiological observations suggest that use of NSAIDs triggers exacerbations of asthma and lung inflammation such as severe chronic eosinophilic rhinosinusitis with nasal polyposis, a condition called as NSAID-exacerbated respiratory disease (NERD). My goal in this application is to discover the scientific facts as to how asthma is developed and exacerbated by stimuli of allergic substances or drugs and how to control these allergic chemical reactions for treatment of asthma and NERD.

A subset of immune cells called type 2 innate lymphoid cells (ILC2s) has recently been demonstrated to mediate the development and exacerbation of asthma in both animal models and patients with asthma. But signals that negatively control ILC2 function in the context of asthma remain to be revealed. In this CDA application, I will define the role of prostaglandins in protection against type 2 allergic lung inflammation and the precise cellular and molecular mechanisms using pharmacological, immunological and genetic approaches, as well as experimental models and via analysis of clinical samples from asthma patients. This coherent portfolio of experiments will help dissect the specific pathogenic mechanisms for the development of asthma and NERD by dysfunction of the physiological prostaglandin signalling in patients. Successful validation of prostaglandin signalling in this context will provide new therapeutic options for the treatment of related allergic lung inflammation.

Asthma is a chronic, allergic inflammatory lung disease generally characterized by increased numbers of eosinophils and lymphocytes producing type 2 cytokines. However, the pathogenic mechanisms involved in the development of asthma and the regulatory mechanisms for controlling allergic immune responses in the airways are not fully understood. Further, more than 1/3 of asthma patients have an aspirin allergy or a reaction to non-steroidal anti-inflammatory drugs (NSAID), needing an improved understanding of the mechanisms behind this disease. In this CDA fellowship, I will investigate the cellular and molecular mechanisms that underpin regulation of type 2 immune responses and allergic lung inflammation in asthma and how this is controlled by prostaglandin signalling pathways that are activated in response to allergens and pathogens.

Prostaglandins (PGs), especially PGE2, are produced by multiple types of lung cells (e.g. epithelial cells, macrophages and dendritic cells etc) in response to various stimuli. In this proposed project, we will study how PGs regulate group 2 innate lymphoid cells (ILC2s) and allergic lung inflammation and, conversely, how down-regulation of PG signalling by NSAIDs exacerbates allergic lung inflammation. To address these questions, we will examine the mechanistic contribution of the PGE2 pathway to the control of allergen/pathogen-induced accumulation and activation of ILC2s and asthmatic lung inflammation using acute and chronic lung inflammation models and novel transgenic animals with specific deletion of PGE2 receptors in lymphocytes. Small molecule compounds targeting the PGE2 pathway will be used for pharmacological manipulation of type 2 immune responses in vitro and in vivo. In addition, I will also develop methods to analyse the effects of PGE2 signalling on human ILC2 response from healthy individuals and asthma patients in collaboration with our clinical colleagues.

This research aims to understand the basic immunological and pathogenic mechanisms underlying how asthma is developed and exacerbated by challenges from aeroallergens or drugs such as NSAIDs. The primary immediate beneficiaries will be academic researchers in the fields of asthma and allergic lung disease, inflammation, immunology, lipid mediators and GPCRs as well as the wider scientific community (described in the 'Academic Beneficiaries' section).

The main beneficiaries outside of academic environment will be clinicians and patients. While NSAIDs are widely used to reduce body temperature and release pain response, these drugs have also many severe side effects. Importantly, use of NSAIDs has been suggested as a risk factor for developing and worsening asthma. Our research will offer an explanation for this phenomenon and potentially provide strategies to avoid this side effect (e.g., administration of a PGE2 analogue or receptor agonists).

Another main beneficiary will be the pharmaceutical industry. Although current anti-asthmatic therapies (e.g., corticosteroids, beta-agonists, leukotriene antagonists, anti-IgE antibodies etc) have helped millions of patients with control of both asthma symptoms and asthma exacerbations, there is no effective preventive strategy for asthma or a known cure, and the effects of these drugs rapidly disappear when they are discontinued. Our work will identify a novel therapeutic approach, i.e., targeting the PGE2 pathway on lung immune cells. The results of our proposed work may suggest an alternative therapy that targets PGE2 receptor using small compounds. Importantly, several pharmaceutical firms, eg Merck, GSK, Pfizer, Astellas, Eisai, etc, have made enormous efforts to develop dozens of compounds targeting the PGE2 receptors with distinct chemical structures. They are, however, keen to discover their potential clinical use. The data and the models developed from this proposed work have the potential to demonstrate clinical application of these compounds. Therefore this study and the future research that it will create will be of considerable interest to the pharmaceutical industry for drug development in chronic inflammatory diseases. Where possible this will be exploited by the applicant through the University of Edinburgh Research and Innovation technology transfer office (http://www.researchinnovation.ed.ac.uk/Default.asp).

By generating new understanding of the development and progression of asthma and allergic inflammation, this research has the potential to impact on the nation's health. This will benefit government, charities and people suffering from chronic inflammatory disorders. Novel therapies will have the potential to clinical care but also will alleviate patients' sufferings and mental health burden. The wider public will also have the opportunity to benefit directly from this research theme through the Edinburgh Science Festival and the University's Open Days (as detailed in the 'Communication Plan' section). The applicant will use his research theme to encourage careers in science and medicine and raising awareness of health issues.