Researchers uncover more detail of the molecular triggers behind asthma attacks

A new study has tracked the molecular events that happen during asthma attacks to help explain how a common cold can trigger these attacks.

Published in the American Journal of Respiratory and Critical Care Medicine, the research used novel sampling techniques to observe what happens in people’s noses and lungs during asthma attacks induced by a cold virus. The research showed that in people with asthma, a small molecule called IL-33 plays an important role in activating such attacks, and that it might be possible to inhibit them by blocking IL-33.

Viral infection of the airways is the cause of about 80 to 90 per cent of asthma attacks, with most of these infections caused by rhinoviruses – the viruses behind the common cold. Although the effects of rhinoviruses are usually relatively mild for most people, in people with asthma they can infect the lungs and elicit severe asthma attacks, sometimes leading to hospitalisation.

An asthma attack is characterised by inflammation and obstruction of the airways, and increased mucus production. These are all part of the type-2 immune response, which usually occurs in response to allergies but not in response to viral infections. Better understanding of how a rhinovirus infection can trigger such a response could be extremely valuable in the development of new treatments for asthma attacks.

The new study was conducted by researchers from the Medical Research Council (MRC) & Asthma UK Centre in Allergic Mechanisms of Asthma at Imperial College London and King’s College London. They inoculated 39 asthmatic and non-asthmatic volunteers with a rhinovirus. They found that samples from the nose and lung of asthmatics experiencing an attack showed an increase in the molecule IL-33. As the levels of virus reproduction increased, so too did the amount of IL-33 in the airway and markers of type-2 immune responses and the severity of the asthma symptoms.

It has been known for a long time that a virus infection induces a type-1 immune response, and allergies induce a type-2 immune response, and that each suppresses the other. So, accordingly, a virus infection should in theory suppress an allergic response rather than making it worse and inducing an asthma attack.

The new research shows that IL-33 is one of very few molecules called cytokines, which are released by lung lining cells in response to a virus infection, and which leads to a ‘cascade’ of type-2 immune responses responsible for asthma attacks. The research demonstrated that, when asthmatics experience increases in levels of IL-33, they also experience increases in other type-2 cytokines, suggesting that IL-33 plays a role in triggering the asthmatic cascade in response to a rhinovirus.

To investigate the molecular mechanism in more detail and to see whether targeting IL-33 with drugs might have the potential to treat asthma attacks, the researchers analysed cells from the linings of the airways in culture together with cells from the immune system. This showed that blocking IL-33 abolished the type-2 cascade of cytokines induced by a rhinovirus, suggesting that targeting IL-33 could stop the cascade leading to asthma attacks.

Dr David Jackson, who conducted the study and Senior Clinical Research Fellow at the National Heart and Lung Institute at Imperial College London, said: “We have closely examined the evolution of an asthma attack in humans in real-time by using these novel and more effective sampling techniques that apply strips of material to the nose and the airways. Our findings indicate that in asthmatics, an increase in viral particles in the airway leads to an increase in the levels of IL-33 in the airway, which then triggers  a cascade of signals leading to an asthma attack. Our evidence strongly suggests that inhibiting IL-33  significantly limits activation of downstream type-2 inflammatory pathways and the associated symptoms that are the hallmarks of an asthma attack.”

Previous research conducted at the MRC and Asthma UK Centre in Allergic Mechanisms of Asthma has indicated that another cytokine called IL-25 could also play a role in triggering the cytokine cascade to generate the type 2 responses characteristic of an asthma attack. The researchers suggested that further analysis is needed to assess the relative contribution of the different cytokines to asthma attacks.

Professor Sebastian Johnston, also from National Heart and Lung Institute at Imperial College London and lead author of the study, said: “We are now at a stage where blocking the actions of IL-33 seems a new and promising approach to treating or preventing acute attacks of asthma. Pharmaceutical companies should develop a drug to block IL-33, or its receptor and then start clinical trials to test its safety and effectiveness. As part of the clinical trials, it is important to ensure that blocking IL-33 has no other effects on the immune system and also to investigate how it might interact with steroid treatments currently used to control asthma. Our hope is that we could use our novel experimental clinical model of an asthma attack developed in this study to test new medication for asthma attacks in the future.”

Professor Johnston is the Director of the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma and Asthma UK Clinical Chair. The study was funded by the European Research Council, the MRC, Asthma UK, the National Institute for Health Research Imperial Biomedical Research Centre and the Novartis Institute for Biomedical Research.

Reference: Jackson et al. ‘IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo’ American Journal of Respiratory and Critical Care Medicine, 2014. Doi: 10.1164/rccm.201406-1039OC