Molecular mechanisms underlying the development and propagation of preschool wheeze and asthma: the role of interleukin (IL)-33 and activin A

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Context of the Research: Although approximately 40% of children under 5 years old wheeze, most grow out of their symptoms, and only some of the wheezers, (about one-third) develop asthma by school-age. We know that children who develop asthma have damage and scarring of the tubes (airways) in their lungs very early, between about 1 and 3 years of age, which remains at least until early adulthood. The factors that determine which preschool wheezers will develop asthma include a genetic susceptibility, development of early allergies and also getting early lung infections, especially with viruses. We are not able to predict which preschool wheezers will develop asthma, and importantly, there are no medicines which stop children from having reduced lung function and lessen airway scarring and damage. It is difficult to make measurements of lung scarring in very young children, since this needs samples taken from the lungs during a general anaesthetic. We have already developed a novel newborn mouse model to mimic how early preschool wheeze in infants caused by allergies leads to school-aged asthma. We have used house dust mites to cause mouse asthma. So far, we have shown that two chemicals seem very important in causing this type of allergic asthma. They are called interleukin (IL)-33 and activin. We think that these are new molecules whose action could be blocked as a treatment to stop the development of asthma from preschool wheeze. However, we have not yet explored the effect of virus infection in this model, and critically, as happens to young children, we have not looked at the interplay of viruses and allergies in our mouse model. Aims and Objectives: The aim of this project is therefore to make a newborn mouse model of virus lung infection, using 2 viruses that cause wheezing in young children. We will then look at the production of the important molecules that we have already found in the allergic asthma model in the virus infection model alone, and when both virus infection and house dust mites are used together. We think that the molecules will have different importance in young mice which are still developing disease compared to older mice with the full blown disease. Once we have established the important molecules that are involved in virus induced disease, allergy induced disease, and a combination of both, we will confirm the findings from the animal experiments in samples from children with severe symptoms. At the Brompton Hospital, we have developed a programme of using a special camera (bronchoscope) to look into the lungs of children with really severe wheeze or asthma to help to work out why their symptoms are so bad. In addition, if the child's parents agree, we have permission from the ethics committee to use any excess samples that remain after the clinical report for research. We will look at blood samples, airway washings and tiny pieces of tissue (biopsies) from the airways, and compare preschool children who only wheeze with virus infections, to those who wheeze with and without viruses, to school-aged children who have asthma. The samples are so tiny that we need to make targeted measurements, hence the need for the animal model to guide us as to which molecules are most promising. We will ascertain the role of at least 2 new molecules (IL-33 and activin) in the development of asthma from preschool wheeze. By also comparing the molecules in preschool children with wheezing to those in older children with asthma, we will be able to decide whether blocking one or other of the molecules may be better for treating younger children, when they are developing asthma, compared to older children who already have asthma. Potential Applications and Benefits: This project will allow us to work out whether targeting and blocking the action of these very new molecules might be the best way of stopping the very early damage and scarring that occurs in the lungs of young children that wheeze and develop asthma.