Title: The impact of pre- and perinatal ADAM33 induced airway remodeling on sensitivity to environmental challenges and the early life development of asthma.
Funder: Asthma UK

Abstract: Asthma is characterized by chronic inflammation and airway remodelling. It has its origins in early life with evidence of airway remodelling and eosinophilic inflammation in pre-school wheezers, and these are associated with asthma at school age. Multiple susceptibility genes are involved in asthma, but very little is known about the function of these genes and how they increase airway tissue susceptibility to common environmental triggers, especially allergens. ADAM33, a susceptibility gene, is associated with asthma, bronchial hyper-responsiveness (BHR) and reduced lung function in early life. A soluble form of ADAM33 (sADAM33) is increased in bronchoalveolar lavage fluid (BALF) from asthmatics and inversely correlated with lung function. Since ADAM33 is a membrane-anchored protein, we postulate that, in asthma, loss of its membrane tether leads to a disease-related gain of function. Consistent with this, human sADAM33 in transgenic murine lungs causes increases in bronchial smooth muscle and remodelling without airway inflammation or BHR. The importance of ADAM33 in airway remodelling has been confirmed in Adam33 null mice challenged with house dust mite (HDM) resulting in a significant decrease in airway remodelling, BHR and, surprisingly, inflammation compared to controls. As IL-13 instillation into sADAM33 transgenic mice induced significantly more eotaxin than controls, our data suggest that remodelled airways might augment allergic inflammation. Furthermore, since sADAM33 is increased in lungs of neonatal mouse pups borne of allergic mothers, we postulate that maternal allergy during pregnancy can induce sADAM33 in developing lungs to cause airway (p)remodelling, leading offspring with airways predisposed to have a heightened response to allergic triggers. Therefore, we now wish to test the hypothesis that sADAM33 induced airway (p)remodelling leads to increased sensitivity to environmental factors to cause airway dysfunction and asthma in early life. Specifically, we propose that animals with (p)remodelled airways will develop inflammation at lower doses of allergen (HDM) and that the combined effect of inflammation acting on the remodelled airways will cause BHR. To test our hypothesis, we will study transgenic mice with sADAM33 induced from in utero and ADAM33 null mice offspring from an maternal allergic environment for up to 1 month post partum. We will expose sADAM33 and ADAM33 null and control offspring mice to intranasal/intratracheal challenges of increasing doses of IL-13/allergen and measure lung function/BHR. We will harvest BALF and lung tissue for analysis of indices of airway inflammation and remodelling and for RNAseq to identify key pathways, which will be mapped to specific cell types (collaboration Jeffrey Whitsett, Cincinnati, US). We will also study sADAM33 in amniotic fluid from allergic/asthmatic mothers (collaboration Bas Rijn, Southampton) and the presence of sADAM33 in human paediatric asthma BALF samples will be correlated with inflammation and remodelling in biopsies from children and any novel pathways identified from the genomic analysis confirmed (collaboration Andrew Bush, Sejal Saglani, London and Graham Roberts, Southampton). These studies will address key gene and environment interactions that contribute to the early life origins of asthma. This knowledge will help us to develop novel early preventative or curative interventions in the treatment of asthma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY