ADAM33 KNOCK-OUT IS PROTECTIVE AGAINST POSTNATAL AIRWAY HYPERRESPONSIVENESS CAUSED BY MATERNAL ALLERGY

Background Maternal allergy is a strong risk factor for developing asthma and airway hyperresponsiveness (AHR). ADAM33 has been identified as an asthma susceptibility gene and is associated with AHR and impaired lung function in early life. Our aim was to investigate the effects of maternal murine allergic airway inflammation on the lungs of offspring before and after birth. We hypothesised that the effects of maternal allergy will be modified in Adam33 knock out (KO) compared to wild-type (WT) offspring. Methods Allergic airway inflammation in pregnant heterozygous (Adam33±) mice was induced by exposure to house dust mite (HDM) through intranasal challenges during pregnancy. Control mice were challenged with saline. WT (Adam33+/+) and KO (Adam33-/-) offspring from the same litters were studied on embryonic day (ED)17.5 and 2 or 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine and bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissue was obtained for RTqPCR, Western blot and immunohistochemistry. Results At 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to WT offspring of control mothers. KO of Adam33 protected against AHR in the offspring of allergic mothers. Adam33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. Differential cell counts in the BALF and mRNA expression of inflammatory mediators indicated an absence of allergic airway inflammation in all of the offspring. Remodelling genes were not affected at any time point studied. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in all offspring of HDM challenged mothers. Conclusions This study identifies an in utero gene-environment interaction involving Adam33. This interaction has implications for the subsequent development of AHR in early life. Further studies are needed to elucidate the precise mechanism(s) whereby ADAM33 mediates its effects. Our data suggest modulation of the contractility of the airways, possibly involving muscarinic receptors.