Adam33 null mice do not exhibit post-natal airway hyperresponsiveness as a consequence of maternal allergy

Wandel, Marieke, Davies, Elizabeth R, Kelly, Joanne, Freda Carmichael, Holgate, Stephen T, Whitsett, Jeffrey A., Davies, Donna E and Haitchi, Hans Michael (2018) Adam33 null mice do not exhibit post-natal airway hyperresponsiveness as a consequence of maternal allergy. 32nd Symposium of the Collegium Internationale Allergologium 2018: Allergy Across the Life Course - From Origins Towards Prevention, , Mallorca, Spain. 30 Sep - 05 Oct 2018. pp. 57-104 .

Abstract

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 a potential in utero gene-environment interaction involving Adam33 by determining 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: we established a model of maternal allergic airway inflammation in pregnant heterozygous (Adam33+/-) mice through 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, bronchoalveolar lavage fluid (BALF) was collected for differential cell counts and ELISA, and lung tissue for RTqPCR, Western blot and immunohistochemistry.

Results: Adam33 mRNA expression was significantly enhanced in WT lungs of HDM challenged mothers at ED17.5, but unchanged pp. However, at 4 weeks pp, WT offspring of HDM challenged mothers showed significantly enhanced AHR compared to the offspring of saline challenged mothers. KO offspring of HDM challenged mothers were protected against development of AHR. mRNA expression of typical inflammatory mediators and remodelling genes were not affected at any time point studied; moreover, no inflammatory cells were present in the BALF of any of the offspring. In contrast, Cholinergic Receptor Muscarinic 1 (Chrm1) mRNA was increased at 4 weeks in WT offspring of HDM challenged mothers.

Conclusions: this study identifies an important in utero gene-environment interaction involving Adam33 that 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.

This record has no associated files available for download.

Contributors

Author: Elizabeth R Davies

Author: Donna E Davies

Author: Hans Michael Haitchi

Download statistics