You are here

Article Text

Article menu

Download PDFPDF

Mucosal and microbial drivers of asthma
S28 Adam33 knock-out is protective against post-natal airway hyperresponsiveness caused by maternal allergy
Free
  1. M Wandel1,
  2. ER Davies1,
  3. JFC Kelly1,
  4. ST Holgate2,
  5. JA Whitsett3,
  6. DE Davies1,
  7. HM Haitchi1
  1. 1The Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
  2. 2National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  3. 3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

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 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.

https://doi.org/10.1136/thorax-2018-212555.34

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.