Maternal allergic airway inflammation during pregnancy alters offspring’s airway hyperresponsiveness dependent on muscarinic receptor and adam33 mediated mechanisms

Background Maternal allergic asthma is a strong risk factor for the development of asthma and airway hyperresponsiveness (AHR) in children. ADAM33, an asthma susceptibility gene, has been associated with AHR and impaired lung function in early life. Our aim was to investigate how the maternal allergic environment during pregnancy interacts with the ADAM33 status of their offspring, and the effects this has on the lungs of offspring after birth. We hypothesised that the effects of maternal allergy will be different in Adam33 knock-out (KO) compared to wild-type (WT) offspringMethods Allergic airway inflammation (AAI) during pregnancy was induced in heterozygous (Adam33 ±) mice through intranasal house dust mite (HDM) challenges. Control mice were challenged with saline. WT and KO (Adam33 -/-) offspring from the same litters were studied 4 weeks post partum (pp). Lung function was measured in response to increasing doses of methacholine. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for RTqPCR, Western Blots and immunostainings. Precision-cut lung slices (PCLS) from 4-weeks old offspring were investigated for airway contraction in response to different agonists and antagonists in vitro.Results Allergen-naïve WT offspring of allergic mothers showed AHR 4 weeks pp compared to those of control mothers, whereas KO offspring from the same litter were protected. Expression of the muscarinic M1 receptor was elevated in both KO and WT offspring lungs of HDM-challenged dams. Experiments using muscarinic receptor antagonists and methacholine in PCLS confirmed that maternal AAI causes increased bronchoconstriction through vagal reflexes in WT offspring. KO offspring were protected from this effect due to decreased sensitivity of airway smooth muscle, suggested by a delayed response to a thromboxane-receptor agonist in PCLS.Conclusions Our studies show how gene-environment interactions between Adam33 and maternal AAI determine development of AHR in early life. While the AAI of the mother leads to an increased pulmonary muscarinic M1 receptor expression, the absence of Adam33 alters the airway smooth muscle function in the offspring. Together these changes manifest in AHR only in WT offspring, but not in KO offspring. Further studies are needed to determine how ADAM33 KO changes smooth muscle function in the lungs