Airway hyperresponsiveness in offspring from mothers with allergic airway inflammation during pregnancy is muscarinic receptor and ADAM33 dependent

Wandel, Marieke, Davies, Elizabeth Rhiannon, Kelly, Joanne Freda Carmichael, Holgate, Stephen, Davies, Donna and Haitchi, Hans (2020) Airway hyperresponsiveness in offspring from mothers with allergic airway inflammation during pregnancy is muscarinic receptor and ADAM33 dependent. European Respiratory Society International Congress 2020, Virtual, Vienna, Austria. 06 - 09 Sep 2020. p. 614 . (doi:10.1183/13993003.congress-2020.614).

Abstract

Background: Maternal asthma is a risk factor for asthma and airway hyperresponsiveness (AHR) in children. The asthma susceptibility gene, ADAM33, has been associated with AHR and impaired lung function in early life.

Aims and Objectives: Our aim was to study how a maternal allergic environment in pregnancy interacts with offspring-ADAM33 and the effects on their lungs after birth. We hypothesised that effects of maternal allergic airway inflammation (AAI) will be different in Adam33 knock-out (KO) compared to wild-type (WT) offspring.

Methods: Heterozygous (Adam33+/-) pregnant dams were challenged with allergen to induce AAI and control dams with saline. WT and KO offspring from the same litters were studied 4 weeks post partum for AHR. Bronchoalveolar lavage and lung tissue were studied by RTqPCR, Western blots, immunostainings and precision-cut lung slices (PCLS) in the presence of agonists and antagonists.

Results: Allergen-naïve 4-week old WT offspring of mothers with AAI showed AHR in vivo, whereas KO offspring were protected. The pulmonary muscarinic M1 receptor was increased in all offspring of AAI dams. Ex vivo PCLS studies with methacholine and muscarinic receptor antagonists confirmed vagal reflex bronchoconstriction in WT while KO offspring were protected by a decreased airway smooth muscle constriction, as shown with a thromboxane-receptor agonist.

Conclusions: Gene-environment interactions between Adam33 and maternal AAI determine AHR in early life. While maternal AAI induces AHR in WT offspring via vagal responses, Adam33 KO alters the airway smooth muscle function and suppresses AHR, pointing to a new asthma AHR therapy.

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Contributors

Author: Donna Davies

Author: Hans Haitchi

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