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

Airway hyperresponsiveness in offspring from mothers with allergic airway inflammation during pregnancy is muscarinic receptor and ADAM33 dependent
Airway hyperresponsiveness in offspring from mothers with allergic airway inflammation during pregnancy is muscarinic receptor and ADAM33 dependent
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.
ADAM33, Asthma, Maternal asthma, bronchialhyperresponsiveness, airway hyper-responsiveness, Animal model, muscarinic receptors
614
Wandel, Marieke
96d7313a-83f3-4e81-b91c-4f2049a6866a
Davies, Elizabeth Rhiannon
2e6920ea-b7ce-46e3-918c-5a2095e8e4d2
Kelly, Joanne Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans
68dadb29-305d-4236-884f-e9c93f4d78fe
Wandel, Marieke
96d7313a-83f3-4e81-b91c-4f2049a6866a
Davies, Elizabeth Rhiannon
2e6920ea-b7ce-46e3-918c-5a2095e8e4d2
Kelly, Joanne Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans
68dadb29-305d-4236-884f-e9c93f4d78fe

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).

Record type: Conference or Workshop Item (Paper)

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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More information

Published date: 2020
Venue - Dates: European Respiratory Society International Congress 2020, Virtual, Vienna, Austria, 2020-09-06 - 2020-09-09
Keywords: ADAM33, Asthma, Maternal asthma, bronchialhyperresponsiveness, airway hyper-responsiveness, Animal model, muscarinic receptors

Identifiers

Local EPrints ID: 447202
URI: http://eprints.soton.ac.uk/id/eprint/447202
PURE UUID: f2f60548-9779-4ac0-b63a-425878f5fc87
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 04 Mar 2021 17:46
Last modified: 05 Mar 2021 02:37

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Contributors

Author: Marieke Wandel
Author: Elizabeth Rhiannon Davies
Author: Joanne Freda Carmichael Kelly
Author: Stephen Holgate
Author: Donna Davies ORCID iD
Author: Hans Haitchi ORCID iD

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