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

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

Methods 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.
ADAM33, Maternal asthma, allergic airway inflammation, offspring, AHR, muscarinic receptors
S130
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
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
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
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
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, Whitsett, Jeffrey A., Davies, Donna and Haitchi, Hans (2019) Maternal allergic airway inflammation during pregnancy alters offspring’s airway hyperresponsiveness dependent on muscarinic receptor and adam33 mediated mechanisms. British Thoracic Society Winter Meeting 2019, Queen Elizabeth II Conference Centre, Westminster, United Kingdom. 04 - 06 Dec 2019. S130 . (doi:10.1136/thorax-2019-BTSabstracts2019.136).

Record type: Conference or Workshop Item (Other)

Abstract

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) offspring

Methods 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.

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More information

e-pub ahead of print date: 12 November 2019
Published date: 6 December 2019
Venue - Dates: British Thoracic Society Winter Meeting 2019, Queen Elizabeth II Conference Centre, Westminster, United Kingdom, 2019-12-04 - 2019-12-06
Keywords: ADAM33, Maternal asthma, allergic airway inflammation, offspring, AHR, muscarinic receptors

Identifiers

Local EPrints ID: 441750
URI: http://eprints.soton.ac.uk/id/eprint/441750
PURE UUID: e1ccdbe5-c066-4362-ba73-e87c31f90f56
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

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Date deposited: 25 Jun 2020 16:48
Last modified: 26 Jun 2020 00:27

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Contributors

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

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