The effect of maternal allergic airway inflammation during pregnancy and ADAM33 in early life development of asthma

Abstract

Asthma is a complex heterogeneous disease influenced by many factors, such as genetic background and environmental exposures. This suggests the potential for geneenvironment interactions in which the genotype of an individual is involved in complex interactions with environmental exposures. Of the many asthma susceptibility genes, A Disintegrin And Metalloproteinase 33 (ADAM33 ) has been linked to asthma and airway hyperresponsiveness (AHR), as well as impaired lung function in early life. Several epidemiological studies have shown that maternal asthma and allergic disease lead to an increased prevalence of AHR and asthma in their offspring. Therefore, it was hypothesised that in utero gene-environment interactions between ADAM33 and maternal allergic airway inflammation lead to increased AHR of the offspring post partum. To investigate this hypothesis, the first objective was to establish a mouse model of allergic airway inflammation during pregnancy. Parents heterozygous for Adam33 (Adam33+/-) were used to allow for wildtype (WT, Adam33+/+) and Adam33 -knock out (KO, Adam33-/-) offspring in the same litter. The second objective was to assess the impact of maternal airway inflammation and Adam33 genotype on AHR in these offspring 4 weeks post partum. The third objective was to investigate the underlying mechanisms of this effect by studying the lungs post partum and in utero to identify changes that can contribute to gene-environment interactions with Adam33. It was found that house dust mite challenge of pregnant dams led to a strong eosinophilic airway inflammation, but this did not have any substantial effect on litter size or off- spring weight. However, at 4 weeks of age, WT offspring of HDM challenged dams exhibited significantly increased AHR in response to methacholine compared to WT offspring of saline challenged control mothers, whereas KO littermates of HDM challenged dams were protected. Analysis of the developing lung on ED17.5 by RNA sequencing revealed that loss of Adam33 caused a defect in muscle development and contraction, as well as an impairment of calcium and cGMP-PKG signalling, two pathways involved in the mediation of muscle contraction. The hyporesponsive phenotype of Adam33 -KO airway smooth muscle (ASM) was confirmed 4 weeks post partum by using a thromboxane-analogue in precision-cut lung slices. It was found that the AHR in WT offspring of HDM challenged dams at 4 weeks was caused by an increased expression of the muscarinic M1 receptor (CHRM1), which caused an enhancement of vagal reflexes mediating stronger airway contraction. While KO offspring of HDM challenged mothers showed a similar increase in CHRM1, failure to observe increased AHR was due to hyporesponsive ASM as previously observed; this counteracted the increased vagal reflexes and thus prevented AHR. These data demonstrate for the first time that maternal allergic airway inflammation during pregnancy leads to AHR in allergen-naive offspring 4 weeks post partum. Furthermore, the data identify a role for Adam33 during muscle development in utero, and show that loss of Adam33 can counteract the increased airway contractility mediated by maternal allergy, so protecting against AHR. These studies highlight the importance of gene and environment interactions in the development of asthma in early life and point to potential approaches for future therapeutic intervention.

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Identifiers

ORCID for Hans Haitchi: orcid.org/0000-0001-8603-302X

ORCID for Donna Davies: orcid.org/0000-0002-5117-2991

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