Intrauterine Growth Restriction Promotes Postnatal Airway Hyperresponsiveness Independent of Allergic Disease

Jack O Kalotas,Kimberley C W Wang,Peter B Noble,Carolyn J Wang

doi:10.3389/fmed.2021.674324

Abstract

Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness.Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control – normoxic and saline challenge; IUGR – hypoxic and saline challenge; Allergy – normoxic and OVA challenge; and IUGR + Allergy – hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry.Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome.Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.

Highlights

Intrauterine growth restriction (IUGR) is associated with asthma
Airway remodeling is a change in the structure of the airway wall [5], exerting a multitude of effects, including increased airway smooth muscle (ASM) force production [1], and reduced and more variable airway caliber [1, 6], all of which at least contribute to the onset of Airway hyperresponsiveness (AHR)
We examined the interaction between IUGR and allergy and hypothesized that persistent biological changes after IUGR worsens the response to allergy and this manifests as more severe bronchoconstriction to contractile stimulation i.e., AHR

Summary

Introduction

Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness. Airway hyperresponsiveness (AHR), a major functional impairment in asthma, results in disproportionate airway narrowing that produces airflow limitation [1]. A relationship between AHR and allergy has been established; inflammation, orchestrated by T-helper 2 (Th2) cells, results in the release of bronchoactive mediators including histamine, leukotriene B4, prostaglandin D2 and cytokines along with the recruitment of immune cells [2, 3] which mediate excessive airway constriction. Airway remodeling is a change in the structure (mass, thickness, or volume) of the airway wall [5], exerting a multitude of effects, including increased airway smooth muscle (ASM) force production [1], and reduced and more variable airway caliber [1, 6], all of which at least contribute to the onset of AHR

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