Development of an experimental model of maternal allergic asthma during pregnancy

Abstract

Key pointsr We studied the effects of preconceptional allergen sensitisation and repeated airway allergen challenges during pregnancy on maternal immune and airway functions during pregnancy, and maternal, fetal and placental phenotype in late pregnancy in sheep.r This protocol induced maternal responses consistent with an allergic asthmatic phenotype.During pregnancy, lung resistance and the eosinophil influx induced by allergen challenges increased progressively in allergic sheep, and in late pregnancy airway smooth muscle content was greater in allergic than control ewes.r Effects on fetal growth and development were consistent with those of maternal asthma in humans. Maternal allergic asthma decreased relative fetal weight by 12%, reduced fetal lung expression of surfactant protein B, and altered placental morphology.r This provides an animal model in which to identify mechanisms underlying fetal effects of maternal asthma in pregnancy, including fetal physiological responses to exacerbations, and to evaluate responses to clinically used treatments and novel interventions.Abstract Maternal asthma during pregnancy adversely affects pregnancy outcomes but identification of the cause/s, and the ability to evaluate interventions, is limited by the lack of an appropriate animal model. We therefore aimed to characterise maternal lung and cardiovascular responses and fetal-placental growth and lung surfactant levels in a sheep model of allergic asthma. Immune and airway functions were studied in singleton-bearing ewes, either sensitised before pregnancy to house dust mite (HDM, allergic, n = 7) or non-allergic (control, n = 5), and subjected to repeated airway challenges with HDM (allergic group) or saline (control group) throughout gestation. Maternal lung, fetal and placental phenotypes were characterised at 140 ± 1 days gestational age (term, ß147 days). The eosinophil influx into lungs was greater after HDM challenge in allergic ewes than after saline challenge in control ewes before mating and in late gestation. Airway resistance increased throughout pregnancy in allergic but not control ewes, consistent with increased airway smooth muscle in allergic ewes. Maternal allergic asthma decreased relative fetal weight (−12%) and altered placental phenotype to a more mature form. Expression of surfactant protein B mRNA was 48% lower in fetuses from allergic ewes than

Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft

“…Clifton et al . () introduce an ovine experimental model to investigate the effects on the fetus of maternal asthma in pregnancy, permitting evaluation of current as well as novel clinical interventions.…”

Maternal allergic asthma during pregnancy alters fetal lung and immune development in sheep: potential mechanisms for programming asthma and allergy

“…To investigate mechanisms for effects of maternal asthma on the fetus and offspring, and to evaluate interventions, we established a sheep model of maternal allergic asthma induced by allergen sensitization before mating and repeated airway challenges during pregnancy, which decreases fetal growth and alters fetal lung development (Clifton et al . ). This protocol generates an asthmatic phenotype in pregnant ewes (Clifton et al .…”

Pre-birth origins of allergy and asthma

“…Sheep are sensitised systematically by repeated immunisation with allergen, followed by repeated airway challenges with aerosolised allergen, utilising a protocol that induces an allergic asthmatic phenotype in non-pregnant sheep (Bischof et al 2003, Bischof et al 2008). We mated ewes that had been sensitised and commenced airway challenges to house dust mite prior to pregnancy, and continued airway challenges with house dust mite throughout pregnancy (Clifton et al 2015). These pregnant ewes developed characteristics of allergic asthma including increased lung resistance, progressive increases in the eosinophil influx induced by airway allergen challenges, and increased deposition of smooth muscle around lung airways (Clifton et al 2015).…”

“…In order to directly evaluate the acute fetal and long-term progeny effects of maternal allergic asthma, and to enable evaluation of the effects of clinical and experimental interventions on these, we have recently developed an ovine model of maternal allergic asthma in pregnancy (Clifton et al 2015). Sheep are sensitised systematically by repeated immunisation with allergen, followed by repeated airway challenges with aerosolised allergen, utilising a protocol that induces an allergic asthmatic phenotype in non-pregnant sheep (Bischof et al 2003, Bischof et al 2008).…”

“…We mated ewes that had been sensitised and commenced airway challenges to house dust mite prior to pregnancy, and continued airway challenges with house dust mite throughout pregnancy (Clifton et al 2015). These pregnant ewes developed characteristics of allergic asthma including increased lung resistance, progressive increases in the eosinophil influx induced by airway allergen challenges, and increased deposition of smooth muscle around lung airways (Clifton et al 2015). The 12% reduction in relative fetal weight in late pregnancy in this model is consistent with effects of maternal asthma in human pregnancy, although additional studies are needed to determine whether fetal responses to maternal allergic asthma in sheep are sex-dependent as occurs in humans (Clifton et al 2009, Clifton et al 2015.…”