In utero exposure to experimental maternal asthma alters fetal airway development in sheep

The mechanisms linking maternal asthma (MA) exposure in utero and subsequent risk of asthma in childhood are not fully understood. Pathological airway remodelling, including reticular basement membrane thickening, has been reported in infants and children who go on to develop asthma later in childhood. This suggests altered airway development before birth as a mechanism underlying increased risk of asthma in children exposed in utero to MA. We hypothesised that in utero MA exposure would reduce airway diameter and increase airway-associated smooth muscle area and reticular basement membrane thickness in neonatal offspring. Experimental MA was induced by maternal sensitisation followed by airway challenges with house dust mite before and during pregnancy. Lambs from control (n = 16) or MA (n = 26) ewes were delivered at ∼140 days gestation (term = 150 days), ventilated for 45 min, then humanely killed. Left lungs were inflation-fixed, and cross-sections of generation 2-5 airways were collected. Airway sections were stained with Haematoxylin and Eosin, Masson's Trichrome and Gordon and Sweet's histological stains for morphological analysis. Lamb body and lung weights were similar between groups (P > 0.5 and P > 0.7, respectively). Lambs that were exposed to MA had narrower airway diameters (P = 0.019) and thinner reticular basement membrane (P = 0.016) but similar airway-associated smooth muscle area (P = 0.152) compared with unexposed control lambs. Our results demonstrate a potential mechanism for increased risk of asthma in children of mothers with asthma, independent of genetic risk or behavioural changes during pregnancy.