A disrupted airway epithelium rather than an altered immune system orchestrates the fetal origin of asthma in mice

BACKGROUND: Prenatal challenges such as maternal stress perception increase the risk and severity of asthma during childhood. However, insights into the trajectories and targets underlying the pathogenesis of prenatally-triggered asthma are largely unknown. The developing lung and immune system may constitute such targets. OBJECTIVE: We here aimed to identify the differential sex-specific effects of prenatal challenges on lung function, immune response and asthma severity in mice. METHODS: We generated bone marrow chimeric (BMC) mice harboring either prenatally stress-exposed lungs or immune system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNAseq) of lungs as well as assessment of airway epithelial barrier function in OVA-sensitized control and prenatally stressed offspring were also performed. RESULTS: Profoundly enhanced airway hyperresponsiveness, inflammation and fibrosis were exclusively present in female BMC mice with prenatally stress-exposed lungs. These effects were significantly perpetuated if both, lungs and immune system, had been exposed to prenatal stress. A prenatally stress-exposed immune system alone did not suffice to increase the severity of these asthma features. RNAseq analysis of lungs from prenatally stressed, non-BMC, OVA-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling and tight junction formation. A tight junction disruption could also be independently confirmed. In line with this, we identified an altered peri-/postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice. CONCLUSION: We here show that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by the immune system.CAPSULE SUMMARY: Early detection of potential aberrations in lung development, which may subsequently lead to postnatal lung dysfunction and disease, will allow the design of efficient prediction, disease prevention and treatment strategies.