A prenatally disrupted airway epithelium orchestrates the fetal origin of asthma in mice.
Animals
Asthma
/ immunology
Bone Marrow
/ immunology
Cells, Cultured
Disease Models, Animal
Female
Immunity
/ immunology
Inflammation
/ immunology
Lung
/ immunology
Male
Mice
Mice, Inbred C57BL
Ovalbumin
/ immunology
Pregnancy
Prenatal Exposure Delayed Effects
/ immunology
Respiratory Hypersensitivity
/ immunology
Respiratory Mucosa
/ immunology
Tight Junctions
/ immunology
Prenatal stress
airway epithelium
asthma
bone marrow transplantation
lung development
mouse models
sexual dimorphism
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
11
10
2019
revised:
27
12
2019
accepted:
29
01
2020
pubmed:
20
4
2020
medline:
20
2
2021
entrez:
20
4
2020
Statut:
ppublish
Résumé
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. Here we have aimed to identify the differential sex-specific effects of prenatal challenges on lung function, immune response, and asthma severity in mice. We generated bone marrow chimeric (BMC) mice harboring either prenatally stress-exposed lungs or a prenatally stress-exposed immune (hematopoietic) system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNA sequencing) of lungs and assessment of airway epithelial barrier function in ovalbumin-sensitized control and prenatally stressed offspring was also performed. 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 the lungs and the 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. RNA sequencing analysis of lungs from prenatally stressed, non-BMC, ovalbumin-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling, and tight junction formation. It was also possible to independently confirm a tight junction disruption. In line with this, we identified an altered perinatal and/or postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice. Here we have shown that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by a predisposed immune system.
Sections du résumé
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
Here we have 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 a prenatally stress-exposed immune (hematopoietic) system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNA sequencing) of lungs and assessment of airway epithelial barrier function in ovalbumin-sensitized control and prenatally stressed offspring was 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 the lungs and the 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. RNA sequencing analysis of lungs from prenatally stressed, non-BMC, ovalbumin-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling, and tight junction formation. It was also possible to independently confirm a tight junction disruption. In line with this, we identified an altered perinatal and/or postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice.
CONCLUSION
Here we have shown that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by a predisposed immune system.
Identifiants
pubmed: 32305348
pii: S0091-6749(20)30335-3
doi: 10.1016/j.jaci.2020.01.050
pii:
doi:
Substances chimiques
Ovalbumin
9006-59-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1641-1654Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.