Zazara Dimitra E, Wegmann Michael, Giannou Anastasios D, Hierweger Alexandra Maximiliane, Alawi Malik, Thiele Kristin, Huber Samuel, Pincus Maike, Muntau Ania C, Solano Maria Emilia, Arck Petra C
Department of Obstetrics and Prenatal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Division of Asthma Exacerbation & Regulation, Priority Area Asthma and Allergy, Leibniz Lung Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Borstel, Germany.
J Allergy Clin Immunol. 2020 Jun;145(6):1641-1654. doi: 10.1016/j.jaci.2020.01.050. Epub 2020 Apr 15.
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.
产前挑战，如母亲的压力感知，会增加儿童患哮喘的风险和严重程度。然而，对于产前引发哮喘的发病机制所涉及的轨迹和靶点，我们知之甚少。发育中的肺和免疫系统可能构成此类靶点。
在此，我们旨在确定产前挑战对小鼠肺功能、免疫反应和哮喘严重程度的性别差异效应。
我们构建了骨髓嵌合（BMC）小鼠，其肺部或免疫系统在产前受到应激暴露，然后通过卵清蛋白诱导过敏性哮喘。对卵清蛋白致敏的对照小鼠和产前应激的后代小鼠的肺进行下一代测序（RNA测序），并评估气道上皮屏障功能。
气道高反应性、炎症和纤维化显著增强仅出现在肺部产前受到应激暴露的雌性BMC小鼠中。如果肺和免疫系统都受到产前应激暴露，这些效应会显著持续存在。仅产前受到应激暴露的免疫系统不足以增加这些哮喘特征的严重程度。对产前应激、非BMC、卵清蛋白致敏的雌性小鼠的肺进行RNA测序分析，发现参与哮喘发病机制、组织重塑和紧密连接形成的基因表达失调。还能够独立证实紧密连接破坏。与此一致的是，我们发现产前应激的雌性小鼠中参与肺发育的基因在围产期和/或产后表达发生改变，同时肺泡化受损。
在此我们表明，哮喘的胎儿起源是由气道上皮破坏所调控，并由预先存在易感性的免疫系统进一步加剧。
