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* Department of Pediatrics, Division of Pneumology and Immunology,
Department of Internal Medicine/Psychosomatics, Division of Psycho-Neuro-Immunology, and
Neuroscience Program, Charité, University Medicine Berlin, Germany; and
Centre for Integrative Physiololgy, University of Edinburgh, Edinburgh, United Kingdom
Allergic asthma is one of the most prevalent and continuously increasing diseases in developed countries. Its clinical features include airway hyperresponsiveness and inflammation upon allergen contact. Furthermore, an emerging area of research subsumed as fetal programming evaluates the impact of environmental insults in utero on the incidence of diseases in later life. The aim of this study was to identify whether prenatal exposure to stress, which constitutes a severe environmental insult, perpetuates airway inflammation in later life. Our experiments were performed in mice and revealed that prenatally stressed adult offspring indeed show an increased vulnerability toward airway hyperresponsiveness and inflammation. Furthermore, we provide persuasive insights on dysregulated pathways of the cellular and humoral immune response upon Ag challenge in prenatally stressed adult offspring, reflected by a Th2 greater Th1 adaptive immune response and increased CCR3 and IgE levels in vivo. Additionally, APCs derived from prenatally stressed offspring trigger clonal expansion of Th2 cells in vitro. We also deliver experimental evidence for a reduced corticotrophin-releasing hormone expression in the paraventricular nucleus of adult offspring in response to prenatal stress. Furthermore, behavioral analyses indicate an increase in anxiety in these mice. In conclusion, our data will facilitate future research aiming to identify the individual impact, hierarchy, and redundancy of multiple key protagonists in airway inflammation in an interdisciplinary context. This will foster the substantiation of disease-prevention strategies, such as asthma, during the prenatal period.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 M.K.P.K. was supported by the new investigator program of the Charité and S.M.B. is a Fellow of the Schering Research Foundation. This work was made possible by research grants from the Charité to P.C.A. and M.K.P.-K.
2 E.H. and P.C.A. jointly supervised this work.
3 Address correspondence and reprint requests to Dr. Petra C. Arck, Department of Internal Medicine/Psychosomatics, Division of Psycho-Neuro-Immunology, Charité, University Medicine Berlin, Germany. E-mail address: petra.arck{at}charite.de
4 Abbreviations used in this paper: CRH, corticotrophin-releasing hormone; PVN, paraventricular nucleus; MCh, methacholine; BAL, bronchoalveolar lavage; PAS, periodic acid-Schiff; CBA, cytometric bead array; DC, dendritic cell; EPM, elevated plus maze; Penh, enhanced pause.
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