Asthma and lower airway disease
Defective epithelial barrier function in asthma

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Background

Asthma is a complex disease involving gene and environment interactions. Although atopy is a strong predisposing risk factor for asthma, local tissue susceptibilities are required for disease expression. The bronchial epithelium forms the interface with the external environment and is pivotally involved in controlling tissue homeostasis through provision of a physical barrier controlled by tight junction (TJ) complexes.

Objectives

To explain the link between environment exposures and airway vulnerability, we hypothesized that epithelial TJs are abnormal in asthma, leading to increased susceptibility to environmental agents.

Methods

Localization of TJs in bronchial biopsies and differentiated epithelial cultures was assessed by electron microscopy or immunostaining. Baseline permeability and the effect of cigarette smoke and growth factor were assessed by measurement of transepithelial electrical resistance and passage of fluorescently labeled dextrans.

Results

By using immunostaining, we found that bronchial biopsies from asthmatic subjects displayed patchy disruption of TJs. In differentiated bronchial epithelial cultures, TJ formation and transepithelial electrical resistance were significantly lower (P < .05) in cultures from asthmatic donors (n = 43) than from normal controls (n = 40) and inversely correlated with macromolecular permeability. Cultures from asthmatic donors were also more sensitive to disruption by cigarette smoke extract. Epidermal growth factor enhanced basal TJ formation in cultures from asthmatic subjects (P < .01) and protected against cigarette smoke–induced barrier disruption (P < .01).

Conclusions

Our results show that the bronchial epithelial barrier in asthma is compromised. This defect may facilitate the passage of allergens and other agents into the airway tissue, leading to immune activation and may thus contribute to the end organ expression of asthma.

Section snippets

Methods

This article has supplementary methodologic data accessible at this article’s Online Repository at www.jacionline.org.

Human wild-type EGF was expressed in Escherichia coli (SinoBio Biotech, Shanghai, China).

TJs are disrupted in airways of asthmatic subjects

Immunohistochemical analysis of occludin, which plays an indispensible role in the regulation of barrier tightness, and ZO-1, which plays a critical role in the establishment of the beltlike TJs,6, 7 was undertaken on bronchial biopsies obtained from normal subjects (n = 7) and asthmatic subjects (n = 19) (Table E1). In well-orientated sections from normal subjects where a clear brush border was evident, occludin and ZO-1 were localized close to the apical surface of the epithelium, forming

Discussion

We report a disease-related deficiency in epithelial TJs in asthma, both in vivo and in vitro, involving reduced TJ protein localization in junctional complexes and an associated increased permeability of the epithelium to ions and macromolecules. Since the airway epithelium is the first barrier to inhaled insults, such a defect may contribute to the susceptibility of epithelium in asthmatic subjects to environmental stimuli and may help explain bronchial hyperresponsiveness through enhanced

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  • Cited by (0)

    This work was funded by Synairgen Research Ltd and the University of Southampton. Stephen T. Holgate is a Medical Research Council Clinical Professor.

    Disclosure of potential conflict of interest: C. Xiao, S. Field, J. Haywood, V. Broughton-Head, J. Sones, and P. Monk are employees of Synairgen Research Limited. R. Djukanović is a cofounder and shareholder of and a consultant for Synairgen. P. H. Howarth has received research support from the National Institute of Health Research (United Kingdom). S. T. Holgate owns shares in and consults for Synairgen; is vice president of the British Lung Foundation; and has received research support from the Medical Research Council. D. E. Davies is a cofounder and shareholder of, is a consultant for, and has received research support from Synairgen. The rest of the authors have declared that they have no conflict of interest.

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