Defective epithelial barrier function in asthma Xiao, Chang, PhD; Puddicombe, Sarah M., PhD; Field, Sarah, PhD ...
Journal of allergy and clinical immunology,
09/2011, Letnik:
128, Številka:
3
Journal Article
Recenzirano
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.
Type I interferons were not present in sufficient quantity to measure; however, the finding of lower CXCL-10 quantities in asthmatic explants was consistent with deficient innate antiviral defences ...in asthma. Because subjects with asthma in our study were on regular ICSs, the effects on influenza susceptibility of which are unknown, we also sought to determine whether the differences seen in the primary comparator groups reflected the effects of FP or disease. Parameter Healthy controls Subjects with moderate asthma P value N 10 10 - Age (y) 27 (22.5-48.0) 35.5 (23.3-48.5) .647∗ Sex (M/F) 6/4 6/4 1.0† FEV1 4.23 (3.03-5.14) 3.55 (2.12-4.59) .142∗ FEV1 % predicted 109.1 (99.6-112.2) 95.9 (63.1-108.0) .017∗ Inhaled steroid dose (μg/d) NA 280 (165.4-394.6) <.001∗ SABA (μg/d) NA 140 (89.98-190.00) <.001∗ Blood eosinophils (%) 2.87 (1.69-5.87) 3.15 (2.04-4.89) .986∗ Total blood IgE 33.3 (7.1-63.5) 89.6 (31.0-179.5) .023∗ Atopy (yes) 3/10 8/10 .025† Feno 18.25 (11.38-33.38) 33.75 (21.50-100.10) .027∗ Sputum eosinophils (%) 0 2.39 (0-3.68) .045∗ Sputum neutrophils (%) 11.4 (7.1-15.7) 64.5 (21.9-74.2) .006∗ Table E2List of antibody clones and fluorophores used for detection of cell types and activation markers on cells dispersed from bronchial biopsy explantsAPC, Antigen-presenting cell; EpCAM, epithelial cell adhesion molecule; FITC, fluorescein isothiocyanate; NA, not available; PE, phycoerythrin. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis, PLoS Med, Vol. 8, 2011, e1001053 4 S.D. Message, V. Laza-Stanca, P. Mallia, H.L. Parker, J. Zhu, T. Kebadze, Proc Natl Acad Sci U S A, Vol. 105, 2008, 13562-13567 5...
Background: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma has been shown to be dependent on CD28/B7 ...costimulation. Objective: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma. Methods: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique. The contribution of IL-16 to the activity was evaluated through use of a neutralizing monoclonal antibody; the contribution of CD28/B7 costimulation to allergen-induced release of TLCA was determined through use of CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and CD86 (B7.2). Results: Induced sputum and unstimulated explants from asthmatic subjects generated significant spontaneous TLCA (P < .05). Both mild and moderate asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus –induced release of TLCA, but only in mild asthma could sputum and allergen-stimulated explant TLCA be inhibited by anti–IL-16 (median inhibition, 39% and 59%; P < .05). In addition, allergen released significant quantities of IL-16 from mild asthmatic explants (P < .05) but not from moderate asthmatic explants. Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced release of TLCA in mild asthmatic explants by 94% (P < .05) and 62%, but TLCA release from moderate asthmatic explants was unaffected by CTLA4-Ig. Conclusion: These results show that TLCA release in moderate asthmatic airways, in contrast to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not involve IL-16. (J Allergy Clin Immunol 2002;110:906-14.)
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