Rhinitis, sinusitis, and upper airway disease
Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4

https://doi.org/10.1016/j.jaci.2012.05.052Get rights and content

Background

Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far.

Objective

We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS.

Methods

Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-γ, IL-4, and IL-17 on ALI cultures was assessed.

Results

A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-γ and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity.

Conclusion

A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-γ and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS.

Section snippets

Patients

Patients undergoing paranasal sinus surgery because of CRS with and without nasal polyposis were enrolled as study patients. Patients undergoing paranasal sinus surgery for noninflammatory reasons (ie, cerebrospinal fluid leak, bullous middle turbinate, and those undergoing septal surgery) were used as healthy control subjects. Nasal or systemic corticosteroid administration up to 4 weeks before surgery was considered an exclusion criterion. Patients with CRS caused by underlying systemic

Disrupted epithelial integrity and TJs in patients with CRS

We first investigated whether there is any difference in tissue resistance in patients with CRS. Large and intact biopsy specimens were used for resistance assessments in an Ussing chamber to quantify the epithelial integrity directly in affected tissues. The measurement revealed significantly (P = .03) higher trans-tissue resistances in control subjects (105.8 ± 6.4 Ω × cm2) compared with that seen in patients with CRSwNP (48.8 ± 9.6 Ω × cm2). Samples from patients with CRSsNP (81.5 ± 7.9

Discussion

The present study analyzes the function and expression of TJs in patients with CRS. We provide direct in vivo evidence for a defective barrier function in patients with CRSwNP in conjunction with a decreased expression of TJ proteins and mRNA levels compared with that seen in control subjects. Thus far, most of the research has focused on the inflammatory pathomechanisms and identification of proinflammatory mediators in patients with CRS rather than on the effects on the nasal/paranasal sinus

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  • Cited by (0)

    The laboratory of C.A.A. is supported by the European Allergy and Asthma Center Davos (EACD), Swiss National Science Foundation grants 32-132899 and 32-112306, the Christine Kühne Center for Allergy Research and Education (CK-CARE), the Müller-Gierok-Foundation, and University Hospital Zurich.

    Disclosure of potential conflict of interest: M. B. Soyka has received research support from the Müller-Gierok Foundation, the European Allergy and Asthma Center Davos, the Swiss National Foundation, University Hospital Zurich, and CK-CARE and is employed by University Hospital Zurich. C. A. Akdis has received research support from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, the Global Allergy and Asthma European Network, and CK-CARE; has provided legal consultation/expert witness testimony on the topics of Acellion TH2-specific receptors, Aventis T-cell Bell regulation, and allergen-specific immunotherapy (for Stallergenes and Allergopharma); is president of the European Academy of Allergy and Clinical Immunology, a GA2LEN ex-committee member, director of CK-CARE, and a fellow and interest group member for the American Academy of Allergy, Asthma & Immunology. The rest of the authors declare that they have no relevant conflicts of interest.

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