Abstract
BackgroundImpaired epithelial barrier function renders the airway vulnerable to environmental triggers associated with the pathogenesis of bronchial asthma. We investigated the influence of protocadherin-1 (PCDH1), a susceptibility gene for bronchial hyperresponsiveness, on airway epithelial barrier function.MethodsWe applied transepithelial electric resistance and dextran permeability testing to evaluate the barrier function of cultured airway epithelial cells. We studied PCDH1 function by siRNA-mediated knockdown and analyzed nasal or bronchial tissues from 16 patients with chronic rhinosinusitis (CRS) and nine patients with bronchial asthma for PCDH1 expression.ResultsPCDH1 was upregulated with the development of epithelial barrier function in cultured airway epithelial cells. Immunocytochemical analysis revealed that PCDH localized to cell-cell contact sites and colocalized with E-cadherin at the apical site of airway epithelial cells. PCDH1 gene knockdown disrupted both tight and adhesion junctions. Immunohistochemical analysis revealed strong PCDH1 expression in nasal and bronchial epithelial cells; however, expression decreased in inflamed tissues sampled from patients with CRS or bronchial asthma. Dexamethasone (Dex) increased the barrier function of airway epithelial cells and increased PCDH1 expression. PCDH1 gene knockdown eradicated the effect of Dex on barrier function.ConclusionThese results suggest that PCDH1 is important for airway function as a physical barrier, and its dysfunction is involved in the pathogenesis of allergic airway inflammation. We also suggest that glucocorticoids promotes epithelial barrier integrity by inducing PCDH1.
Highlights
Impaired epithelial barrier function renders the airway vulnerable to environmental triggers associated with the pathogenesis of bronchial asthma
Immunohistochemistry We focused on PCDH1 expression in ciliated airway epithelial cells (CECs) from the noninflamed region (NR), where there are few infiltrated inflammatory cells and CECs are histologically intact
Annexin V and propidium iodide staining revealed that PCDH1 knockdown did not lead to apoptotic cell death (Fig. 4. right). These results indicated that neither decreased cell proliferation nor reduced cell viability accounted for the defective epithelial barrier function in PCDH1-depleted monolayers
Summary
Impaired epithelial barrier function renders the airway vulnerable to environmental triggers associated with the pathogenesis of bronchial asthma. We investigated the influence of protocadherin-1 (PCDH1), a susceptibility gene for bronchial hyperresponsiveness, on airway epithelial barrier function. Asthma is a chronic inflammatory disorder of the airways characterized by inflammation, airway hyperresponsiveness, and reversible airflow obstruction [1]. Several cell types have been implicated in the pathogenesis of asthma; airway epithelial barrier dysfunction plays an important role [2]. Bronchial hyperresponsiveness (BHR), the key feature of asthma, is a functional abnormality in which airway constriction is triggered by environmental stimuli that otherwise do not affect healthy individuals. Protocadherin-1 (PCDH1) was recently identified as a susceptibility gene in asthma [6, 7]. Koppelman et al performed linkage and mapping analysis in 200 Dutch
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