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Airway epithelial cells are well-known producers of thymus- and activation-regulated chemokine (TARC), a Th2 cell-attracting chemokine that may play an important role in the development of allergic airway inflammation. However, the mechanism responsible for up-regulation of TARC in allergy is still unknown. In the asthmatic airways, loss of expression of the cell-cell contact molecule E-cadherin and reduced epithelial barrier function has been observed, which may be the result of an inadequate repair response. Because E-cadherin also suppressed multiple signaling pathways, we studied whether disruption of E-cadherin-mediated cell contact may contribute to increased proallergic activity of epithelial cells, e.g., production of the chemokine TARC. We down-regulated E-cadherin in bronchial epithelial cells by small interference RNA and studied effects on electrical resistance, signaling pathways, and TARC expression (by electric cell-substrate impedance sensing, immunodetection, immunofluorescent staining, and real-time PCR). Small interference RNA silencing of E-cadherin resulted in loss of E-cadherin-mediated junctions, enhanced phosphorylation of epidermal growth factor receptor (EGFR), and the downstream targets MEK/ERK-1/2 and p38 MAPK, finally resulting in up-regulation of TARC as well as thymic stromal lymphopoietin expression. The use of specific inhibitors revealed that the effect on TARC is mediated by EGFR-dependent activation of the MAPK pathways. In contrast to TARC, expression of the Th1/Treg cell-attracting chemokine RANTES was unaffected by E-cadherin down-regulation. In summary, we show that loss of E-cadherin-mediated epithelial cell-cell contact by damaging stimuli, e.g., allergens, may result in reduced suppression of EGFR-dependent signaling pathways and subsequent induction of Th2 cell-attracting molecule TARC. Thus, disruption of intercellular epithelial contacts may specifically promote Th2 cell recruitment in allergic asthma.

Introduction: Most patients with asthma and many patients with COPD show bronchial hyperresponsiveness to adenosine (BHRAMP). BHRAMP may be caused by release of mast cell histamine, which induces smooth muscle contraction.Aim of the study: To evaluate whether mast cell numbers in airway smooth muscle are increased in patients with asthma and COPD compared to their age-matched controls, and whether mast cell numbers are correlated with BHRAMP.Patients: Twenty-two non-smoking subjects with asthma (age 31 yr, FEV1: 89% pred, PC(20)AMP: 2.7mg/ml), 18 ex-smoking subjects with COPD (age 62yr, FEV1: 58% pred, PC(20)AMP: 52.4mg/ml).Methods: Snap-frozen bronchial biopsies were immunostained with anti-mast cell tryptase and anti-desmin antibodies. Mast cell number was expressed as the number of tryptase positive cells per area of smooth muscle.Results: There were no significant differences in mast cell number between patients with asthma, COPD, and their respective age-matched healthy controls. Furthermore, there was no significant correlation between mast cell number and FEV, or PC20AMP in any of the groups. Surprisingly, the mast cell number was negatively correlated with reversibility to salbutamol in COPD patients (rho -0.47, P Conclusion: Mast cell numbers in central airway smooth muscle apparently do not contribute importantly to bronchial hyperresponsiveness to adenosine. (C) 2006 Elsevier Ltd. All rights reserved.