Apoptosis and Loss of Adhesion of Bronchial Epithelial Cells in Asthma

Trautmann, Axel; Krüger, Katja; Akdiş, Mübeccel; Müller-Wening, D.; Akkaya, Ahmet; Bröcker, Eva‐B.; Blaser, Kurt; Akdiş, Cezmi A.

doi:10.1159/000088436

Cited by 112 publications

(82 citation statements)

References 55 publications

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“…Airway epithelial integrity is often compromised in asthma, with detachment of ciliated cells, decreased E-cadherin expression at these sites, disruption of tight junctions and increased permeability to allergens [4][5][6]. Many allergens, including house dust mite (HDM), contain proteolytic activity, causing epithelial damage [7,8].…”

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confidence: 99%

Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction

Heijink¹,

Oosterhout²,

Kapùs³

2010

European Respiratory Journal

108

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Impaired airway epithelial barrier function has emerged as a key factor in the pathogenesis of allergic asthma. We aimed to discern the involvement of the epidermal growth factor receptor (EGFR) in allergen-induced epithelial barrier impairment, as we previously observed that house dust mite (HDM) signals through EGFR.We investigated the junctional integrity of human bronchial epithelial cells using electric cellsubstrate impedance sensing and immunofluorescent staining.HDM induced a rapid, transient fall in epithelial resistance, concomitant with delocalisation of Ecadherin and zona occludens (ZO)-1, and proteolytic cleavage of the latter. EGFR inhibition by AG1478 reduced the HDM-triggered decrease in epithelial resistance and improved restoration of epithelial junctions. Similarly, AG1478 increased epithelial barrier recovery upon electroporation-induced injury, although it delayed the migration phase of the wound healing response. HDM-promoted redistribution of E-cadherin was mediated via EGFR-dependent activation of protease-activated receptor (PAR)-2, while the concomitant ZO-1 degradation was PAR-2/EGFR-independent. Importantly, the fibrogenic cytokine transforming growth factor (TGF)-b prolonged HDM-induced EGFR phosphorylation and inhibited ligand-induced EGFR internalisation/degradation, which resulted in sustained E-cadherin and ZO-1 redistribution.Thus, allergen-induced, PAR-2/EGFR-mediated signalling decreases epithelial resistance and promotes junction disassembly. The TGF-b-enhanced EGFR signalling may be an important contributor to barrier dysfunction and increased epithelial vulnerability in response to HDM.

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mentioning

confidence: 99%

Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction

Heijink¹,

Oosterhout²,

Kapùs³

2010

European Respiratory Journal

108

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“…allergens, to subepithelial layers. Indeed, the airway epithelium is often damaged in asthma, with increased permeability and loss of Ecadherin and ZO-1 expression [2][3][4]. Disruption of the epithelial barrier may also relate to structural abnormalities and epithelial remodelling, i.e.…”

mentioning

confidence: 99%

Characterisation of cell adhesion in airway epithelial cell types using electric cell-substrate impedance sensing

Heijink

Brandenburg

Noordhoek

et al. 2009

European Respiratory Journal

131

112

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Research on epithelial cell lines and primary epithelium is required to dissect the mechanisms underlying the structural abnormalities in airway epithelium observed for respiratory diseases, including asthma and chronic obstructive pulmonary disease.The novel electric cell-substrate impedance sensing technique was used to monitor cell adhesion/spreading, barrier function and wound healing. Primary bronchial epithelium was compared with airway epithelial cell lines 16HBE14o-, BEAS-2B, NCI-H292 and A549.BEAS-2B, A549 and primary cells form a confluent monolayer more rapidly than do 16HBE14o-cells. In contrast, 16HBE14o-cells form stronger intercellular contacts, with a 10-fold higher resistance than BEAS-2B, A549 and NCI-H292 cells and a five-fold increase over primary cells. Accordingly, expression of the adhesion molecules zona occludens-1 and E-cadherin was highest in 16HBE14o-cells. These molecules were localised in intercellular junctions in both 16HBE14o-and primary cells. Finally, restoration of barrier function upon injury was impaired in BEAS-2B compared to 16HBE14o-cells.In conclusion, epithelial cell types display remarkable phenotypic differences and should, accordingly, be used to address specific research questions. 16HBE14o-cells appear most suitable for studies on barrier formation, whereas resemblance in attachment of primary and BEAS-2B and A549 cells makes the latter more important for translational research on cell-matrix contact.

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“…Damage to the epithelium may result in loss of E-cadherin membrane expression and intercellular contacts. It has recently been demonstrated that E-cadherin membrane expression is reduced in bronchial biopsies from asthma patients at the sites of epithelial lesions (24). This may have important consequences, given that E-cadherin is known to negatively regulate multiple signaling pathways.…”

mentioning

confidence: 99%

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

Heijink

Kies

Kauffman³

et al. 2007

The Journal of Immunology

153

133

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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.

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Apoptosis and Loss of Adhesion of Bronchial Epithelial Cells in Asthma

Cited by 112 publications

References 55 publications

Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction

Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction

Characterisation of cell adhesion in airway epithelial cell types using electric cell-substrate impedance sensing

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

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