A.J.M. van Oosterhout

University of Groningen, Groningen, Groningen, Netherlands

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Publications (226)793.87 Total impact

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    ABSTRACT: Most patients with allergic asthma are sensitized to house dust mite (HDM). The allergenicity of HDM largely depends on disruption of the integrity and pro-inflammatory activation of the airway epithelium. In this study, we hypothesized that Pim1 kinase activity attenuates HDM-induced asthma by preserving airway epithelial integrity. The effects of Pim1 kinase activity on barrier function and release of the pro-inflammatory mediators IL-1α and CCL20 were studied in vitro in 16HBE and primary bronchial epithelial cells (PBECs). Pim1-proficient and deficient mice were exposed to a HDM-driven model of allergic asthma, and airway hyper-responsiveness (AHR) was measured upon metacholine challenge. Airway inflammation and pro-inflammatory mediators in lung tissue and BAL fluid were determined. We observed that inhibition of Pim1 kinase prolongs the HDM-induced loss of barrier function in 16HBE cells and sensitizes PBECs to HDM-induced barrier dysfunction. Additionally, inhibition of Pim1 kinase increased the HDM-induced pro-inflammatory activity of 16HBE cells as measured by IL-1α secretion. In line herewith, HDM exposure induced an enhanced production of the pro-inflammatory chemokines CCL17 and CCL20 in Pim1-deficient mice compared to wild-type controls. While we observed a marked increase in eosinophilic and neutrophilic granulocytes as well as mucus cell metaplasia and AHR to metacholine in mice exposed to HDM, these parameters were independent of Pim1 kinase activity. In contrast, levels of the Th2-cytokines IL-5 and IL-10 were significantly augmented in HDM-treated Pim1-deficient mice. Taken together, our study shows that Pim1 kinase activity maintains airway epithelial integrity and protects against HDM-induced pro-inflammatory activation of the airway epithelium.
    AJP Lung Cellular and Molecular Physiology 10/2015; 46(suppl 59):ajplung.00043.2015. DOI:10.1152/ajplung.00043.2015 · 4.08 Impact Factor

  • European Respiratory Journal 09/2015; 46(suppl 59):PA5094. DOI:10.1183/13993003.congress-2015.PA5094 · 7.64 Impact Factor
  • Simon Pouwels · Nick Ten Hacken · Jaap Lubbers · Antoon Van Oosterhout · Martijn Nawijn · Irene Heijink ·

    European Respiratory Journal 09/2015; 46(suppl 59):PA5115. DOI:10.1183/13993003.congress-2015.PA5115 · 7.64 Impact Factor
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    ABSTRACT: In Chronic Obstructive Pulmonary Disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. GSK3β inactivation plays a key role in mediating signalling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of p-GSK3β-ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers and non-smokers. We observed increased levels of p-GSK3β-ser9 in monocytes, alveolar macrophages and bronchial epithelial cells from COPD patients and control smokers compared to non-smokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or GM-CSF expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress induced activation of the MEK/ERK-1/2 and PI3K/Akt signalling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub. Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 08/2015; DOI:10.1152/ajplung.00077.2015 · 4.08 Impact Factor
  • Sijranke Post · Dennie Rozeveld · Marnix Jonker · Rainer Bischoff · Antoon van Oosterhout · Irene Heijink ·
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    ABSTRACT: House dust mite (HDM) acts on the airway epithelium to induce airway inflammation in asthma. We previously showed that the ability of HDM to induce allergic sensitization in mice is related to airway epithelial CCL20 secretion. Since A Disintegrin and Metalloprotease (ADAM)s have been implicated in chemokine shedding, we sought to determine their involvement in HDM-induced release of chemokines, including CCL20, by airway epithelial cells. We studied the effects of pharmacological ADAM inhibitors as well as ADAM10 and ADAM17 siRNA downregulation on chemokine release using (multiplex) ELISA in supernatants from HDM-exposed human bronchial epithelial 16HBE cells and primary normal human bronchial epithelial cells (NHBE) at 4-24 hours. HDM markedly increased CCL20 levels in both 16HBE and NHBE cells (16-24 hours). In 16HBE cells, the HDM-induced increase was observed as early as 4 hours upon exposure and the use of specific inhibitors indicated involvement of ADAM10/17-mediated shedding. siRNA knockdown of ADAM10, but not of ADAM17, significantly reduced the HDM-induced release of CCL20 in both 16HBE and NHBE cells. A similar effect was observed for HDM-induced CCL2, CCL5 and CXCL8 release in NHBE cells. The HDM-induced increase in CCL20 levels was not affected by protein synthesis inhibitor cycloheximide nor protein transport inhibitor monensin, indicating that HDM induces surface shedding of chemokines. Our data show for the first time that ADAM10 activity contributes to HDM-induced shedding of chemokines, including CCL20. The ADAM10/CCL20 axis may be a target for novel therapeutic strategies in asthma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Allergy 08/2015; DOI:10.1111/all.12730 · 6.03 Impact Factor
  • Ruben t'Kindt · Eef D Telenga · Lucie Jorge · Antoon J M van Oosterhout · Pat Sandra · Nick H T Ten Hacken · Koen Sandra ·
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    ABSTRACT: Induced lung sputum is a valuable matrix in the study of respiratory diseases. Although the methodology of sputum collection has evolved to a point where it is repeatable and responsive to inflammation, its use in molecular profiling studies is still limited. Here, an in-depth lipid profiling of induced lung sputum using high-resolution liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS) is described. An enormous complexity in lipid composition could be revealed. Over 1500 intact lipids, originating from 6 major lipid classes, have been accurately identified in 120 µL of induced sputum. By number and measured intensity, glycerophospholipids represent the largest lipid class, followed by sphingolipids, glycerolipids, fatty acyls, sterol lipids and prenol lipids. Several prenol lipids, originating from tobacco, could be detected in the lung sputum of smokers. To illustrate the utility of the methodology in studying respiratory diseases, a comparative lipid screening was performed on lung sputum extracts in order to study the effect of Chronic Obstructive Pulmonary Disease (COPD) on the lung barrier lipidome. Results show that sphingolipid expression in induced sputum significantly differs between smokers with and without COPD.
    Analytical Chemistry 04/2015; 87(9). DOI:10.1021/acs.analchem.5b00732 · 5.64 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) are the main proteolytic enzymes involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). A radiolabeled MMP inhibitor, [(18)F]FB-ML5, was prepared, and its in vivo kinetics were tested in a mouse model of pulmonary inflammation. BALB/c mice were exposed for 4 days to cigarette smoke (CS) or air. On the fifth day, a dynamic microPET scan was made with [(18)F]FB-ML5. Standardized uptake values (PET-SUVmean) were 0.19 ± 0.06 in the lungs of CS-exposed mice (n = 6) compared to 0.11 ± 0.03 (n = 5) in air-exposed controls (p < 0.05), 90 min post-injection MMP-9 levels in bronchoalveolar lavage fluid (BALF) were increased from undetectable level to 4615 ± 1963 pg/ml by CS exposure. Increased MMP expression in a COPD mouse model was shown to lead to increased retention of [(18)F]FB-ML5.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 03/2015; 17(5). DOI:10.1007/s11307-015-0847-3 · 2.77 Impact Factor

  • European Respiratory Journal 03/2015; 45(5). DOI:10.1183/09031936.00158 · 7.64 Impact Factor
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    ABSTRACT: Bronchiolitis obliterans syndrome (BOS), the major cause of death on lung transplantation, is characterized by bronchiolar inflammation and tissue remodeling. Matrix metalloproteinases (MMPs) have been implicated in these processes, although it is still unclear whether MMP activity and binding to their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), is abnormal in BOS. We studied total MMP-1,-2,-3,-7,-8,-9,-12,-13 levels, their activity state using activity-based extraction and their binding to TIMP-1, -2, -3, and -4 in bronchoalveolar lavage (BAL) of lung transplant recipients with good outcome and BOS using a multiplex immunoassay. The BAL levels of TIMP-1 and -2 and MMP-2, -3, -7, -8, and -9 were significantly increased in BOS compared to good outcome recipients. Interestingly, activity of MMP-7, but none of the other MMPs, was detected in good outcome recipients, whereas no active MMPs were observed in BOS recipients. However, BAL levels of TIMP-bound MMP-8 and -9 were higher in BOS than in good outcome recipients, suggesting activity of these MMPs in an earlier stage. We demonstrate that development of BOS is associated with increased levels of TIMP-1 and -2 and total MMP-2, -3, -7, -8, and -9. Although active MMP-7 was only observed in good outcome recipients, levels of TIMP-bound MMP-8 and -9 were higher in BOS. By enabling profiling of active and TIMP-bound MMPs, our novel method may open opportunities for the screening of early predictors for BOS.
    Transplantation 02/2015; Online First(9). DOI:10.1097/TP.0000000000000602 · 3.83 Impact Factor

  • Cytometry Part B Clinical Cytometry 01/2015; 88(1). DOI:10.1002/cyto.b.21181 · 2.40 Impact Factor
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    ABSTRACT: Rationale: Cigarette smoking, the major causative factor for the development of chronic obstructive pulmonary disease (COPD), is associated with neutrophilic airway inflammation. Cigarette smoke (CS) exposure can induce a switch from apoptotic to necrotic cell death in airway epithelium. Therefore, we hypothesized that CS promotes neutrophil necrosis with subsequent release of damage-associated molecular patterns (DAMPs), including HMGB1, alarming the innate immune system. Methods: We studied the effect of smoking 2 cigarettes on sputum neutrophils in healthy individuals and of 5 days CS or air exposure on neutrophil counts, MPO and HMGB1 levels in bronchoalveolar lavage fluid of BALB/c mice. In human peripheral blood neutrophils, mitochondrial membrane potential, apoptosis/necrosis markers, caspase activity and DAMP release were studied after CS exposure. Finally, we assessed the effect of neutrophil-derived supernatants on the release of chemo-attractant CXCL8 in normal human bronchial epithelial (NHBE) cells. Results: Cigarette smoking caused a significant decrease in sputum neutrophil numbers after 3 hours. In mice, neutrophil counts were significantly increased 16 hours after repeated CS exposure, but reduced 2 hours after an additional exposure. In vitro, CS induced necrotic neutrophil cell death, as indicated by mitochondrial dysfunction, inhibition of apoptosis and DAMP release. Supernatants from CS-treated neutrophils significantly increased the release of CXCL8 in NHBE cells. Conclusions: Together, we show for the first time that CS exposure induces neutrophil necrosis, leading to DAMP release, which may amplify CS-induced airway inflammation by promoting airway epithelial pro-inflammatory responses.
    American Journal of Respiratory Cell and Molecular Biology 09/2014; 52(5). DOI:10.1165/rcmb.2013-0505OC · 3.99 Impact Factor
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    ABSTRACT: Protocadherin-1 (PCDH1) is a novel susceptibility gene for airway hyperresponsiveness, first identified in families exposed to cigarette smoke and is expressed in bronchial epithelial cells. Here, we asked how mouse Pcdh1 expression is regulated in lung structural cells in vivo under physiological conditions, and in both short-term cigarette smoke exposure models characterized by airway inflammation and hyperresponsiveness and chronic cigarette smoke exposure models. Pcdh1 gene-structure was investigated by Rapid Amplification of cDNA Ends. Pcdh1 mRNA and protein expression was investigated by qRT-PCR, western blotting using isoform-specific antibodies. We observed 87% conservation of the Pcdh1 nucleotide sequence, and 96% conservation of the Pcdh1 protein sequence between men and mice. We identified a novel Pcdh1 isoform encoding only the intracellular signalling motifs. Cigarette smoke exposure for 4 consecutive days markedly reduced Pcdh1 mRNA expression in lung tissue (3 to 4-fold), while neutrophilia and airway hyperresponsiveness was induced. Moreover, Pcdh1 mRNA expression in lung tissue was reduced already 6 hours after an acute cigarette-smoke exposure in mice. Chronic exposure to cigarette smoke induced loss of Pcdh1 protein in lung tissue after 2 months, while Pcdh1 protein levels were no longer reduced after 9 months of cigarette smoke exposure. We conclude that Pcdh1 is highly homologous to human PCDH1, encodes two transmembrane proteins and one intracellular protein, and is regulated by cigarette smoke exposure in vivo.
    PLoS ONE 07/2014; 9(7):e98197. DOI:10.1371/journal.pone.0098197 · 3.23 Impact Factor
  • Irene H Heijink · Jacobien A Noordhoek · Wim Timens · Antoon J M van Oosterhout · Dirkje S Postma ·

    American Journal of Respiratory and Critical Care Medicine 06/2014; 189(11):1439-42. DOI:10.1164/rccm.201311-1982LE · 13.00 Impact Factor
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    ABSTRACT: Rationale: Cigarette smoke is the major risk factor in the development of chronic obstructive pulmonary disease (COPD). Lipidomics is a novel and emerging research field that may provide new insights in the origins of chronic inflammatory diseases like COPD. Objective: To investigate whether expression of the sputum lipidome is affected by COPD or cigarette smoking. Methods: Lipid expression was investigated with liquid chromatography and high-resolution quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) in induced sputum comparing smokers with and without COPD, and never-smokers. Changes in lipid expression after 2-month smoking cessation were investigated in smokers with and without COPD. Measurements and Main Results: >1500 lipid compounds were identified in sputum. The class of sphingolipids was significantly higher expressed in smokers with COPD than in smokers without COPD. At single compound level, 168 sphingolipids, 36 phosphatidylethanolamine lipids and 5 tobacco-related compounds were significantly higher expressed in smokers with COPD compared to smokers without COPD. The 13 lipids with a high fold change between smokers with and without COPD showed high correlations with lower lung function and inflammation in sputum. 20 (glyco)sphingolipids and 6 tobacco-related compounds were higher expressed in smokers without COPD compared to never-smokers. Two-month smoking cessation reduced expression of 26 sphingolipids in smokers with and without COPD. Conclusions: Expression of lipids from the sphingolipid pathway are higher in smokers with COPD compared to smokers without COPD. Considering their potential biological properties, they may play a role in the pathogenesis of COPD.
    American Journal of Respiratory and Critical Care Medicine 05/2014; DOI:10.1164/rccm.201312-2210OC · 13.00 Impact Factor
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    ABSTRACT: Background: There is need for an accurate diagnostic test in mastocytosis patients with wasp venom allergy (WVA) and monitoring of these patients during immunotherapy (IT). In this study, we aimed to evaluate sensitivity and specificity of the Basophil Activation Test (BAT) as a diagnostic and monitoring test in patients with mastocytosis and WVA. Methods: Seventeen patients with mastocytosis and WVA and six mastocytosis patients without WVA were included. BAT was performed before the start of IT (first visit) and at 6 weeks (second visit) and 1 year (third visit), after reaching the maintenance dose. Of 17 patients included, 11 completed the third visit. In mastocytosis patients with WVA, dose-dependent wasp-venom induced upregulation of CD63 and CD203c expression on basophils was observed compared with mastocytosis patients without WVA. Serum specific IgE, IgG4, and tryptase levels were measured in all patients. Results: BAT had a sensitivity of 87% and specificity of 100% in diagnosing WVA in mastocytosis patients. Basophil allergen threshold sensitivity with respect to CD63 and CD203c was significantly decreased in the second visit compared with the first visit and increased significantly in the third visit compared with the second visit. Specific IgE levels increased significantly in the second visit compared with first and decreased significantly in the third visit compared with the second. Specific IgG4 levels rose significantly in the second visit compared with the first and on the third visit compared with the second. Tryptase levels did not change significantly during the study. Conclusions: BAT represents a diagnostic test with 100% specificity in allergic patients with mastocytosis and these patients are better to be monitored for a longer period during IT.
    Cytometry Part B Clinical Cytometry 05/2014; 86(3). DOI:10.1002/cytob.21148 · 2.40 Impact Factor
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    ABSTRACT: Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM-driven allergic airway disease.
    PLoS ONE 03/2014; 9(3):e91206. DOI:10.1371/journal.pone.0091206 · 3.23 Impact Factor
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    ABSTRACT: Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17-cell chemoattractant CCL20.We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o- cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases.We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNF)-α-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o- cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-α-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels.We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma.
    European Respiratory Journal 03/2014; 44(2). DOI:10.1183/09031936.00209513 · 7.64 Impact Factor
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    Simon D Pouwels · Irene H Heijink · Antoon J M van Oosterhout · Martijn C Nawijn ·

    European Respiratory Journal 12/2013; 43(4). DOI:10.1183/09031936.00127813 · 7.64 Impact Factor
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    ABSTRACT: We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function. We induced oxidative stress by H2O2 and/or cigarette smoke extract (CSE) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) derived by brushings from asthma patients, COPD patients, and smoking and non-smoking control individuals. We investigated effects of budesonide on barrier function (electrical resistance) and TNF-α-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)). We observed that H2O2 and CSE reduce epithelial resistance. Budesonide significantly counteracted this effect, likely by protection against epidermal growth factor receptor-dependent cell-cell contact disruption. Furthermore, budesonide suppressed proinflammatory cytokine production. H2O2 pretreatment reduced this effect of budesonide on cytokine production in both 16HBE cells and PBECs. Importantly, PBECs from asthma and COPD patients were less sensitive to budesonide with respect to cytokine production and barrier function than PBECs from control subjects. Together, our data indicate that budesonide suppresses epithelial proinflammatory responses and barrier dysfunction and that oxidative stress reduces these effects in airway epithelium from asthma and COPD patients. Therefore, restoration of corticosteroid responsiveness in asthma and COPD may act to improve the airway epithelial barrier.
    Thorax 08/2013; 69(1). DOI:10.1136/thoraxjnl-2013-203520 · 8.29 Impact Factor
  • S Post · M C Nawijn · M R Jonker · N Kliphuis · M van den Berge · A J M van Oosterhout · I H Heijink ·
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    ABSTRACT: House dust mite (HDM) affects the immunological and physical barrier function of airway epithelium, leading to allergic sensitization, airway remodeling, and eosinophilic inflammation in mouse models, although the mechanisms are still largely unknown. Given the implications for adenosine triphosphate (ATP)-dependent Ca(2+) signaling in allergic sensitization in mice, we sought to determine the role of intracellular Ca(2+) concentration ([Ca(2+) ]i ) in HDM-induced barrier dysfunction and pro-inflammatory activity of bronchial epithelium. We investigated the effect of HDM on accumulation of [Ca(2+) ]i levels, barrier function, and CCL20 release in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) from healthy subjects and asthma patients. Involvement of ATP-dependent activation of purinergic receptors and downstream Ca(2+) influx was studied, using the ATP hydrolyzing agent apyrase, the purinergic receptor agonist PPADS, the calcium chelator BAPTA-AM, and calpain inhibitors. Asthma PBECs were more susceptible to HDM-induced barrier dysfunction, CCL20 secretion, and Ca(2+) influx than healthy PBECs. Furthermore, we show that the HDM-induced increase in CCL20 in PBECs and 16HBE cells and the HDM-induced barrier dysfunction in 16HBE cells are dependent on [Ca(2+) ]i accumulation. Additionally, we demonstrate that [Ca(2+) ]i accumulation is initiated partly through the activation of purinergic receptors, which contributes to HDM-induced epithelial barrier dysfunction by disruption of cell-cell contacts, but not CCL20 secretion. Our data show for the first time that Ca(2+) signaling plays a crucial role in barrier dysfunction and the pro-inflammatory response of bronchial epithelium upon HDM exposure and may thus have important implications for the development of allergic asthma.
    Allergy 08/2013; 68(9). DOI:10.1111/all.12202 · 6.03 Impact Factor

Publication Stats

4k Citations
793.87 Total Impact Points


  • 2004-2015
    • University of Groningen
      • • Department of Pathology and Medical Biology
      • • Department of Pathology and Laboratory Medicine
      Groningen, Groningen, Netherlands
  • 2009-2012
    • Universitair Medisch Centrum Groningen
      • Department of Pathology and Medical Biology
      Groningen, Groningen, Netherlands
  • 1984-2004
    • Utrecht University
      • • Division of Pharmacology and Pathofysiology
      • • Division of Pharmacology
      • • Division of Veterinary Pharmacy
      • • Division of Veterinary Pharmaceuticals, Pharmacology and Toxicology
      Utrecht, Utrecht, Netherlands
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 2003
    • Ghent University
      • Center for Medical Genetics
      Gand, Flanders, Belgium
  • 1995
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands