Airway Epithelial Changes in Smokers but Not in Ex-Smokers with Asthma

Broekema, Martine; Hacken, Nick H. T. ten; Volbeda, Franke; Lodewijk, Monique E.; Hylkema, Machteld N.; Postma, Dirkje S.; Timens, Wim

doi:10.1164/rccm.200906-0828oc

Cited by 94 publications

(103 citation statements)

References 46 publications

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“…Inherited differences in the cell cycle response to inflammatory and other oxidative stressors could hence in part underlie asthma etiology. In agreement, asthma risk factors with oxidative properties like tobacco smoke or air pollutants were shown to alter cell proliferation in the airways (28) and to alter lung function in a manner dependent on cell cycle gene variants (15).…”

Section: Asthma: High Inflammatory Stress and Altered Cell Cycle Controlmentioning

confidence: 60%

The Association of a Variant in the Cell Cycle Control GeneCCND1and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

Thun¹,

Imboden²,

Berger³

et al. 2013

Journal of Asthma

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OBJECTIVE: The molecular mechanisms underlying the association between obesity (BMI 30 kg/m(2)) and asthma are poorly understood. Since shifts in the fate of bronchial cells due to lowgrade systemic inflammation may provide a possible explanation, we investigated whether two of the best documented functional variants in cell cycle control genes modify the obesity-asthma association. METHODS: We genotyped 5930 SAPALDIA cohort participants for the single-nucleotide polymorphisms (SNPs) rs9344 in the cyclin D1 gene (CCND1) and rs1042522 in the gene encoding tumor protein 53 (TP53). We assessed the independent association of these SNPs and obesity with asthma prevalence and incidence. RESULTS: The CCND1 SNP modified the association between obesity and asthma prevalence (p(interaction )= 0.03). The odds ratios (ORs) and 95% confidence intervals (CIs) for reporting a physician diagnosis of asthma at baseline, comparing obese with non-obese participants, were 1.09 (0.51-2.33), 1.64 (0.94-2.88), and 3.51 (1.63-7.53) for GG, GA, and AA genotypes, respectively. We found comparable genotype differences for incident asthma within the 11 years of follow-up. As for the TP53 SNP, the interactions with obesity status with respect to asthma were not statistically significant. CONCLUSIONS: Our results suggest that obesity may contribute to asthma and associated tissue remodeling by modifying the processes related to the CCND1 gene activity. Objective. The molecular mechanisms underlying the association between obesity (BMI 30 kg/m 2 ) and asthma are poorly understood. Since shifts in the fate of bronchial cells due to low-grade systemic inflammation may provide a possible explanation, we investigated whether two of the best documented functional variants in cell cycle control genes modify the obesity-asthma association. Methods. We genotyped 5930 SAPALDIA cohort participants for the single-nucleotide polymorphisms (SNPs) rs9344 in the cyclin D1 gene (CCND1) and rs1042522 in the gene encoding tumor protein 53 (TP53). We assessed the independent association of these SNPs and obesity with asthma prevalence and incidence. Results. The CCND1 SNP modified the association between obesity and asthma prevalence (p interaction ¼ 0.03). The odds ratios (ORs) and 95% confidence intervals (CIs) for reporting a physician diagnosis of asthma at baseline, comparing obese with non-obese participants, were 1.09 (0.51-2.33), 1.64 (0.94-2.88), and 3.51 (1.63-7.53) for GG, GA, and AA genotypes, respectively. We found comparable genotype differences for incident asthma within the 11 years of follow-up. As for the TP53 SNP, the interactions with obesity status with respect to asthma were not statistically significant. Conclusions. Our results suggest that obesity may contribute to asthma and associated tissue remodeling by modifying the processes related to the CCND1 gene activity.of Asthma, 2013; 50(2): 147-154 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 0277-0903 print/1532-4303

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Section: Asthma: High Inflammatory Stress and Altered Cell Cycle Controlmentioning

confidence: 60%

The Association of a Variant in the Cell Cycle Control GeneCCND1and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

Thun¹,

Imboden²,

Berger³

et al. 2013

Journal of Asthma

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“…In addition, a direct toxic effect of cigarette smoke on epithelial cells has been documented (Broekema et al 2009;Lin et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Claudin-3 and Clara Cell 10 kDa Protein as Early Signals of Cigarette Smoke–Induced Epithelial Injury along Alveolar Ducts

et al. 2012

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Smoking-associated chronic obstructive pulmonary disease is characterized by inflammation, changes affecting small airways, and development of emphysema. Various short-and long-term models have been introduced to investigate these processes. The aim of the present study was to identify markers of early epithelial injury/adaptation in a short-term animal model of cigarette smoke exposure. Initially, male BALB/c mice were exposed to smoke from one to five cigarettes and lung changes were assessed 4 and 24 hr after smoking cessation. Subsequently, animals were exposed to smoke from five cigarettes for 2 consecutive days and lungs investigated daily until the seventh postexposure day. Lung homogenates cytokines were determined, bronchioloalveolar fluid cells were counted, and lung tissue was analyzed by immunohistochemistry. Exposure to smoke from a single cigarette induced slight pulmonary neutrophilia. Smoke from two cigarettes additionally induced de novo expression of tight junction protein, claudin-3, by alveolar duct (AD) epithelial cells. Further increases in smoke exposure induced epithelial changes in airway progenitor regions. During the recovery period, the severity/frequency of epithelial reactions slowly decreased, coinciding with the switch from acute to a chronic inflammatory reaction. Claudin-3 and Clara cell 10 kDa protein were identified as possible markers of early tobacco smoke-induced epithelial injury along ADs.

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“…Smoking is not only associated with increased numbers of mucus-producing cells [2,3], but also with increased mucosal permeability [4] and increased permeability to allergens in vitro [5,6]. Similarly, cigarette smoke may facilitate transepithelial crossing of viruses and bacteria, with crucial consequences, since bacterial infections have been implicated in nearly 50% of COPD exacerbations [7].…”

mentioning

confidence: 99%

Cigarette smoke impairs airway epithelial barrier function and cell–cell contact recovery

Heijink¹,

Brandenburg²,

Postma³

et al. 2011

Eur Respir J

196

150

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Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces aberrant airway epithelial structure and function. The underlying mechanisms are unresolved so far.We studied effects of cigarette smoke extract (CSE) on epithelial barrier function and wound regeneration in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) from COPD patients, nonsmokers and healthy smokers.We demonstrate that CSE rapidly and transiently impairs 16HBE barrier function, largely due to disruption of cell-cell contacts. CSE induced a similar, but stronger and more sustained, defect in PBECs. Application of the specific epidermal growth factor receptor (EGFR) inhibitor AG1478 showed that EGFR activation contributes to the CSE-induced defects in both 16HBE cells and PBECs. Furthermore, our data indicate that the endogenous protease calpain mediates these defects through tight junction protein degradation. CSE also delayed the reconstitution of 16HBE intercellular contacts during wound healing and attenuated PBEC barrier function upon wound regeneration. These findings were comparable between PBECs from smokers, healthy smokers and COPD patients.In conclusion, we demonstrate for the first time that CSE reduces epithelial integrity, probably by EGFR and calpain-dependent disruption of intercellular contacts. This may increase susceptibility to environmental insults, e.g. inhaled pathogens. Thus, EGFR may be a promising target for therapeutic strategies to improve mucosal barrier function in cigarette smoking-related disease.

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Airway Epithelial Changes in Smokers but Not in Ex-Smokers with Asthma

Cited by 94 publications

References 46 publications

The Association of a Variant in the Cell Cycle Control GeneCCND1and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

The Association of a Variant in the Cell Cycle Control GeneCCND1and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

Claudin-3 and Clara Cell 10 kDa Protein as Early Signals of Cigarette Smoke–Induced Epithelial Injury along Alveolar Ducts

Cigarette smoke impairs airway epithelial barrier function and cell–cell contact recovery

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