Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Boudewijn, Ilse M.; Faiz, Alen; Steiling, Katrina; Wiel, Erica van der; Telenga, Eef D.; Hoonhorst, Susan; Hacken, Nick H. T. ten; Brandsma, Corry‐Anke; Kerstjens, Huib A. M.; Timens, Wim; Heijink, Irene H.; Jonker, Marnix; Bruin, Harold G. de; Vroegop, J. Sebastiaan; Pasma, Henk; Boersma, Wim; Wielders, Pascal; Elshout, Frank van den; Mansour, Khaled; Spira, Avrum; Lenburg, Marc E.; Guryev, Victor; Postma, Dirkje S.; Berge, Maarten van den

doi:10.1186/s12931-017-0696-5

Cited by 35 publications

(31 citation statements)

References 42 publications

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“…It should be noted that our study relies solely on the use of ex vivo HBE derived from the three subject populations. Although there is ample precedent for ex vivo airway epithelial cells from different subject populations to retain phenotypic differences in culture (48)(49)(50), confirmation that our findings reflect in vivo responses will require additional studies to analyze IL-17C expression from epithelial cells obtained directly from the airways from subject groups during in vivo infections.…”

Section: Discussionmentioning

confidence: 88%

Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment

Jamieson

Traves

Kooi

et al. 2019

The Journal of Immunology

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Virus-bacteria coinfections are associated with more severe exacerbations and increased risk of hospital readmission in patients with chronic obstructive pulmonary disease (COPD). The airway epithelium responds to such infections by releasing proinflammatory and antimicrobial cytokines, including IL-17C. However, the regulation and role of IL-17C is not well understood. In this study, we examine the mechanisms regulating IL-17C production and its potential role in COPD exacerbations. Human bronchial epithelial cells (HBE) obtained from normal, nontransplanted lungs or from brushings of nonsmokers, healthy smokers, or COPD patients were exposed to bacteria and/or human rhinovirus (HRV). RNA and protein were collected for analysis, and signaling pathways were assessed with pharmacological agonists, inhibitors, or small interfering RNAs. HBE were also stimulated with IL-17C to assess function. HRV-bacterial coinfections synergistically induced IL-17C expression. This induction was dependent on HRV replication and required NF-kB-mediated signaling. Synergy was lost in the presence of an inhibitor of the p38 MAP kinase pathway. HBE exposed to IL-17C show increased gene expression of CXCL1, CXCL2, NFKBIZ, and TFRC, and release CXCL1 protein, a neutrophil chemoattractant. Knockdown of IL-17C significantly reduced induction of CXCL1 in response to HRV-bacterial coinfection as well as neutrophil chemotaxis. HBE from healthy smokers release less IL-17C than cells from nonsmokers, but cells from COPD patients release significantly more IL-17C compared with either nonsmokers or healthy smokers. These data suggest that IL-17C may contribute to microbial-induced COPD exacerbations by promoting neutrophil recruitment.

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Section: Discussionmentioning

confidence: 88%

Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment

Jamieson

Traves

Kooi

et al. 2019

The Journal of Immunology

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“…For this study, patients with persistent asthma were included, based on the presence of bronchial hyper-responsiveness after methacholine challenges, characteristic asthma symptoms and a doctor's diagnosis of asthma 26 . In parallel, sixteen healthy controls were included with no history of respiratory disease, normal spirometry and absence of bronchial hyperresponsiveness (NORM study 27,28 ). The NORM study was also approved by the Medical Ethical Committee of the University Medical Center Groningen and participants gave their informed consent.…”

Section: Patient Selection and Cd4 + T Cell Isolation From Pbmcs Thementioning

confidence: 99%

“…We reasoned that inflammatory cells may provide a target for WNT5A, explaining the changes in Th2 cytokine expression. Therefore, and to provide translational relevance for our findings, CD4 + T cells obtained from healthy controls (taken from the NORM cohort 27,28 ) and asthmatic patients (taken from the ROORDA cohort 25 ) were cultured in the absence and presence of WNT5A and/or anti-CD3/anti-CD28 to activate the cells and subsequently subjected to bulk RNA sequencing. In our initial studies, libraries prepared out www.nature.com/scientificreports www.nature.com/scientificreports/ of CD4 + T cells from the asthma cohort were used for the RNA sequencing analysis.…”

Section: Induced Wnt5a Expression Increases Production Of Th2-cytokinmentioning

confidence: 99%

Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation

Koopmans

Hesse

Nawijn

et al. 2020

Sci Rep

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Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smoothmuscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4 + T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4 + T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth musclederived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling. Asthma is a heterogeneous disease characterized by chronic inflammation of the large and small airways. More than 200 million people worldwide are estimated to be affected by asthma 1. Asthma is characterized by episodic changes in respiratory symptoms such as breathlessness, wheezing, chest tightness and coughing, reflecting airway hyper-responsiveness (AHR). Apart from this variable component of AHR, asthma is characterized by the development of structural changes in the airways, termed airway remodelling, which contribute to airflow obstruction 2. Airway smooth muscle (ASM) is a central player in the pathology of asthma. Airway smooth muscle thickness correlates with asthma severity and lung function 3. In line with this, bronchial thermoplasty (BT) results in diminished ASM mass in severe asthmatics for up to at least two years 4 , which is associated with improvement in quality of life, and a reduction in symptoms and number of exacerbations 5. ASM cells are major

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“…Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract by inducing a variety gene-expression alterations associated with smoking (8,9); smoking cessation (10); chronic obstructive pulmonary disease (COPD;refs. 11,12); bronchial premalignant lesions (13); and lung cancer (14). There is significant overlap between bronchial and nasal smoking-and lung cancer-associated gene-expression changes (15), suggesting the ability to detect lung disease-related biology throughout the intra-and extra-thoracic airway.…”

Section: Introductionmentioning

confidence: 99%

Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial

Garland

Guillen-Rodriguez

Hsu

et al. 2019

Cancer Prevention Research

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A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, doubleblinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Lowdose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of À4.55 AE 11.52 from baseline 15.44 AE 13.79 ng/mg creatinine for arms combined, P ¼ 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature (P < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.

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Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Cited by 35 publications

References 42 publications

Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment

Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment

Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation

Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial

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