Eef D. Telenga

Obesity in asthma: more neutrophilic inflammation as a possible explanation for a reduced treatment response

The incidence of asthma and obesity is increasing worldwide, and reports suggest that obese patients have more severe asthma. We investigated whether obese asthma patients have more severe airway obstruction and airway hyper‐responsiveness and a different type of airway inflammation than lean asthmatics. Furthermore, we assessed the effect of obesity on corticosteroid treatment response.

Untargeted Lipidomic Analysis in Chronic Obstructive Pulmonary Disease. Uncovering Sphingolipids

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, such as COPD. OBJECTIVES 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 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 More than 1,500 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 with 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. Twenty (glyco)sphingolipids and six tobacco-related compounds were higher expressed in smokers without COPD compared with 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 is higher in smokers with COPD compared with smokers without COPD. Considering their potential biologic properties, they may play a role in the pathogenesis of COPD.

Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells

Background 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. Methods 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)). Results 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. Conclusions 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.

Inhaled corticosteroids in chronic obstructive pulmonary disease: a review.

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airflow obstruction and a progressive lung function decline. Although widely used, the efficacy of inhaled corticosteroids (ICS) in the treatment of COPD remains a matter of debate. Areas covered in this review: This article reviews the evidence about the effects of inhaled corticosteroids in the treatment of COPD. What the reader will gain: Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. Based on these findings, it was concluded that the use of ICS did not influence the natural course of COPD. However, this conclusion has been challenged by two subsequent studies, TORCH and GLUCOLD, which both showed a reduction in lung-function decline over time with the use of ICS. These two studies indicate that ICS might indeed influence the natural course of the disease, at least in a subgroup of COPD patients. Take home message: Further studies are needed to identify which individuals have a favorable short- and long-term response to ICS treatment.

Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics

BackgroundIt has been suggested that smoking asthmatics benefit less from corticosteroid treatment than never-smoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment.MethodsWe analyzed FEV1, PC20 methacholine and PC20 AMP, (differential) cell counts in sputum and blood in ex-, current- and never-smokers at baseline (n=114), after 2-week treatment with fluticasone 500 or 2000 μg/day (n=76) and after 1-year treatment with fluticasone 500 μg/day or a variable dose of fluticasone based on a self-management plan (n=64).ResultsA total of 114 patients were included (29 ex-, 30 current- and 55 never-smokers. At baseline, ex- and current-smokers had less eosinophils in sputum and blood than never-smokers. Blood neutrophil counts were higher in current- than in never-smokers. A higher number of cigarettes smoked daily was associated with lower blood and sputum eosinophils. After 2-week ICS treatment, FEV1 %predicted improved less in current-smokers than never-smokers (2.4% versus 8.1%, p=0.010) and ex-smokers tended to improve less than never-smokers (4.1%, p=0.067). In contrast, no differences in ICS treatment response in lung function or inflammatory cells were found between the three groups after 1 year.ConclusionsEx- and current-smokers have less eosinophils and more neutrophils in their sputum and blood than never-smokers. Although ex- and current-smokers have a reduced short-term corticosteroid treatment response, we did not find a difference in their long-term treatment response.

Small airways in asthma: their independent contribution to the severity of hyperresponsiveness

To the Editor: Bronchial hyperresponsiveness (BHR), i.e. increased narrowing of the airways after exposure to non-allergic stimuli, is a hallmark of asthma. BHR is a risk factor for asthma development and, additionally, a marker of worse disease outcome in asthma [1, 2]. It is generally acknowledged that obstruction of the large airways due to inflammation and remodelling contributes to more severe BHR. This is plausible, given that BHR is expressed as the concentration or dose of a stimulus that induces a 20% fall in forced expiratory volume in 1 s (FEV1). Recent studies suggest that asthmatics with BHR have more severe small airways obstruction [3, 4]. However, little is known about the converse, i.e. the association between small airways obstruction and the severity of BHR. Our aim was to assess: 1) whether asthma patients with small airways obstruction express more severe BHR than those without small airways obstruction; and 2) whether small airways obstruction is associated with more severe BHR independently of FEV1. We analysed data from patients with mild-to-moderate asthma who were included in a previously published study on inhaled corticosteroids (ICS) in primary care [5]. All subjects underwent spirometry before and after 1 mg terbutaline, measuring FEV1, forced vital capacity (FVC) and mean expiratory flow at 50% of FVC (MEF50). BHR was assessed using a histamine challenge test, measuring the provocative dose causing a 20% fall in FEV1 (PD20) (histamine). All patients were hyperresponsive to histamine (PD …

Less small airway dysfunction in asymptomatic bronchial hyperresponsiveness than in asthma

Bronchial hyperresponsiveness (BHR) can be present in subjects without any respiratory symptoms. Little is known about the role of the small airways in asymptomatic subjects with BHR.

Advanced glycation end products in the skin are enhanced in COPD

BACKGROUND Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity. METHODS 202 mild-to-very-severe COPD patients and 83 old (40-75 years) and 110 young (18-40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co-morbidities and lung function values were obtained. RESULTS COPD patients (FEV₁=55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p<0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV₁/FVC, MEF₅₀/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p<0.05). CONCLUSIONS SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD.

Budesonide and fluticasone propionate differentially affect the airway epithelial barrier

BackgroundCOPD patients have a higher risk of pneumonia when treated with fluticasone propionate (FP) than with placebo, and a lower risk with budesonide (BUD). We hypothesized that BUD and FP differentially affect the mucosal barrier in response to viral infection and/or cigarette smoke.MethodsWe assessed protective effects of equivalent concentrations of BUD and FP on cytokine production and barrier function (electrical resistance) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) upon exposure to viral mimetic poly-(I:C) and/or cigarette smoke extract (CSE) or epidermal growth factor (EGF).ResultsBUD and FP were equally effective in suppressing poly-(I:C)- and/or CSE-induced IL-8 secretion in 16HBE and PBECs. Poly-(I:C) substantially decreased electrical resistance in 16HBE cells and both BUD and FP fully counteracted this effect. However, FP hardly affected 16HBE barrier dysfunction induced by CSE with/without poly-(I:C), whereas BUD (16 nM) provided full protection, an effect likely mediated by affecting EGFR-downstream target GSK-3β. Similarly, BUD, but not FP, significantly improved CSE-induced barrier dysfunction in PBECs. Finally, BUD, but not FP, exerted a modest but significant protective effect against Streptococcus Pneumoniae-induced barrier dysfunction, and BUD, but not FP, prevented cellular adhesion and/or internalization of these bacteria induced by poly-(I:C) in 16HBE.ConclusionsCollectively, both BUD and FP efficiently control epithelial pro-inflammatory responses and barrier function upon mimicry of viral infection. Of potential clinical relevance, BUD more effectively counteracted CSE-induced barrier dysfunction, reinforcing the epithelial barrier and potentially limiting access of pathogens upon smoking in vivo.

Shifted T-cell polarisation after agricultural dust exposure in mice and men

Rationale A low prevalence of asthma and atopy has been shown in farmers and agricultural workers. However, in these workers, a higher prevalence of respiratory symptoms has been reported, in which T helper 1 (Th1) and/or Th17 responses may play a role. Aim We investigated the effect of exposure to dust extracts (DEs) from different farms on airway inflammation and T-cell polarisation in a mouse model and assessed T-cell polarisation in agricultural workers from the same farms. Methods DEs were prepared from settled dust collected at cattle and pig farms and bulb and onion industries. Mice were exposed to phosphate-buffered saline (PBS), DEs, house dust mite (HDM) or HDM+DE via nasal instillation, four times per week during 5 weeks. Hyperresponsiveness, airway inflammation, IgE levels and T-cell polarisation were assessed. Th-cell and T cytotoxic (Tc)-cell subsets were investigated in peripheral blood samples from 33 agricultural workers and 9 non-exposed controls. Results DEs induced interleukin(IL)-17, IL-1β and IL-6 in mouse lung homogenates. DE-exposed mice had more mixed inflammatory infiltrates in the lungs, and more neutrophils compared with PBS-exposed mice. DEs protected against the HDM-induced Th2 response and methacholine hyperresponsiveness. Interestingly, occupationally exposed humans had higher frequencies of Th cells spontaneously expressing IL-17 and interferon γ compared with controls. Conclusion Chronic exposure to different types of farm dust induces a Th/Tc-17 inflammatory response in mice and agricultural workers. This may contribute to the low prevalence of Th2-related diseases but may constitute a risk for other chronic respiratory diseases.