Expression of Stress-Induced Genes in Bronchoalveolar Lavage Cells and Lung Fibroblasts from Healthy and COPD Subjects.

Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized endoplasmic reticulum (ER) in fibroblasts from COPD with different responses to chemical stressors compared to healthy subjects. Here, we aimed to investigate differences in stress-related gene expressions within lung cells from COPD and healthy subjects. Bronchoalveolar lavage (BAL) cells were collected from seven COPD and 35 healthy subjects. Lung fibroblasts were derived from 19 COPD and 24 healthy subjects and exposed to cigarette smoke extract (CSE). Gene and protein expression and cell proliferation were investigated. Compared to healthy subjects, we found lower gene expression of CHOP in lung fibroblasts from COPD subjects. Exposure to CSE caused inhibition of lung fibroblast proliferation in both groups, though the changes in ER stress-related gene expressions (ATF6, IRE1, PERK, ATF4, CHOP, BCL2L1) and genes relating to proteasomal subunits mostly occurred in healthy lung fibroblasts. No differences were found in BAL cells. In this study, we have found that lung fibroblasts from COPD subjects have an atypical ER stress gene response to CSE, particularly in genes related to apoptosis. This difference in response to CSE may be a contributing factor to COPD progression.

Neutrophil phenotypes in bronchial airways differentiate single from dual responding allergic asthmatics.

INTRODUCTION: Allergic asthmatics with both an early (EAR) and a late allergic reaction (LAR) following allergen exposure are termed 'dual responders' (DR), while 'single responders' (SR) only have an EAR. Mechanisms that differentiate DR from SR are largely unknown, particularly regarding the role and phenotypes of neutrophils. Therefore, we aimed to study neutrophils in DR and SR asthmatics. METHODS: Thirty-four allergic asthmatics underwent an inhaled allergen challenge, samples were collected before and up to 24 h post-challenge. Cell differentials were counted from bronchial lavage, alveolar lavage and blood; and tissue neutrophils were quantified in immune-stained bronchial biopsies. Lavage neutrophil nuclei lobe segmentation was used to classify active (1-4 lobes) from suppressive neutrophils (≥5 lobes). Levels of transmigration markers: soluble (s)CD62L and interleukin-1Ra, and activity markers: neutrophil elastase (NE), DNA-histone complex and dsDNA were measured in lavage fluid and plasma. RESULTS: Compared with SR at baseline, DR had more neutrophils in their bronchial airways at baseline, both in the lavage (p = .0031) and biopsies (p = .026) and elevated bronchial neutrophils correlated with less antitransmigratory IL-1Ra levels (r = -0.64). DR airways had less suppressive neutrophils and more 3-lobed (active) neutrophils (p = .029) that correlated with more bronchial lavage histone (p = .020) and more plasma NE (p = .0016). Post-challenge, DR released neutrophil extracellular trap factors in the blood earlier and had less pro-transmigratory sCD62L during the late phase (p = .0076) than in SR. CONCLUSION: DR have a more active airway neutrophil phenotype at baseline and a distinct neutrophil response to allergen challenge that may contribute to the development of an LAR. Therefore, neutrophil activity should be considered during targeted diagnosis and bio-therapeutic development for DR.

Eosinophils-from cradle to grave: An EAACI task force paper on new molecular insights and clinical functions of eosinophils and the clinical effects of targeted eosinophil depletion.

Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti-inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy-driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non-immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non-specific eosinophil-targeting therapies. Despite the overall favourable safety profile of the currently available anti-eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences.

Allergen provocation tests in respiratory research: building on 50†years of experience.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.

Plasma proteome changes linked to late phase response after inhaled allergen challenge in asthmatics.

BACKGROUND: A subset of individuals with allergic asthma develops a late phase response (LPR) to inhaled allergens, which is characterized by a prolonged airway obstruction, airway inflammation and airway hyperresponsiveness. The aim of this study was to identify changes in the plasma proteome and circulating hematopoietic progenitor cells associated with the LPR following inhaled allergen challenge. METHODS: Serial plasma samples from asthmatics undergoing inhaled allergen challenge were analyzed by mass spectrometry and immunosorbent assays. Peripheral blood mononuclear cells were analyzed by flow cytometry. Mass spectrometry data were analyzed using a linear regression to model the relationship between airway obstruction during the LPR and plasma proteome changes. Data from immunosorbent assays were analyzed using linear mixed models. RESULTS: Out of 396 proteins quantified in plasma, 150 showed a statistically significant change 23 h post allergen challenge. Among the most upregulated proteins were three protease inhibitors: alpha-1-antitrypsin, alpha-1-antichymotrypsin and plasma serine protease inhibitor. Altered levels of 13 proteins were associated with the LPR, including increased factor XIII A and decreased von Willebrand factor. No relationship was found between the LPR and changes in the proportions of classical, intermediate, and non-classical monocytes. CONCLUSIONS: Allergic reactions to inhaled allergens in asthmatic subjects were associated with changes in a large proportion of the measured plasma proteome, whereof protease inhibitors showed the largest changes, likely to influence the inflammatory response. Many of the proteins altered in relation to the LPR are associated with coagulation, highlighting potential mechanistic targets for future treatments of type-2 asthma.

A breathing mask attenuates acute airway responses to exercise in sub-zero environment in healthy subjects.

PURPOSE: Cold air exposure is associated with increased respiratory morbidity and mortality. Repeated inhalation of cold and dry air is considered the cause of the high prevalence of asthma among winter endurance athletes. This study assessed whether a heat- and moisture-exchanging breathing device (HME) attenuates airway responses to high-intensity exercise in sub-zero temperatures among healthy subjects. METHODS: Using a randomized cross-over design, 23 healthy trained participants performed a 30-min warm-up followed by a 4-min maximal, self-paced running time trial in - 15 °C, with and without HME. Lung function was assessed pre- and immediately post-trials. Club cell protein (CC-16), 8-isoprostane, and cytokine concentrations were measured in plasma and urine pre- and 60 min post trials. Symptoms were assessed prior to, during, and immediately after each trial in the chamber. RESULTS: HME use attenuated the decrease in forced expiratory volume in 1 s (FEV1) post trials (∆FEV1: mean (SD) HME - 0.5 (1.9) % vs. no-HME - 2.7 (2.7) %, p = 0.002). HME also substantially attenuated the median relative increase in plasma-CC16 concentrations (with HME + 27% (interquartile range 9-38) vs no-HME + 121% (55-162), p < 0.001) and reduced airway and general symptom intensity, compared to the trial without HME. No significant changes between trials were detected in urine CC16, 8-isoprostane, or cytokine concentrations. CONCLUSION: The HME attenuated acute airway responses induced by moderate-to-maximal-intensity exercise in - 15 °C in healthy subjects. Further studies are needed to examine whether this HMEs could constitute primary prevention against asthma in winter endurance athletes.

Cold air exposure at - 15 °C induces more airway symptoms and epithelial stress during heavy exercise than rest without aggravated airway constriction.

PURPOSE: Exposure to cold air may harm the airways. It is unclear to what extent heavy exercise adds to the cold-induced effects on peripheral airways, airway epithelium, and systemic immunity among healthy individuals. We investigated acute effects of heavy exercise in sub-zero temperatures on the healthy airways. METHODS: Twenty-nine healthy individuals underwent whole body exposures to cold air in an environmental chamber at - 15 °C for 50 min on two occasions; a 35-min exercise protocol consisting of a 5-min warm-up followed by 2 × 15 min of running at 85% of VO2max vs. 50 min at rest. Lung function was measured by impulse oscillometry (IOS) and spirometry before and immediately after exposures. CC16 in plasma and urine, and cytokines in plasma were measured before and 60 min after exposures. Symptoms were surveyed pre-, during and post-trials. RESULTS: FEV1 decreased after rest (- 0.10 ± 0.03 L, p < 0.001) and after exercise (- 0.06 ± 0.02 L, p = 0.012), with no difference between trials. Exercise in - 15 °C induced greater increases in lung reactance (X5; p = 0.023), plasma CC16 (p < 0.001) as well as plasma IL-8 (p < 0.001), compared to rest. Exercise induced more intense symptoms from the lower airways, whereas rest gave rise to more general symptoms. CONCLUSION: Heavy exercise during cold air exposure at - 15 °C induced signs of an airway constriction to a similar extent as rest in the same environment. However, biochemical signs of airway epithelial stress, cytokine responses, and symptoms from the lower airways were more pronounced after the exercise trial.

Human Primary Airway Basal Cells Display a Continuum of Molecular Phases from Health to Disease in Chronic Obstructive Pulmonary Disease.

Airway basal cells are crucial for regeneration of the human lung airway epithelium and are believed to be important contributors to chronic obstructive pulmonary disease (COPD) and other lung disorders. To reveal how basal cells contribute to disease and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and NGFR (nerve-growth factor receptor) expression. The basal cell population was found to be molecularly and functionally heterogeneous, in contrast to cultured basal cells. In addition, significant differences were found, such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single-cell RNA sequencing on primary basal cells from healthy donors and patients with Global Initiative for Chronic Obstructive Lung Disease stage IV COPD, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response-related genes GADD45B and AHSA1, together with with genes involved in the response to hypoxia, such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.

Cognitive dysfunction and quality of life during pollen season in children with seasonal allergic rhinitis.

BACKGROUND: Allergic rhinitis often gives rise to impaired quality of life and is believed to also affect cognitive function. We aimed to examine whether cognitive functions were impaired during grass pollen season in symptomatic allergic children and to relate the degree of impairment to quality of life and biomarkers related to stress and inflammation. METHODS: Forty-three grass pollen-allergic children (age 8-17 years) with non-satisfactory effect of medication (antihistamines and nasal steroids daily) during previous seasons were included. In addition, 26 matched non-allergic children were included as controls. Both groups performed cognitive tests (CANTAB) and completed Quality of Life questionnaires outside and during the pollen season. Blood samples were collected and analyzed for stress and inflammatory biomarkers. Pollen level was measured daily. RESULTS: Impaired cognitive function was found in spatial working memory, where the allergic group made more errors compared to the non-allergic group during pollen season, but not off-season. No significant differences could be seen between the allergic group and the controls in the other tests investigating visual memory or attention. Quality of health questionnaires revealed more symptoms and impaired quality of life in allergic compared to non-allergic children, and increased symptoms in allergic children were associated with longer reaction time for simple movement during pollen season. No differences in stress or inflammatory biomarkers could be found between the groups. CONCLUSION: Cognitive function was affected during pollen season in pollen-allergic children, and the more symptoms the allergic children had, the longer the reaction time in the cognitive tests.

Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm.

AIM: Very preterm birth may be associated with lung function impairment later in life. It is not known if this is caused by prematurity per se or by associated perinatal events, such as maternal-foetal inflammation and severity of early neonatal lung disease. We assessed these factors in a prospective cohort of very preterm infants followed from birth to middle school age. METHODS: In 71 infants with a gestational age of median 27.4 (range 23.9-31.7) weeks, pro-inflammatory and modulatory cytokines were measured in umbilical cord blood and in arterial blood sampled at 6, 24 and 72 h after birth, and cumulated cytokine concentrations were calculated as area under the curve (AUC). At median 12.6 (range 12.3-13.5) years of age, pulmonary function testing was done in 53 children. RESULTS: There was a positive correlation between days on mechanical ventilation and AUC for IL-6 (p = 0.001), IL-8 (p = 0.015) and IL-10 (p = 0.006). Infants with bronchopulmonary dysplasia (BPD; n = 32) had higher AUC for the cytokines IL-6, IL-8 and IL-10 than those without BPD (all p < 0.01). Higher levels of AUC for IL-6 at birth correlated with lower forced expiratory volume in 1 s (p = 0.030) and lower mean expiratory flow rate between 25 and 75% of forced vital capacity (p = 0.034). CONCLUSION: Perinatal inflammation, assessed by circulating cytokines in the first three days of life, was associated with BPD and with airway obstruction at 12 years of age.

Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva.

The antimicrobial peptide LL-37 is active against oral bacteria and has been demonstrated to be present in human saliva, but its distribution in different fractions of saliva is not known. LL-37 is formed from its intracellular pro-form, hCAP18, in an extracellular enzymatic reaction catalyzed by proteinase 3 and kallikrein 5. Here, we prepared cell-containing and cell-free fractions of unstimulated human whole saliva by centrifugation after depolymerization of mucins with dithiothreitol, and measured the levels of hCAP18/LL-37 in these fractions using ELISA. Cellular expression of hCAP18/LL-37 was determined by western blotting and immunocytochemistry. The ELISA analyses demonstrated that both cells and cell-free saliva contained hCAP18/LL-37. Western blot analysis of cell-pellet homogenates showed a strong band corresponding to hCAP18 at the correct molecular weight and a weak band corresponding to LL-37. Phase-contrast and light microscopy revealed that the cells consisted of desquamated epithelial cells. These cells expressed cytoplasmic immunoreactivity for hCAP18/LL-37. The peripheral part of the cytoplasm, corresponding to the plasma membrane, was particularly rich in hCAP18/LL-37 immunoreactivity. No immunoreactivity was observed after omission of the primary antibody. We conclude that desquamated epithelial cells of human whole saliva contain antimicrobial hCAP18/LL-37, suggesting that these cells may take part in the innate immune system by harboring and releasing these peptides.

Lung function and pulmonary vascular resistance are not associated in 6-year-old children born extremely preterm.

AIM: Children born preterm are at increased risk of reduced lung function. The aim was to test whether lung function was associated with pulmonary vascular resistance. METHODS: Participants were recruited from a population-based cohort born in 2004-2007. Lung function was assessed with spirometry after administration of a beta2-agonist. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1 ) were determined. Estimations of pulmonary vascular resistance, arterial dimensions, right ventricular wall thickness, sphericity, and systolic (TAPSE) and diastolic functions were performed with echocardiography. Adjusted regression analyses were used to study associations. RESULTS: Sixty-six children (33 boys) born at 22-26 weeks of gestational age (birthweights 460-1134 g) were assessed at a mean age of 6.7 years. Despite large variations in lung function with FVC z-scores ranging from -4.6 to +2.8, there were no associations between lung function and pulmonary arterial pressure, right ventricular structure or function. Children with higher FVC z-scores (r = .52, ß = .55 mm, P = .015) and higher FEV1 z-scores (r = .58, ß = .73 mm, P = .001) exhibited larger pulmonary arteries. CONCLUSION: In children born extremely preterm, lung function was not associated with pulmonary vascular resistance. Routine echocardiographic evaluation of extremely preterm children may not be indicated at age 6.5 years.

Osteopontin protects against pneumococcal infection in a murine model of allergic airway inflammation.

BACKGROUND: In atopic asthma, chronic Th2-biased inflammation is associated with an increased risk of pneumococcal infection. The anionic phosphoglycoprotein osteopontin (OPN) is highly expressed in asthma and has been ascribed several roles during inflammation. This study aimed to investigate whether OPN affects inflammation and vulnerability to pneumococcal infection in atopic asthma. METHODS: House dust mite (HDM) extract was used to induce allergic airway inflammation in both wild-type (Spp1+/+ ) and OPN knockout (Spp1-/- ) C57BL/6J mice, and the airway was then infected with Streptococcus pneumoniae. Parameters reflecting inflammation, tissue injury, and bacterial burden were measured. In addition, samples from humans with allergic asthma were analyzed. RESULTS: Both allergen challenge in individuals with allergic asthma and the intranasal instillation of HDM in mice resulted in increased OPN levels in bronchoalveolar lavage fluid (BALF). More immune cells (including alveolar macrophages, neutrophils, eosinophils, and lymphocytes) and higher levels of proinflammatory cytokines were found in Spp1-/- mice than in Spp1+/+ mice. Moreover, OPN-deficient mice exhibited increased levels of markers reflecting tissue injury. Upon infection with S. pneumoniae, Spp1+/+ mice with allergic airway inflammation had a significantly lower bacterial burden in both BALF and lung tissue than did Spp1-/- mice. Furthermore, Spp1-/- mice had higher levels of cytokines and immune cells in BALF than did Spp1+/+ mice. CONCLUSION: OPN reduces inflammation, decreases tissue injury, and reduces bacterial loads during concurrent pneumococcal infection and allergic airway inflammation in a murine model. These findings suggest that OPN significantly affects vulnerability to pneumococcal infection in atopic asthma.

Toward clinically applicable biomarkers for asthma: An EAACI position paper.

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.

The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers.

Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics.

BACKGROUND: Club cell protein (CC16) is a pneumoprotein secreted by epithelial club cells. CC16 possesses anti-inflammatory properties and is a potential biomarker for airway epithelial damage. We studied the effect of inhaled allergen on pulmonary and systemic CC16 levels. METHODS: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Bronchoscopy with bronchoalveolar lavage (BAL) and brushings was performed before and 24 h after the challenge. CC16 was quantified in BAL and CC16 positive cells and CC16 mRNA in bronchial brushings. CC16 was measured in plasma and urine before and repeatedly after the challenge. Thirty subjects performed a mannitol inhalation challenge prior to the allergen challenge. RESULTS: Compared to baseline, CC16 in plasma was significantly increased in all subjects 0-1 h after the allergen challenge, while CC16 in BAL was only increased in subjects without a late allergic response. Levels of CC16 in plasma and in the alveolar fraction of BAL correlated significantly after the challenge. There was no increase in urinary levels of CC16 post-challenge. Mannitol responsiveness was greater in subjects with lower baseline levels of CC16 in plasma. CONCLUSIONS: The increase in plasma CC16 following inhaled allergen supports the notion of CC16 as a biomarker of epithelial dysfunction.

Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease.

BACKGROUND: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD. METHODS: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype. RESULTS: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes. CONCLUSIONS: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.

Sex differences in asthma in swimmers and tennis players.

BACKGROUND: Elite athletes, independent of sport, have increased risk of developing asthma, but little is known about sex difference among adolescent athletes. OBJECTIVE: To investigate and compare sex-related differences according to symptoms and treatment of asthma, allergy, and health among elite athletes and a reference group. METHODS: Adolescent elite swimmers (n = 101), tennis players (n = 86), and a reference group (n = 1,628) responded to a questionnaire about respiratory symptoms, allergy, health behavior, psychosomatic symptoms, self- esteem, and well-being. The athletes performed a mannitol provocation and a sport-specific exercise provocation. Atopy was assessed by skin prick tests, and fractional exhaled nitric oxide was measured. RESULTS: The females reported more asthma symptoms than the males in both the reference group (29.1% vs 22.3%) and the athlete group (56.4% vs 40.2%). However, no significant differences were found in physician-diagnosed asthma or treatment with inhaled corticosteroids. More female athletes had a positive mannitol provocation result (48.7% vs 35.8% in male athletes), and more female swimmers had a positive exercise provocation result (15.1% vs 7.7% in male swimmers). The females in all groups had more psychosomatic symptoms compared with the respective males, and the males in the reference group reported higher self-esteem and felt more well-being compared with the reference group females. CONCLUSION: Overall, we found a higher prevalence of asthma symptoms in the females. However, the frequency of physician-diagnosed asthma and the prescription of inhaled corticosteroids were the same in both sexes. This finding demonstrates an insufficient diagnosis of asthma in females.

Revisiting the role of the mast cell in asthma.

PURPOSE OF REVIEW: In humans, mast cells are ubiquitously present in tissues adjacent to external environment and consequently have an important sentential role in host defence, homeostasis and repair. Their key role in allergen-mediated conditions has been recognized for many decades already. So far, therapies targeting mast cells offered clinical efficacy in allergic conditions except for asthma. More recently, sophisticated sampling and detection techniques revealed pleiotrophic immunological and functional properties of mast cells in and beyond asthma with potential clinical and management implications. These findings bring back the mast cell as a key player in the field of asthma and warrant a review of the recent literature. RECENT FINDINGS: The heterogeneity of human mast cells has been recognized: MCTC expressing both tryptase and chymase and MCT expressing tryptase only. Apart from this subphenotyping, mast cells may comprise and produce several other mediators and cytokines. Their immunological and functional properties depend on their (co)localization within the human body and can alter under changing conditions (e.g. pathogens, allergens, etc). Recent data revealed a novel mast cell phenotype within the alveolar tissue of patients with asthma. Increasing evidence shows a key role for alveolar mast cells in the pathophysiology of viral respiratory infections and in the development of allergen sensitization and asthma. SUMMARY: Increasing evidence points toward a key role of mast cells in the pathophysiology and pathogenesis of asthma and this warrants further investigation and the development of effective targeted therapies.