Systemic IL-26 correlates with improved asthma control in children sensitized to dog allergen.

BACKGROUND: Interleukin (IL)-26 is produced by T helper type 17 (Type 17) cells and exerts immunomodulatory plus antimicrobial effects. Previous studies show that local IL-26 concentrations in the airways are higher in patients with uncontrolled than in those with controlled asthma, and that this intriguing cytokine bears biomarker potential. Here, we determined how systemic IL-26 relates to allergen sensitization, asthma severity, and to IL-17 A in children. METHODS: Serum samples were obtained from children with (n = 60) and without (n = 17) sensitization to dog allergen, and IL-26 and IL-17 A protein concentrations were measured using ELISA. Self-reported history, including medication use and validated symptom-based questionnaire scores, was recorded. RESULTS: The serum concentrations of IL-26 were enhanced in allergen-sensitized subjects and correlated with those of IL-17 A in a positive manner. However, the IL-26 concentrations did not markedly differ between allergen-sensitized subjects with and without asthma, eczema, allergic rhinitis, or a history of food allergy. Notably, IL-26 concentrations correlated with increasing Asthma Control Test (ACT) scores in a positive manner and with inhaled corticosteroid in a negative manner, amongst sensitized subjects with asthma. Moreover, subjects with asthma requiring ≥ 1 course of oral corticosteroids in the preceding 12 months had decreased IL-26 concentrations. CONCLUSION: This study forwards evidence that systemic IL-26, just like IL-17 A, is involved in allergen sensitization among children. The association of systemic IL-26 with improved asthma control is compatible with the cellular sources being recruited into the airways in severe asthma, which supports that this kinocidin bears potential as a biomarker and therapeutic target.

Protein N-glycosylation in the bronchoalveolar space differs between never-smokers and long-term smokers with and without COPD.

Chronic obstructive pulmonary disease (COPD) kills millions of people annually and patients suffering from exacerbations of this disorder display high morbidity and mortality. The clinical course of COPD is associated with dysbiosis and infections, but the underlying mechanisms are poorly understood. Glycosylation of proteins play roles in regulating interactions between microbes and immune cells, and knowledge on airway glycans therefore contribute to the understanding of infections. Furthermore, glycans have biomarker potential for identifying smokers with enhanced risk for developing COPD as well as COPD subgroups. Here, we characterized the N-glycosylation in the lower airways of healthy never-smokers (HNS, n = 5) and long-term smokers (LTS) with (LTS+, n = 4) and without COPD (LTS-, n = 8). Using mass spectrometry, we identified 57 highly confident N-glycan structures whereof 38 oligomannose, complex, and paucimannose type glycans were common to BAL samples from HNS, LTS- and LTS+ groups. Hybrid type N-glycans were identified only in the LTS+ group. Qualitatively and quantitatively, HNS had lower inter-individual variation between samples compared to LTS- or LTS+. Cluster analysis of BAL N-glycosylation distinguished LTS from HNS. Correlation analysis with clinical parameters revealed that complex N-glycans were associated with health and absence of smoking whereas oligomannose N-glycans were associated with smoking and disease. The N-glycan profile from monocyte-derived macrophages differed from the BAL N-glycan profiles. In conclusion, long-term smokers display substantial alterations of N-glycosylation in the bronchoalveolar space, and the hybrid N-glycans identified only in long-term smokers with COPD deserve to be further studied as potential biomarkers.

Increased cytotoxic T-cells in the airways of adults with former bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) in preterm-born infants is a risk factor for chronic airway obstruction in adulthood. Cytotoxic T-cells are implicated in COPD, but their involvement in BPD is not known. OBJECTIVES: To characterise the distribution of airway T-cell subsets in adults with a history of BPD. METHODS: Young adults with former BPD (n=22; median age 19.6 years), age-matched adults born preterm (n=22), patients with allergic asthma born at term (n=22) and healthy control subjects born at term (n=24) underwent bronchoalveolar lavage (BAL). T-cell subsets in BAL were analysed using flow cytometry. RESULTS: The total number of cells and the differential cell counts in BAL were similar among the study groups. The percentage of CD3+CD8+ T-cells was higher (p=0.005) and the proportion of CD3+CD4+ T-cells was reduced (p=0.01) in the BPD group, resulting in a lower CD4/CD8 ratio (p=0.007) compared to the healthy controls (median 2.2 versus 5.3). In BPD and preterm-born study subjects, both CD3+CD4+ T-cells (rs=0.38, p=0.03) and CD4/CD8 ratio (rs=0.44, p=0.01) correlated positively with forced expiratory volume in 1 s (FEV1). Furthermore, CD3+CD8+ T-cells were negatively correlated with both FEV1 and FEV1/forced vital capacity (rs= -0.44, p=0.09 and rs= -0.41, p=0.01, respectively). CONCLUSIONS: Young adults with former BPD have a T-cell subset pattern in the airways resembling features of COPD. Our findings are compatible with the hypothesis that CD3+CD8+ T-cells are involved in mechanisms behind chronic airway obstruction in these patients.

Involvement of IL-26 in bronchiolitis obliterans syndrome but not in acute rejection after lung transplantation.

BACKGROUND:  The main long-term complication after lung transplantation is bronchiolitis obliterans syndrome (BOS), a deadly condition in which neutrophils may play a critical pathophysiological role. Recent studies show that the cytokine interleukin IL-26 can facilitate neutrophil recruitment in response to pro-inflammatory stimuli in the airways. In this pilot study, we characterized the local involvement of IL-26 during BOS and acute rejection (AR) in human patients. METHOD:  From a biobank containing bronchoalveolar lavage (BAL) samples from 148 lung transplant recipients (LTR), clinically-matched patient pairs were identified to minimize the influence of clinical confounders. We identified ten pairs (BOS/non-BOS) with BAL samples harvested on three occasions for our longitudinal investigation and 12 pairs of patients with and without AR. The pairs were matched for age, gender, preoperative diagnosis, type of and time after surgery. Extracellular IL-26 protein was quantified in cell-free BAL samples using an enzyme-linked immunosorbent assay. Intracellular IL-26 protein in BAL cells was determined using immunocytochemistry (ICC) and flow cytometry. RESULTS:  The median extracellular concentration of IL-26 protein was markedly increased in BAL samples from patients with BOS (p < 0.0001) but not in samples from patients with AR. Intracellular IL-26 protein was confirmed in alveolar macrophages and lymphocytes (through ICC and flow cytometry) among BAL cells obtained from BOS patients. CONCLUSIONS:  Local IL-26 seems to be involved in BOS but not AR, and macrophages as well as lymphocytes constitute cellular sources in this clinical setting. The enhancement of extracellular IL-26 protein in LTRs with BOS warrants further investigation of its potential as a target for diagnosing, monitoring, and treating BOS.

Mucin Binding to Moraxella catarrhalis during Airway Inflammation Is Dependent on Sialic Acid.

Chronic obstructive pulmonary disease (COPD) is associated with colonization by bacterial pathogens and repeated airway infections, leading to exacerbations and impaired lung function. The highly glycosylated mucins in the mucus lining the airways are an important part of the host defense against pathogens. However, mucus accumulation can contribute to COPD pathology. Here, we examined whether inflammation is associated with glycosylation changes that affect interactions between airway mucins and pathogens. We isolated mucins from lower airway samples (n = 4-9) from long-term smokers with and without COPD and from never-smokers. The most abundant terminal glycan moiety was N-acetylneuraminic acid (Neu5Ac) among smokers with and without COPD and N-acetyl-hexoseamine among never-smokers. Moraxella catarrhalis bound to MUC5 mucins from smokers with and without COPD. M. catarrhalis binding correlated with inflammatory parameters and Neu5Ac content. M. catarrhalis binding was abolished by enzymatic removal of Neu5Ac. Furthermore, M. catarrhalis bound to α2,6 sialyl-lactose, suggesting that α2,6 sialic acid contributes to M. catarrhalis binding to mucins. Furthermore, we detected more M. catarrhalis binding to mucins from patients with pneumonia than to those from control subjects (n = 8-13), and this binding correlated with C-reactive protein and Neu5Ac levels. These results suggest a key role of inflammation-induced Neu5Ac in the adhesion of M. catarrhalis to airway mucins. The inflammation-induced ability of MUC5 mucins to bind M. catarrhalis is likely a host defense mechanism in the healthy lung, although it cannot be excluded that impaired mucociliary clearance limits the effectiveness of this defense in patients with COPD.

IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (n = 23) of long-term smokers with and without COPD in vivo and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components in vitro. Pulmonary macrophages were stimulated with IL-36 cytokines in vitro, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components in vitro. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. In vitro, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.

Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort.

We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.

Assessment of chronic bronchitis and risk factors in young adults: results from BAMSE.

BACKGROUND: Chronic bronchitis is associated with substantial morbidity among elderly adults, but little is known about its prevalence and risk factors in young adults. Our aim was to assess the prevalence and early-life risk factors for chronic bronchitis in young adults. METHODS: Questionnaire data and clinical measures from the 24-year follow-up of the Swedish BAMSE (Child (Barn), Allergy, Milieu, Stockholm, Epidemiological) cohort were used. We assessed chronic bronchitis (CB) as the combination of cough and mucus production in the morning during winter. Environmental and clinical data from birth and onwards were used for analyses of risk factors. RESULTS: At the 24-year follow-up, 75% (n=3064) participants completed the questionnaire and 2030 performed spirometry. The overall prevalence of CB was 5.5% (n=158) with similar estimates in males and females. 49% of CB cases experienced more than three self-reported respiratory infections in the past year compared to 18% in non-CB subjects (p<0.001), and 37% of cases were current smokers (versus 19% of non-CB cases). Statistically significant lower post-bronchodilator forced expiratory volume in 1 s/forced vital capacity were observed in CB compared to non-CB subjects (mean z-score -0.06 versus 0.13, p=0.027). Daily smoking (adjusted (a)OR 3.85, p<0.001), air pollution exposure (black carbon at ages 1-4 years aOR 1.71 per 1 µg·m-3 increase, p=0.009) and exclusive breastfeeding for ≤4 months (aOR 0.66, p=0.044) were associated with CB. CONCLUSION: Chronic bronchitis in young adults is associated with recurrent respiratory infections. Besides smoking, our results support the role of early-life exposures, such as air pollution and exclusive breastfeeding, for respiratory health later in life.

Heparin-binding protein in lower airway samples as a biomarker for pneumonia.

OBJECTIVES: Ventilator-associated pneumonia (VAP) is difficult to diagnose using clinical criteria and no biomarkers have yet been proved to be sufficiently accurate. The use of the neutrophil-derived Heparin-binding protein (HBP) as a biomarker for pneumonia was investigated in this exploratory case-control study in two intensive care units at a tertiary referral hospital. METHODS: Patients with clinical signs of pneumonia were recruited and bronchoalveolar lavage fluid (BALF) or bronchial wash (BW) samples were collected. Mechanically ventilated and lung healthy subjects were recruited as controls. HBP was measured with enzyme-linked immunosorbent assay. RESULTS: BALF was collected from 14 patients with pneumonia and 14 healthy controls. Median HBP in BALF pneumonia samples was 14,690 ng/ml and controls 16.2 ng/ml (p < 0.0001). BW was collected from 10 pneumonia patients and 10 mechanically ventilated controls. Median HBP in BW pneumonia was 9002 ng/ml and controls 7.6 ng/ml (p < 0.0001). CONCLUSIONS: These data indicate that HBP concentrations is significantly higher in lower airway samples from patients with pneumonia than control subjects and is a potentially useful biomarker for diagnosis of VAP.

Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden.

OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disorder. Next to tobacco smoking, occupational exposure is the most important risk factor for COPD in high-income countries. To enable preventative measures, more knowledge is needed on which specific occupational exposures that are related to risk of developing COPD in men and women. METHODS: A population-based cohort was formed from subjects responding to the Stockholm Public Health Surveys in 2002, 2006, and 2010, followed up until 2014. The dataset was linked to a quantitative job exposure matrix via occupational titles from the 1990 nation-wide Population and housing census. We identified COPD among subjects having medication for COPD and/or reporting a physician's diagnosis of COPD. The gender-specific risks to develop COPD from occupational particle-exposure were estimated by proportional hazards regression model, adjusted for age and individual data on tobacco-smoking. RESULTS: Men exposed to respirable crystalline silica (RCS) (HR 1.46, CI 1.13-1.90), gypsum and insulation material (HR 1.56, CI 1.18-2.05), diesel exhaust (HR 1.18, CI 0.99-1.41) and high levels of particles from asphalt/bitumen (HR 1.71, CI 1.06-2.76) as well as welding fumes (HR 1.57, CI 1.12-2.21) had an increased smoking-adjusted risk for developing COPD. An increased risk was also observed among women highly exposed to various organic particles from soil, leather, plastic, soot, animal, textile, flour (HR 1.53, CI 1.15-2.04). Furthermore, a significant positive exposure-response trend was found among men exposed to RCS, iron dust, gypsum and insulation material, and diesel exhaust. A tendency towards an exposure-response relationship was also seen among both men and women exposed to welding fumes and various organic particles, and among men exposed to particles from asphalt/bitumen. The population attributable fraction for COPD from occupational exposure to particles was 10.6% among men and 6.1% among women. CONCLUSIONS: This study indicates an increased smoking-adjusted risk of developing of COPD due to occupational exposure to particles. A positive exposure-response relationship was found for RCS, gypsum and insulation, diesel exhaust, and welding fumes. Also, exposure to high levels of asphalt/bitumen and various organic particles was associated with a higher risk for COPD. Reduction of these exposures in the work environment are important to prevent future cases of COPD. More studies are needed to investigate exposure-response relationships further, but this study indicates that the European occupational exposure limit (OEL) for RCS needs to be re-evaluated.

Increased MUC1 plus a larger quantity and complex size for MUC5AC in the peripheral airway lumen of long-term tobacco smokers.

There is little information on mucins versus potential regulatory factors in the peripheral airway lumen of long-term smokers with (LTS+) and without (LTS-) chronic obstructive pulmonary disease (COPD). We explored these matters in bronchoalveolar lavage (BAL) samples from two study materials, both including LTS+ and LTS- with a very similar historic exposure to tobacco smoke, and healthy non-smokers (HNSs; n=4-20/group). Utilizing slot blot and immunodetection of processed (filtered and centrifuged), as well as unprocessed BAL samples from one of the materials, we compared the quantity and fraction of large complexes of mucins. All LTS displayed an enhanced (median) level of MUC5AC compared with HNS. LTS- displayed a higher level of large MUC5AC complexes than HNS while LTS+ displayed a similar trend. In all LTS, total MUC5AC correlated with blood leukocytes, BAL neutrophil elastase and net gelatinase activity. Large mucin complexes accounted for most MUC5B, without clear group differences. In all LTS, total MUC5B correlated with total MUC5AC and local bacteria. In the same groups, large MUC5B complexes correlated with serum cotinine. MUC1 was increased and correlated with BAL leukocytes in all LTS whereas MUC2 was very low and without clear group differences. Thus, the main part of MUC5AC and MUC5B is present as large complexes in the peripheral airway lumen and historic as well as current exposure to tobacco smoke emerge as potential regulatory factors, regardless of COPD per se. Bacteria, leukocytes and proteinases also constitute potential regulatory factors, of interest for future therapeutic strategies.

Long-term dietary fiber intake and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.

PURPOSE: Until now, only two prospective cohort studies have investigated dietary fiber intake in relation to risk of chronic obstructive pulmonary disease (COPD), but neither examined long-term fiber intake. Both studies reported that total fiber intake was associated with decreased COPD risk; however, results for specific fiber sources were inconsistent. Thus, we prospectively evaluated the association between baseline and long-term intake of dietary fiber and COPD risk in a population-based prospective cohort of 35,339 Swedish women. METHODS: Dietary fiber intake was assessed in 1987 and 1997 with a food frequency questionnaire. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During follow-up (2002-2014), 1557 COPD cases were identified via linkage to the Swedish National Patient Register. Long-term high dietary fiber intake (≥ 26.5 vs. < 17.6 g/day) was associated with a 30% (95% CI 17-41%) lower risk of COPD. For specific fiber sources, cereal (≥ 16.3 vs. < 9.4 g/day; HR 0.67, 95% CI 0.55-0.81) and fruit fiber (≥ 7.6 vs. < 2.6 g/day; HR 0.65, 95% CI 0.5-0.81), but not vegetable fiber intake (≥ 5.4 vs. < 2.2 g/day; HR 1.03, 95% CI 0.81-1.28) were associated with lower COPD risk. Current and ex-smokers with low long-term total fiber intake (< 17.6 g/day) compared to never smokers with high intake (≥ 26.5 g/day) had a 33-fold (95% CI 23.6-46.6) and tenfold (95% CI 7.0-16.3), respectively, higher risk of COPD. CONCLUSIONS: Our findings indicate that high fiber intake is a modifiable lifestyle factor which may decrease COPD risk primarily in current and ex-smokers.

Alcohol Consumption and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.

Studies indicate an inverse association between moderate alcohol consumption and chronic inflammatory diseases; however, the association between alcohol consumption and chronic obstructive pulmonary disease (COPD) incidence has not been widely studied. We investigated the associations of total alcohol consumption and intake of specific alcoholic beverages with risk of COPD in a population-based prospective cohort study, the Cohort of Swedish Men (n = 44,254). Alcohol consumption was assessed with a self-administered questionnaire in 1997. During follow-up (1998-2014), 2,177 COPD cases were ascertained. Moderate alcohol consumption was associated with the lowest risk of COPD. A J-shaped association was observed for ethanol consumption (P for nonlinearity = 0.003) and beer consumption (P for nonlinearity < 0.001); for wine consumption, a U-shaped association was observed (P for nonlinearity < 0.001). Defining a "standard drink" as 12 g of ethanol, the multivariable-adjusted hazard ratios were 0.77 (95% confidence interval (CI): 0.66, 0.90) and 0.92 (95% CI: 0.81, 1.05) for beer consumption of 4.1-6.0 and >6.0 standard drinks/week (SDW) versus <1.0 SDW, respectively; 0.80 (95% CI: 0.69, 0.93) and 1.00 (95% CI: 0.83, 1.21) for wine consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively; and 1.10 (95% CI: 0.98, 1.24) and 1.20 (95% CI: 0.99, 1.44) for liquor consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively. In conclusion, our findings suggest that moderate beer and wine consumption, but not liquor consumption, may decrease risk of COPD. Additional studies are needed to confirm these associations.

Pulmonary outcomes in adults with a history of Bronchopulmonary Dysplasia differ from patients with asthma.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a risk factor for respiratory disease in adulthood. Despite the differences in underlying pathology, patients with a history of BPD are often treated as asthmatics. We hypothesized that pulmonary outcomes and health-related quality of life (HRQoL) were different in adults born preterm with and without a history of BPD compared to asthmatics and healthy individuals. METHODS: We evaluated 96 young adults from the LUNAPRE cohort ( clinicaltrials.gov/ct2/show/NCT02923648 ), including 26 individuals born preterm with a history of BPD (BPD), 23 born preterm without BPD (preterm), 23 asthmatics and 24 healthy controls. Extensive lung function testing and HRQoL were assessed. RESULTS: The BPD group had more severe airway obstruction compared to the preterm-, (FEV1- 0.94 vs. 0.28 z-scores; p ≤ 0.001); asthmatic- (0.14 z-scores, p ≤ 0.01) and healthy groups (0.78 z-scores, p ≤ 0.001). Further, they had increased ventilation inhomogeneity compared to the preterm- (LCI 6.97 vs. 6.73, p ≤ 0.05), asthmatic- (6.75, p = 0.05) and healthy groups (6.50 p ≤ 0.001). Both preterm groups had lower DLCO compared to healthy controls (p ≤ 0.001 for both). HRQoL showed less physical but more psychological symptoms in the BPD group compared to asthmatics. CONCLUSIONS: Lung function impairment and HRQoL in adults with a history of BPD differed from that in asthmatics highlighting the need for objective assessment of lung health.

Long-term unprocessed and processed red meat consumption and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.

PURPOSE: Limited studies have examined red meat consumption in relation to risk of chronic obstructive pulmonary disease (COPD), and none have examined the impact of long-term diet on COPD risk. We sought to investigate the association between long-term red meat consumption and risk of COPD. METHODS: The population-based prospective Swedish Mammography Cohort included 34,053 women, aged 48-83 years, followed for the current analyses from 2002 to 2014. Unprocessed and processed red meat consumption was assessed with a self-administered questionnaire in 1987 and 1997. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a mean follow-up of 11.6 years (2002-2014; 393,831 person-years), 1488 COPD cases were ascertained via linkage to the Swedish health registers. A positive association between long-term processed red meat (average from 1987 to 1997) and risk of COPD was observed. In contrast, no association was observed with unprocessed red meat with corresponding HRs of 1.36 (95% CI 1.03-1.79) for processed and 0.87 (95% CI 0.74-1.02) for unprocessed red meat among women who consumed ≥ 50 g/day compared to < 25 g/day. The observed association with processed meat was confined to ex-smokers (P for interaction = 0.30); women consuming of ≥ 50 g/day of processed meat had a 2.3-fold (95% CI 1.24-4.12) higher risk of COPD than those consuming < 25 g/day. No similar associations were observed among current or never smokers. CONCLUSION: In this prospective cohort of women with moderate red meat consumption, long-term processed red meat consumption was associated with an increased risk of COPD particularly among ex-smokers.

Dietary Fiber Intake and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.

BACKGROUND: The limited literature suggests that dietary fiber intake from whole grains, fruits, and vegetables is negatively associated with chronic obstructive pulmonary disease (COPD) via fiber's anti-inflammatory properties. Therefore, we investigated the association between total fiber and fiber sources and risk of COPD in the population-based prospective Cohort of Swedish Men (45,058 men, ages 45-79 years) with no history of COPD at baseline. METHODS: Dietary fiber intake was assessed with a self-administered questionnaire in 1997 and was energy adjusted using the residual method. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) adjusted for potential confounders. RESULTS: During a mean follow-up of 13.1 years (1998-2012), 1,982 incident cases of COPD were ascertained via linkage to the Swedish health registers. A strong inverse association between total fiber intake (≥36.8 vs. <23.7 g/day) and COPD was observed in current smokers (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.43, 0.67) and ex-smokers (HR = 0.62; 95% CI = 0.50, 0.78) but not in never smokers (HR = 0.93; 95% CI = 0.60, 1.45; P interaction = 0.04). For cereal fiber, HRs for highest versus lowest quintile were 0.62 (95% CI = 0.51, 0.77; P trend < 0.001) in current smokers and 0.66 (95% CI = 0.52, 0.82; P trend < 0.001) in ex-smokers; for fruit fiber, the HR was 0.65 (95% CI = 0.52, 0.81; P trend < 0.001) in current smokers and 0.77 (95% CI = 0.61, 0.98; P trend = 0.17) in ex-smokers; and for vegetable fiber, it was 0.71 (95% CI = 0.57, 0.88; P trend = 0.003) in current smokers and 0.92 (95% CI = 0.71, 1.19; P trend = 0.48) in ex-smokers. CONCLUSIONS: Our findings indicate that high fiber intake was inversely associated with COPD incidence in men who are current or ex-smokers.

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.

Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines.

Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro, and exploring the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airway structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.

Fruit and vegetable consumption and risk of COPD: a prospective cohort study of men.

BACKGROUND: Antioxidants present in fruits and vegetables may protect the lung from oxidative damage and prevent COPD. AIMS: To determine the association between fruit and vegetable consumption and risk of COPD by smoking status in men. METHODS: The population-based prospective Cohort of Swedish Men included 44 335 men, aged 45-79 years, with no history of COPD at baseline. Fruit and vegetable consumption was assessed with a self-administered questionnaire. RESULTS: During a mean follow-up of 13.2 years, 1918 incident cases of COPD were ascertained. A strong inverse association between total fruit and vegetable consumption and COPD was observed in smokers but not in never-smokers (p-interaction=0.02). The age-standardised incidence rate per 100 000 person-years in the lowest quintile (<2 servings/day) of total fruit and vegetable consumption was 1166 in current smokers and 506 in ex-smokers; among those in the highest quintile (≥5.3 servings/day), 546 and 255 per 100 000 person-years, respectively. The multivariable HR of COPD comparing extreme quintiles of total fruit and vegetable consumption was 0.60 (95% CI 0.47 to 0.76, p-trend <0.0001) in current smokers and 0.66 (95% CI 0.51 to 0.85, p-trend=0.001) in ex-smokers. Each one serving per day increment in total fruit and vegetable consumption decreased risk of COPD significantly by 8% (95% CI 4% to 11%) in current smokers and by 4% (95% CI 0% to 7%) in ex-smokers. CONCLUSIONS: These results indicate that high consumption of fruits and vegetables is associated with reduced COPD incidence in both current and ex-smokers but not in never-smokers.

Consumption of Unprocessed and Processed Red Meat and the Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.

Consumption of both processed and unprocessed red meat has been associated with a higher risk of major chronic diseases. However, only processed meat consumption has been studied in relation to chronic obstructive pulmonary disease (COPD). Therefore, we endeavored to determine the association between the risk of COPD and consumption of processed and unprocessed red meat while taking into account smoking status. The population-based prospective Cohort of Swedish Men included 43,848 men who were 45-79 years of age and had no history of COPD or cancer at baseline. Meat consumption was assessed using a self-administered questionnaire in 1997. During 13.2 years of follow-up, 1,909 COPD cases were ascertained. Consumption of processed meat was associated with risk of COPD: Compared with men who consumed less than 25 g/day of processed meat, men who consumed 75 g/day or more had a multivariable-adjusted hazard ratio of 1.21 (95% confidence interval: 1.02, 1.44; P for trend = 0.03). The positive association was confined to current smokers (P for interaction = 0.003); among smokers who consumed 75 g/day or more of processed red meat, the hazard ratio was 1.26 (95% confidence interval: 1.00, 1.60) when compared with persons who consumed less than 25 g/day. Consumption of unprocessed red meat was not associated with COPD incidence. Findings from this prospective study indicate that high consumption of processed red meat is associated with an increased COPD risk among smokers.