Urokinase‐type plasminogen activator system and human cationic antimicrobial protein 18 in serum and induced sputum of patients with chronic obstructive pulmonary disease

Background and objective: There is increasing evidence that the innate immune system plays an important role in the pathogenesis of COPD. The objective of this study was to quantify several innate immune biomarkers in serum and induced sputum of COPD patients, and healthy non‐smokers and smokers. Methods: Serum and induced sputum levels of urokinase‐type plasminogen activator (uPA), urokinase‐type plasminogen activator receptor (uPAR), urokinase‐type plasminogen activator inhibitor (PAI‐1) and human cationic antimicrobial protein 18 (CAP18) were measured by ELISA, in 13 patients with stage I or stage II COPD (COPD I + II), 15 patients with stage III or stage IV COPD (COPD III + IV), 18 healthy non‐smokers and 14 healthy smokers. In addition, membrane‐bound uPAR in peripheral blood and induced sputum was assessed by flow cytometry. Results: Levels of uPAR, PAI‐1 and CAP18 were elevated in induced sputum of COPD I + II and COPD III + IV patients, compared with healthy non‐smokers (P < 0.05) and healthy smokers (P < 0.05). uPAR, PAI‐1 and CAP18 levels were significantly higher in COPD III + IV patients compared with COPD I + II patients (P < 0.05). The expression of uPAR on induced sputum neutrophils and macrophages was significantly higher in COPD patients compared with healthy non‐smokers (P < 0.05) and healthy smokers (P < 0.05). Sputum uPAR and CAP18 levels showed significant inverse correlations with FEV₁% and 6MWD, and significant positive correlations with St. George's Respiratory Questionnaire scores. Conclusions: In COPD patients, increased induced sputum levels of uPAR, PAI‐1 and CAP18 were associated with airflow limitation, health status and exercise tolerance, suggesting that these biomarkers may be implicated in the pathogenesis of COPD.     

Effects of Active Smoking on Airway and Systemic Inflammation Profiles in Patients With Chronic Obstructive Pulmonary Disease

BackgroundThe markers that characterize local and systemic inflammation in chronic obstructive pulmonary disease (COPD) remain unclear, as do their correlations with smoking status and presence of disease. The aim of this study was to assess markers of inflammation in the peripheral blood and airways of current smokers without COPD, of current smokers with COPD and of ex-smokers with COPD.MethodsIn this study, 17 current smokers with COPD (mean age: 58.2 ± 9.6 years; mean forced expiratory volume in 1 second [FEV₁]: 56.1 ± 15.9%), 35 ex-smokers with COPD (mean age: 66.3 ± 7.3 years; mean FEV₁: 47.9 ± 17.2%) and 20 current smokers without COPD (mean age: 49.1 ± 6.2 years; mean FEV₁: 106.5 ± 15.8%) were evaluated. Spirometry findings, body composition and serum/induced sputum concentrations of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8 and IL-10, together with serum C-reactive protein (CRP) levels, were assessed.ResultsSerum TNF-α concentration was higher in all current smokers than in ex-smokers with COPD. In current smokers without COPD, serum CRP level was lower than in ex-smokers with COPD and significantly lower than in current smokers with COPD. Sputum TNF-α concentration was higher in current and ex-smokers with COPD than in current smokers without COPD. Multiple regression analyses showed that serum TNF-α was associated with active smoking, and serum CRP and sputum TNF-α were associated with COPD diagnosis.ConclusionsSmoking is associated with higher systemic inflammation in patients with COPD. Current findings also support the hypothesis that smoking and COPD have different effects on the regulation of airway and systemic inflammatory processes.     

Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin‐induced mouse model of asthma

Background and objective: In asthma, reduced histone deacetylase activity and enhanced histone acetyltransferase activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III histone deacetylase, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated. Methods: The effect of SRT1720, a synthetic activator of Sirt1, in an ovalbumin (OVA)‐induced asthma mouse model was investigated. The effect of SRT1720 and resveratrol on OVA stimulation in splenocytes from OVA‐sensitized and challenged mice was also examined. Results: In OVA‐sensitized and challenged mice (OVA mice) compared with saline‐sensitized and challenged mice (control mice), Sirt1 messenger RNA expression in the lungs was decreased (P = 0.02), while cellular infiltration, airway eosinophilia and bronchoalveolar lavage (BAL) fluid levels of interleukin (IL)‐4, IL‐5 and IL‐13 were increased (P < 0.01). In OVA mice, SRT1720 treatment decreased total and eosinophil cell counts and IL‐5 and IL‐13 levels in the BAL fluid compared with the vehicle treatment (P < 0.05). In OVA mice, SRT1720 treatment also decreased inflammatory cell lung infiltrates histologically (P = 0.002). Both SRT1720 and resveratrol suppressed OVA‐induced cell proliferation and IL‐6 (P < 0.05) and tumour necrosis factor‐α (TNF‐α) (P < 0.05) production in splenocytes (P < 0.01). Conclusions: The Sirt1 activator SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA‐induced mouse model of asthma. SRT1720 and resveratrol suppressed OVA‐induced splenocyte proliferation and TNF‐α and IL‐6 production. Sirt1 activators might have beneficial effects in asthmatics by suppressing inflammation.     

Systemic inflammation in nonischemic dilated cardiomyopathy

We investigated links between inflammatory systemic activation and clinical presentation of nonischemic dilated cardiomyopathy (NIDC). Thirty-one consecutive patients with NIDC (age 57 ± 10 years, left ventricular ejection fraction 32% ± 7%) were enrolled in the study: subjects with ischemic heart disease, valvular heart disease, congenital malformations, pulmonary, renal, inflammatory, or metabolic diseases were excluded. All patients underwent physical examination, electrocardiography, chest radiology, echocardiography, and coronary angiography. Plasma levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen were ascertained. New York Heart Association (NYHA) functional class was significantly correlated with concentrations of fibrinogen (r = 0.42, P < 0.05) and CRP (r = 0.52, P < 0.01), and with ESR (r = 0.46, P < 0.05). Left ventricular ejection fraction was inversely related to fibrinogen (r = −0.41, P < 0.05) and ln CRP (r = −0.46, P < 0.05). Correlations between NYHA class and markers of inflammation remained significant also after correction for age, sex, and cardiovascular risk factors. Ongoing treatment with statins was associated with reduced CRP levels. Inflammatory markers are increased in patients with NIDC proportionally with severity of symptoms and systolic impairment. Systemic inflammation might be related to deterioration of NYHA class.     

Intestinal parasites: Associations with intestinal and systemic inflammation

The aim of the present study was to evaluate associations between intestinal parasitic infection with intestinal and systemic inflammatory markers in school‐aged children with high rates of obesity. Plasma concentrations of C‐Reactive Protein (CRP), leptin, TNF‐α, IL‐6 and IL‐10 were measured as systemic inflammation markers and count of stool leukocytes as marker of intestinal inflammation in 291 children (6‐10 years). Intestinal parasitic infection was measured by stool examination. Logistic regression analyses were performed to determine the odds of having high inflammatory markers for each parasite or group of parasites as compared to parasite‐free children while adjusting for sex, age, mother's educational level and percentage of body fat. The prevalence of soil‐transmitted helminths and intestinal protozoa infections was 12% and 36%, respectively. Parasitic infection was not associated with CRP, IL‐6, IL‐10 or TNF‐α. Children infected with Ascaris lumbricoides (aOR: 5.91, 95% CI: 1.97‐17.70) and Entamoeba coli (aOR: 8.46, 95% CI: 2.85‐25.14) were more likely to have higher stool leucocytes than parasite‐free children. Children with multiple infections (aOR: 10.60, 95% CI: 2.85‐25.14) were more likely to have higher leptin concentrations than parasite‐free children. Intestinal parasitic infection was not associated with systemic inflammation, but was associated with intestinal inflammation. Having multiple infections were associated with higher leptin concentrations.     

Exhaled nitric oxide and exhaled breath condensate pH as predictors of sputum cell counts in optimally treated asthmatic smokers

Background and objective: Smoking is thought to modify the pattern of airway inflammation. Induced sputum provides useful information on cellular phenotype in inflammatory airways disorders; however, it is time‐consuming and difficult to implement in everyday clinical practice. The aim of this study was to determine whether exhaled NO (FeNO) and exhaled breath condensate (EBC) pH differed in asthmatic smokers compared with asthmatic non‐smokers and healthy subjects, and to evaluate the performance of FeNO and EBC pH for predicting the cellular phenotype of induced sputum. Methods: Asthmatic smokers (n = 40) and non‐smoking asthmatic patients (n = 43) were recruited for the study. Healthy smoking (n = 30) or non‐smoking (n = 30) subjects served as controls. FeNO and EBC pH were measured and all subjects underwent sputum induction for assessment of cell counts. Results: EBC pH was significantly lower in asthmatic smokers compared with non‐smokers (P < 0.01). FeNO levels were also significantly lower in asthmatic smokers compared with non‐smokers (P < 0.001). EBC pH was inversely associated with sputum eosinophils in both asthmatic smokers and non‐smokers (P < 0.001), whereas it was inversely associated with sputum neutrophils only in asthmatic smokers (P < 0.001). FeNO was positively associated with sputum eosinophils both in asthmatic smokers and non‐smokers (P < 0.001) but was not associated with sputum neutrophils. In asthmatic smokers, FeNO was a better predictor of sputum eosinophilia, whereas EBC pH was a better predictor of sputum neutrophilia. A combination of FeNO ≤ 14 ppb together with EBC pH > 7.20 predicted the paucigranulocytic induced sputum phenotype. Conclusions: EBC pH and FeNO levels were significantly lower in asthmatic smokers compared with non‐smokers. Combined specific cut‐off levels for FeNO and EBC pH may predict the paucigranulocytic phenotype in asthmatic smokers.     

Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus

Background Oxidative stress and increased inflammation have been reported to be increased in subjects with diabetes and to be involved in the pathogenesis of cardiovascular complications after myocardial infarction (MI). It is well recognized that red wine has antioxidant and anti‐inflammatory activities. We examined the effects of moderate red wine intake on echocardiographic parameters of functional cardiac outcome in addition to inflammatory cytokines and nitrotyrosine (oxidative stress marker), in subjects with diabetes after a first uncomplicated MI. Methods One hundred and fifteen subjects with diabetes who had sustained a first non‐fatal MI were randomized to receive a moderate daily amount of red wine (intervention group) or not (control group). Echocardiographic parameters of ventricular dys‐synchrony, circulating levels of nitrotyrosine, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐18 (IL‐18) and C‐reactive protein (CRP) were investigated at baseline and 12 months after randomization. Results After 1 year of diet intervention, concentrations of nitrotyrosine (P < 0.01), CRP (P < 0.01), TNF‐α (P < 0.01), IL‐6 (P < 0.01) and IL‐18 (P < 0.01) were increased in the control group compared with the intervention group. In addition, myocardial performance index (P < 0.02) was higher, and transmitral Doppler flow (P < 0.05), pulmonary venous flow analysis (P < 0.02) and ejection fraction (P < 0.05) were lower in the control group, indicating ventricular dys‐synchrony. The concentrations of nitrotyrosine, CRP, TNF‐α and IL‐6 were related to echocardiographic parameters of ventricular dys‐synchrony. Conclusions In subjects with diabetes, red wine consumption, taken with meals, significantly reduces oxidative stress and pro‐inflammatory cytokines as well as improving cardiac function after MI. Moderate red wine intake with meals may have a beneficial effect in the prevention of cardiovascular complications after MI in subjects with diabetes.     

Pain sensitivity and pain reactivity in osteoarthritis

Objective

To assess experimental pain sensitivity and compare the inflammatory response to pain in 26 osteoarthritis (OA) patients and 33 age‐ and sex‐matched controls from the general population in order to examine the nature of the association between pain and inflammation in OA.

Methods

The participants underwent psychophysical pain testing to assess pain sensitivity in response to heat, cold, and mechanical stimuli. Blood samples were taken at baseline and at 4 time points after testing to determine the effect of acute pain on C‐reactive protein (CRP), interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor α levels.

Results

OA patients had lower pressure pain thresholds (P ≤ 0.003) and higher heat pain ratings (P ≤ 0.04) than controls across multiple body sites. OA patients had higher CRP levels than controls (P = 0.007). CRP levels did not change in response to pain testing. Although not statistically significant, OA patients tended to have higher IL‐6 levels than controls (P = 0.12). IL‐6 levels increased after pain testing in OA patients and controls (P < 0.0001), but the amount of increase was not different between the 2 groups. Among OA patients, heightened pain sensitivity was associated with elevated CRP and IL‐6 levels (P ≤ 0.05).

Conclusion

Compared with controls, OA patients are more sensitive to experimental pain at multiple body sites. IL‐6 levels in OA patients and controls exhibited reactivity to acute painful stimuli, increasing at similar rates after psychophysical pain testing.     

Role of neutrophils in persistent airway obstruction due to refractory asthma

Background and objective: One of the clinical manifestations of refractory asthma (RA) in a certain group of patients is persistent airway obstruction (PAO), despite treatment with high doses of inhaled and/or systemic corticosteroids. Airway neutrophilic inflammation is frequently observed in RA; however, the relationship between neutrophilic inflammation and PAO has not been evaluated in this group of patients. The aim of this study was to compare the clinical parameters and patterns of inflammatory cells between patients with or without PAO due to RA, and to identify the factors associated with PAO. Methods: Seventy‐seven patients with RA were recruited from a cohort of 2298 asthmatic patients. Sputum differential cell counts were performed at initial presentation. Clinical and physiological parameters were compared between patients with (n = 19) or without PAO (n = 58). Results: The group with PAO had a longer duration of asthma and a higher frequency of near‐fatal asthma than the non‐PAO group, although higher doses of inhaled corticosteroids were used in the PAO group (P = 0.037). Neutrophilic inflammation was predominant in the group with PAO, whereas eosinophilic inflammation was predominant in the non‐PAO group (P = 0.003). When both groups were stratified according to smoking status, the non‐smoking PAO group had the longest duration of asthma, with early onset of asthma (P < 0.05). The non‐smoking PAO group tended to have the highest percentage of sputum neutrophils. Irrespective of smoking status, the percentage of sputum eosinophils was significantly higher in the non‐PAO group than in the PAO group. Conclusions: Patients with PAO due to RA show different clinical manifestations when compared with those without PAO and have neutrophil‐dominant airway inflammation.     

Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease

RATIONALE: In addition to pulmonary involvement, stable chronic obstructive pulmonary disease (COPD) is associated with nasal and systemic inflammation. Although exacerbations of COPD are associated with increased pulmonary and systemic inflammation, determinants of the systemic response remain obscure, and nor is it known whether there is nasal involvement. OBJECTIVES: To investigate upper airway, lower airway, and systemic inflammation at exacerbation of COPD. METHODS: We sampled sputum, nasal wash, and serum from 41 exacerbations (East London cohort) for analysis of pathogenic microorganisms and inflammatory indices (sputum/nasal wash leukocytes, interleukin [IL]-6, IL-8, and myeloperoxidase; serum IL-6 and C-reactive protein). Values were compared with stable COPD. MEASUREMENTS AND MAIN RESULTS: Exacerbation of COPD is associated with greater nasal, sputum, and serum inflammation than the stable state. At exacerbation, inflammatory markers were highly correlated within nasal wash and serum (all r >/= 0.62, p < 0.001), but not sputum. The degree of upper airway inflammation correlated with the degree of lower airway inflammation (e.g., nasal wash/sputum myeloperoxidase; r = 0.50, p = 0.001). The degree of systemic inflammation correlated with the degree of lower airway inflammation (e.g., serum IL-6/sputum IL-8; r = 0.35, p = 0.026), and was greater in the presence of a sputum bacterial pathogen (29.0 g/dl C-reactive protein difference, p = 0.002). We did not find relationships between the upper airway and systemic compartments. CONCLUSIONS: Exacerbation of COPD is associated with pan-airway inflammation; the systemic inflammatory response is proportional to that occurring in the lower airway and greater in the presence of a bacterial pathogen.     

Specific biomarkers of myocardial inflammation and remodeling processes as predictors of mortality in high‐risk patients undergoing percutaneous mitral valve repair (MitraClip)

Background

Specific matrix metalloproteinases (MMP‐2, MMP‐9) and inflammatory biomarkers (hsCRP, IL‐6) were found to be consistently up‐regulated in severe mitral valve regurgitation (MR) and are associated with mortality in heart failure patients. The aim of the present study was to examine the prognostic value of biomarkers of cardiac inflammation and remodeling processes in predicting mortality in patients with MR undergoing percutaneous mitral valve repair (PMVR).

Hypothesis

We hypothesize that increased cardiac inflammation and extracellular matrix turnover is predictive for mortality in patients with severe mitral regurgitation undergoing MitraClip.

Methods

A total of 210 consecutive patients undergoing PMVR were included. PMVR was performed according to standard clinical practice. Venous blood samples for biomarker analyses were collected prior to and 6 months after PMVR. Physiological parameters, medication use, safety events, and all‐cause mortality were followed over 12 months.

Results

PMVR was performed successfully in all patients. Twelve months after PMVR there was an effective reduction in the severity of MR (P < 0.001), and an improvement in New York Heart Association class (P < 0.01) was documented. Elevated inflammatory biomarkers (AUC_hsCRP: 0.738 [IQR, 0.626–0.849], P = 0.001; AUC_IL‐6: 0.811 [IQR, 0.724–0.899], P = 0.001) and biomarkers reflecting cardiac remodeling processes (AUC_MMP‐2: 0.723 [IQR, 0.641–0.804], P = 0.001; AUC_MMP‐9: 0.618 [IQR, 0.534–0.701], P = 0.01) were predictors of adverse cardiac events and mortality in patients with congestive heart failure undergoing PMVR.

Conclusions

The present study is the first to identify biomarkers reflecting inflammation (hsCRP, IL‐6) and cardiac remodeling processes (MMP‐2, MMP‐9) as predictors of mortality in high‐risk patients undergoing PMVR.     

Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction

Abstract. Christersson C, Oldgren J, Wallentin L, Siegbahn A (Uppsala University, Uppsala, Sweden). Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction. J Intern Med 2011; 270 : 215–223. Background. Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. Objective. To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). Methods. A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P‐selectin, soluble tissue factor, C‐reactive protein (CRP), interleukin (IL)‐10 and IL‐18 were analysed in serial blood samples. Results. sP‐selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP‐selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL‐18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL‐18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL‐10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002). Conclusion. A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long‐term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.     

Long non-coding RNA ANRIL serves as a potential marker of disease risk,inflammation, and disease activity of pediatric inflammatory bowel disease

BackgroundLong non-coding antisense RNAs in the INK4 locus (lnc-ANRIL) have been reported to be involved in inflammation and immunity. However, few studies have reported its clinical application in pediatric inflammatory bowel disease (IBD). Therefore, we conducted this study to investigate the correlation between lnc-ANRIL expression and disease risk, inflammation, and activity in pediatric IBD patients.MethodsPediatric patients with Crohn's disease (CD; n = 40), ulcerative colitis (UC; n = 40), and controls (n = 20) were recruited. For all pediatric IBD patients, lnc-ANRIL expression in peripheral blood mononuclear cells and serum inflammatory cytokine levels were measured by RT-qPCR and ELISA, respectively. For the controls, lnc-ANRIL expression was also measured.ResultsLnc-ANRIL levels were lower in CD (P = 0.002) and UC (P = 0.001) patients compared with the controls; negatively correlated with C-reactive protein levels (P<0.01), erythrocyte sedimentation rate (P<0.01), disease activity (P<0.05), and severity (P<0.05) in CD and UC patients; and inversely associated with tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17, and IL-23 levels in both CD and UC patients (all P<0.01). Further subgroup analyses revealed that the association between lnc-ANRIL and inflammatory cytokines and disease activity was more remarkable in pediatric patients with moderate or severe IBD.ConclusionLnc-ANRIL may serve as a potential marker for evaluating disease risk and monitoring disease activity in pediatric IBD patients.     

Immunological profile of Fanconi anemia: A multicentric retrospective analysis of 61 patients

In this study, the immunological status of 61 patients with Fanconi anemia (FA) with advanced marrow failure before hematopoietic stem cell transplantation was analyzed by assessing the phenotype of peripheral blood lymphocytes, serum immunoglobulin (Ig) levels, and inflammatory cytokines. In patients with FA, total absolute lymphocytes (P < 0.0001), B cells (P < 0.0001), and NK cells (P = 0.003) were reduced when compared with normal controls. T cells (CD3), that is, cytotoxic T cells, naïve T cells, and regulatory T cells, showed a relative increase when compared with controls. Serum levels of IgG (P < 0.0001) and IgM (P = 0.004) were significantly lower, whereas IgA level was higher (P < 0.0001) than in normal controls. TGF‐β (P = 0.007) and interleukin (IL)‐6 (P = 0.0007) levels were increased in the serum of patients when compared with controls, whereas sCD40L level decreases (P < 0.0001). No differences were noted in the serum levels of IL‐1β, IL‐2, IL‐4, IL‐10, IL‐13, IL‐17, and IL‐23 between FA subjects and controls. This comprehensive immunological study shows that patients with FA with advanced marrow failure have an altered immune status. This is in accordance with some characteristics of FA such as the proinflammatory and proapoptotic status. In addition, B lymphocyte failure may make tight and early immunological monitoring advisable. Am. J. Hematol. 88:472–476, 2013. © 2013 Wiley Periodicals, Inc.     

Airway inflammation in employees involved in cultivating Japanese mushrooms (bunashimeji)

Background and objective: Chronic inhalation of spores may cause respiratory symptoms such as productive cough and sputum. The purpose of this study was to determine the clinical pathophysiology of airway inflammation caused by bunashimeji spores and to investigate whether the spores have direct toxic inflammatory effects. Methods: Sensitized employees with respiratory symptoms and a stimulation index (SI) > 200%, and non‐sensitized employees with a SI < 200% were enrolled. They underwent sputum induction and chest high‐resolution computed tomography (HRCT). The in vitro effect of bunashimeji spore solutions on normal human bronchial epithelial (NHBE) cell cultures was investigated using the air–liquid interface method. Bunashimeji spore solution was added at 10⁴ or 10⁶ spores per 20 μL/well. The interleukin (IL)‐8 and epithelial neutrophil‐activating peptide‐78 (ENA‐78) concentrations in the medium and IL‐8 mRNA expression of NHBE cells were assessed after each stimulation. Results: Sensitized employees were divided into 14 with normal HRCT and 9 with abnormal HRCT. Fifteen of the sensitized group and five of the non‐sensitized group had a productive cough and sputum. The neutrophil counts in induced sputum were significantly higher in subjects with abnormal HRCT than in those with normal HRCT. IL‐8 and ENA‐78 concentrations following stimulation with 10⁴ and 10⁶ spores were significantly increased compared with PBS only on day 9. IL‐8 mRNA expression due to spore stimulation was significantly increased compared with control. IL‐8 mRNA expression with 10⁶ spore stimulation was significantly increased on days 6 and 12 compared with 10⁴ spores. Conclusion: The inhalation of spores directly produces toxic inflammatory effects in the airways, independent of the degree of sensitization.     

High Expression of Cathepsin E is Associated with the Severity of Airflow Limitation in Patients with COPD

Background: It was reported that Cathepsin E (Cat E) plays a critical role in antigen processing and in the development of pulmonary emphysema. The aim of this study was to investigate the role of Cat E and airflow limitation in the pathogenesis of COPD. Methods: Sixty-five patients with COPD, 20 smoking control subjects without COPD and 15 non-smoking healthy control subjects were enrolled. Cat E and EIC (Elastase inhibitory capacity) expressions were measured by ELISA in sputum and serum samples and compared according to different subgroups. Results: Cat E concentrations were significantly higher in patients with COPD than smoking control and non-smoking control subjects (P < 0.01). The levels of CatE were inversely correlated with FEV₁% predicted in COPD patients (r = ?0.95, P < 0.01). The levels of EIC were inversely positively correlated with FEV₁% predicted in COPD patients (r = 0.926, P < 0.01). Levels of Cat E were also inversely correlated with the levels of EIC (r = ?0.922, P < 0.01). Conclusions: Cat E contributes to the severity of airflow limitation during progression of COPD.     

Effect of bronchial colonisation on airway and systemic inflammation in stable COPD

The recovery of potentially pathogenic microorganisms (PPMs) from bronchial secretions is associated with a local inflammatory response in COPD patients. The objective of this study was to determine the relationships between bronchial colonisation and both bronchial and systemic inflammation in stable COPD. In COPD patients recruited on first admission for an exacerbation, bacterial sputum cultures, interleukin (IL)-1β, IL-6 and IL-8 levels, and blood C-reactive protein (CRP) were measured in stable condition. Bronchial colonisation was found in 39 of the 133 (29%) patients and was significantly related to higher sputum IL-1β (median [percentile 25-75]; 462 [121-993] vs. 154 [41-477] pg/ml, p = 0.002), IL-6 (147 [71-424] vs. 109 [50-197] pg/ml, p = 0.047) and IL-8 values (15 [9-19] vs. 8 [3-15] (×103) pg/ml, p = 0.002). Patients with positive cultures also showed significantly elevated levels of serum CRP (6.5 [2.5-8.5] vs. 3.5 [1.7-5.4] mg/l, p = 0.016). Bronchial colonisation by Haemophilus influenzae was associated with higher levels of IL-1β and IL-8 and clinically significant worse scores on the activity and impact domains of the St. George's Respiratory Questionnaire. In conclusion, bronchial colonisation is associated with bronchial inflammation and high blood CRP levels in stable COPD patients, being Haemophilus influenzae related to a more severe inflammatory response and impairment in health-related quality of life.     

Impact of long‐term treatment with low‐dose inhaled corticosteroids on the bone mineral density of chronic obstructive pulmonary disease patients: Aggravating or beneficial?

Background and objective: Chronic obstructive pulmonary disease (COPD) is characterized by a low‐level systemic chronic inflammatory activity that is responsible for many of the disease's extra‐pulmonary manifestations, including osteoporosis and fragility fractures. These manifestations are also well‐documented side‐effects of oral corticosteroids. It was hypothesized that low levels of inhaled corticosteroids, due to their anti‐inflammatory properties and their low circulating levels, might preserve the bone mineral density (BMD) of COPD patients. Methods: Two hundred and fifty‐one male ex‐smokers with COPD patients grouped on the basis of their diffusion capacity value as predominantly bronchitic or predominantly emphysematic and 313 male controls with similar age and smoking history were enrolled in the study. Each of the patient's categories was randomized into two separate subgroups. Patients enrolled in subgroups B_neg(n = 91, 36%) and E_neg(n = 37, 14.7%) were treated with long‐acting β2‐agonists and anticholinergics, while subgroups B_ICS(n = 87, 35%) and E_ICS(n = 38, 15.1%) were additionally receiving low‐dose inhaled corticosteroids. Patients and controls were evaluated by clinical examination, lung function testing and BMD measurement every 6 months for 4 years. Results: According to the findings, emphysematic patients demonstrated an increased rate of BMD loss compared with bronchitic patients (P = 0.01). Furthermore, a reduction of the annual BMD loss in bronchitic patients on inhaled corticosteroids (P = 0.02) was measured, without a corresponding benefit for the emphysematics (P = not significant). Conclusions: Long‐term administration of low‐dose inhaled corticosteroids decelerates the annual BMD loss in bronchitic patients, possibly by reducing both pulmonary and systemic chronic inflammation caused by COPD.     

Melatonin ameliorates low‐grade inflammation and oxidative stress in young Zucker diabetic fatty rats

The aim of this study was to investigate the effects of melatonin on low‐grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n = 30) and lean littermates (ZL) (n = 30) were used. At 6 wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10 mg/kg/day) for 6 wk. Vehicle and melatonin were added to the drinking water. Pro‐inflammatory state was evaluated by plasma levels of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and C‐reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe²⁺/H₂O₂ inducement. ZDF rats exhibited higher levels of IL‐6 (112.4 ± 1.5 pg/mL), TNF‐α (11.0 ± 0.1 pg/mL) and CRP (828 ± 16.0 µg/mL) compared with lean rats (IL‐6, 89.9 ± 1.0, P < 0.01; TNF‐α, 9.7 ± 0.4, P < 0.01; CRP, 508 ± 21.5, P < 0.001). Melatonin lowered IL‐6 (10%, P < 0.05), TNF‐α (10%, P < 0.05), and CRP (21%, P < 0.01). Basal and Fe²⁺/H₂O₂‐induced LPO, expressed as malondialdehyde equivalents (µmol/L), were higher in ZDF rats (basal, 3.2 ± 0.1 versus 2.5 ± 0.1 in ZL, P < 0.01; Fe²⁺/H₂O₂‐induced, 8.7 ± 0.2 versus 5.5 ± 0.3 in ZL; P < 0.001). Melatonin improved basal LPO (15%, P < 0.05) in ZDF rats, and Fe²⁺/H₂O₂‐ induced LPO in both ZL (15.2%, P < 0.01) and ZDF rats (39%, P < 0.001). These results demonstrated that oral melatonin administration ameliorates the pro‐inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease.     

Novel Inflammatory Marker in Dialysis Patients: YKL‐40

YKL‐40 has been introduced as a marker of inflammation in different clinical situations. The association between YKL‐40 and inflammation in chronic renal failure patients has not been researched currently. The objectives of this study were to establish serum YKL‐40 concentrations in dialysis patients with chronic renal failure compared to healthy subjects and to explore its relationships with a proinflammatory cytokine, interleukine‐6 (IL‐6) and an acute phase mediator, high sensitivity C‐reactive protein (hs‐CRP). The study population included hemodialysis patients (N = 43; mean age of 40.9 ± 14.5), peritoneal dialysis patients (N = 38; mean age of 45.8 ± 13.7) and healthy subjects (N = 37; mean age of 45.5 ± 10.6). Serum concentrations of YKL‐40, IL‐6, hs‐CRP and routine laboratory measures were evaluated. Compared to the healthy subjects, hemodialysis and peritoneal dialysis patients had higher concentrations of YKL‐40, IL‐6, hs‐CRP, as well as lower concentrations of hemoglobin, serum albumin and high density lipoprotein‐cholesterol (P < 0.001). YKL‐40 concentrations were positively correlated with serum creatinine (P < 0.001, r = 0.495), IL‐6 (P < 0.001, r = 0.306), hs‐CRP (P = 0.001, r = 0.306) levels and inversely correlated with hemoglobin (P = 0.002, r = ?0.285), serum albumin (P < 0.001, r = ?0.355) and high density lipoprotein‐cholesterol (P = 0.001, r = ?0.306). In multivariate regression analysis YKL‐40 was associated with creatinine, serum albumin and hs‐CRP concentrations after adjustments with covariates. Dialysis patients with chronic renal failure have elevated serum YKL‐40 concentrations. Associations with standard inflammatory parameters suggest that YKL‐40 might be a novel inflammatory marker in this population.