Pattern Of Airway Inflammation Research Articles

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

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. 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. 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. 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.

Can inhaled corticosteroids prevent asthma exacerbations?

asthma exacerbations occur unpredictably, are a cause of morbidity and mortality, and contribute significantly to increased healthcare costs. Inhaled corticosteroids reduce exacerbations and improve quality of life. the aetiopathology of asthma exacerbations is heterogeneous. Attempts to phenotype the heterogeneity of the pattern of airway inflammation by noninvasive monitoring of airway inflammation has identified a subgroup of patients with eosinophilic inflammation who are most likely to respond to steroid therapy. Strategies directed to normalize eosinophilic airway inflammation with corticosteroids have consistently led to a marked reduction in exacerbations. In contrast, their role in modulating the natural history of disease is less certain. in the near future, improvements in our understanding of the mechanisms of exacerbations may identify therapeutic targets. While we await these developments, inhaled corticosteroids remain the first choice anti-inflammatory therapy for asthma.

P21 Success rate of sputum induction in the Leicester paediatric severe asthma clinic using

BackgroundAsthma is a common disease affecting about one in four children in the UK. It is characterised by variable airway obstruction, bronchial hyper responsiveness and influx of inflammatory cells into...

Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia

Potential bacterial pathogens are found in the airways in several diseases that are associated with neutrophilic inflammation. The aim of this study was to characterize subjects with stable asthma, with no symptoms of respiratory infection, to assess whether key potentially pathogenic bacteria were present in significant quantities in the airways and to correlate this with the pattern of airway inflammation and oxidative stress. Subjects with stable asthma (n = 115) and healthy controls (n = 8) underwent clinical assessment, including hypertonic saline challenge combined with sputum induction. A significant load of potentially pathogenic bacteria (> 106 cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.

Animal study for airway inflammation triggered by gastroesophageal reflux

Background Gastroesophageal reflux disease with extra-esophageal symptoms, especially those with respiratory distress was attracting more and more attention. The related mechanisms were still in controversy. The purpose of the work was to explore airway inflammation triggered by gastroesophageal reflux. Methods Sixteen Sprague-Dawley rats were used as study group and 9 as control. In the study group, a plastic extender with a trumpet-shaped distal end was inserted into the lower esophagus to dilate the cardia, the pylorus was ligated. One ml of 0.1 mol/L hydrochloric acid was injected into the stomach. While a simple laparotomy was performed for control animals. All animals from two groups were sacrificed 24 hours after operation. Then tracheotomy was carried and the bronchoalveolar lavage fluid was collected in all animals. Cells in the fluid were counted and levels of interleukin (IL)-5, -6, -8 in it were measured. Results Compared with control group, the study group presented a neutrophil pattern of airway inflammation and an elevated concentration of IL-5, -6, -8 with no significant difference regarding eosinophil count. Conclusion The gastroesophageal reflux-triggered airway inflammation is characterized by a neutrophilic airway inflammation which differed from that caused by asthma, and enhanced levels of IL-5, -6 and -8, which are similar to that caused by asthma.

Biological Markers in Induced Sputum of Patients with Different Phenotypes of Chronic Airway Obstruction

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by a combination of 3 different disorders, namely chronic asthma, chronic bronchitis and pulmonary emphysema, sometimes simultaneously present in the same subject. Objectives: The aim of our study was to compare sputum inflammatory markers in patients with different phenotypes of chronic airway obstruction. Methods: Forty-five subjects (forced expiratory volume in 1 s/vital capacity, FEV₁/VC: 58.8 ± 12.2%; FEV₁: 49.8 ± 11.5% of predicted) were classified as chronic asthma (n = 10) or COPD patients (n = 35); the latter were further divided into patients with prevalent chronic bronchitis (n = 24) or prevalent pulmonary emphysema (n = 11) according to clinical history and functional evaluation, and underwent sputum induction and analysis of inflammatory cell and soluble mediators. Results: Patients with chronic asthma showed higher sputum eosinophil percentages and eosinophilic cationic protein levels, and lower neutrophil percentages and neutrophil elastase levels than COPD patients. Neutrophil chemotactic activity in sputum supernatant was higher than the pool of normal subjects both in chronic asthma and COPD patients. No difference in sputum cell composition and levels of soluble mediators was observed between patients with chronic bronchitis and patients with pulmonary emphysema. Conclusions: The pattern of airway inflammation in induced sputum of patients with chronic asthma is different from that of COPD patients with a similar FEV₁. Among COPD patients, however, the pattern of airway inflammation shows no difference between chronic bronchitis and patients with pulmonary emphysema, suggesting that these two clinically and functionally distinct phenotypes share a common inflammatory pattern as detected by induced sputum.

Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD.

BackgroundSmoking activates and recruits inflammatory cells and proteases to the airways. Matrix metalloproteinase (MMP)-12 may be a key mediator in smoke induced emphysema. However, the influence of smoking and its cessation on airway inflammation and MMP-12 expression during COPD is still unknown. We aimed to analyse airway inflammatory cell patterns in induced sputum (IS) and bronchoalveolar lavage (BAL) from COPD patients who are active smokers and who have ceased smoking >2 years ago.Methods39 COPD outpatients – smokers (n = 22) and ex-smokers (n = 17) were studied. 8 'healthy' smokers and 11 healthy never-smokers were tested as the control groups. IS and BAL samples were obtained for differential and MMP-12+-macrophages count analysis.ResultsThe number of IS neutrophils was higher in both COPD groups compared to both controls. The amount of BAL neutrophils was higher in COPD smokers compared to healthy never-smokers. The number of BAL MMP-12+-macrophages was higher in COPD smokers (1.6 ± 0.3 × 106/ml) compared to COPD ex-smokers, 'healthy' smokers and healthy never-smokers (0.9 ± 0.4, 0.4 ± 0.2, 0.2 ± 0.1 × 106/ml respectively, p < 0.05).ConclusionThe lower amount of BAL neutrophils in COPD ex-smokers, compared to COPD smokers, suggests positive alterations in alveolar compartment after smoking cessation. Smoking and disease itself may stimulate MMP-12 expression in airway compartments (IS and BAL) from COPD patients.

Patogeneza i klinika nieastmatycznego eozynofilowego zapalenia oskrzeli

The introduction of induced sputum, as the diagnostic and research tool allowed to define nonasthmatic eosinophilic bronchitis characterized as a chronic cough in patients with no symptoms or objective evidence of variable airflow obstruction, with normal airway hyperresponsiveness and sputum eosinophilia. Eosinophilic bronchitis is an important cause of chronic cough. Studies in which the assessment of airway inflammation has been undertaken in chronic cough patients have shown that nonasthmatic eosinophilic bronchitis accounts for 10 to 30% of cases referred for specialist investigation. Eosinophilic bronchitis, like asthma, is characterized by eosinophilic airway inflammation, but unlike asthma, there is no airway hyperresponsiveness or bronchoconstriction. The airway immunopathology of asthma and eosinophilic bronchitis are almost identical. An obvious question is why an apparently similar pattern of airway inflammation is associated with different functional abnormalities in patients with nonasthmatic eosinophilic bronchitis and asthma. The differences in functional association may be related to differences in the localization of mast cells within the airway wall, with airway smooth muscle infiltration occurring in patients with asthma, and epithelial infiltration in patients with nonasthmatic eosinophilic bronchitis.

Inflammation, Oxidative Stress and Systemic Effects in Mild Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary diseases (COPD) is a pulmonary disease characterized by systemic abnormalities. The aim of this study is to investigate inflammation and systemic effects in mild COPD. Twenty-seven mild stable smoking related COPD patients and 15 age-matched healthy subjects were enrolled in the study. IL-6, TNF-alpha and IL-4 in plasma, sputum and exhaled breath condensate were measured. We also measured exhaled nitric oxide (NO) and pH in sputum and in breath condensate. Moreover, fat-free mass, body mass index (BMI), respiratory muscle strength, plasma oxidative stress and C-reactive protein (CRP) were measured. Higher concentrations were found of CRP, of diacron reactive oxygen metabolites (DROMs) and of IL-6, TNF-alpha and IL-4 either in plasma or in supernatant of induced sputum or in exhaled breath condensate of COPD subjects compared to healthy controls. Furthermore, higher concentrations were observed of exhaled NO and lower exhaled pH in breath condensate of COPD when compared with healthy subjects. In the group of COPD patients, the subjects with airway reversibility showed an increase of sputum eosinophils and exhaled NO, whereas the subjects without airway obstruction reversibility showed an increase in sputum neutrophils, TNF-alpha and IL-6. We also found a trend towards a decrease in fat-free mass and respiratory muscle strength in COPD compared to healthy subjects and a negative correlation between these systemic indices (fat-free mass, maximal inspiratory pressure, maximal expiratory pressure) and TNF-alpha concentrations in the blood, sputum and breath condensate. We conclude that mild COPD subjects present an increase in inflammatory markers in blood and in airways of similar pattern and furthermore, the neutrophilic pattern of airway inflammation observed in the group of COPD subjects without an airway obstruction reversibility makes it more likely that systemic features are present.

Airways disease: phenotyping heterogeneity using measures of airway inflammation.

Despite asthma and chronic obstructive pulmonary disease being widely regarded as heterogeneous diseases, a consensus for an accurate system of classification has not been agreed. Recent studies have suggested that the recognition of subphenotypes of airway disease based on the pattern of airway inflammation may be particularly useful in increasing our understanding of the disease. The use of non-invasive markers of airway inflammation has suggested the presence of four distinct phenotypes: eosinophilic, neutrophilic, mixed inflammatory and paucigranulocytic asthma. Recent studies suggest that these subgroups may differ in their etiology, immunopathology and response to treatment. Importantly, novel treatment approaches targeted at specific patterns of airway inflammation are emerging, making an appreciation of subphenotypes particularly relevant. New developments in phenotyping inflammation and other facets of airway disease mean that we are entering an era where careful phenotyping will lead to targeted therapy.

The reclassification of asthma based on subphenotypes

Despite asthma being widely regarded as a heterogeneous disease, a consensus for an accurate system of classification has not been agreed. Recent studies have suggested that the recognition of subphenotypes of asthma based on the pattern of airway inflammation may be particularly useful in increasing our understanding of the disease. The present review discusses the important literature in this field, placing current work in its historical context. The use of noninvasive markers of airway inflammation has suggested the presence of four distinct phenotypes: eosinophilic, neutrophilic, mixed inflammatory and paucigranulocytic asthma. Recent studies suggest that these subgroups may differ in their aetiology, immunopathology and response to treatment. Several studies have focused on refractory asthma as a distinct phenotype with evidence of a more distal pattern of airway inflammation and of upregulation of the tumour necrosis factor-alpha axis. Finally, novel treatment approaches targeted at specific patterns of airway inflammation are emerging, making an appreciation of subphenotypes particularly relevant. The present review will discuss limitations to current classification systems, identify key current studies based on identifying inflammatory subphenotypes and provide suggestions for a novel approach that may further improve our understanding in this area.

How Viral Infections Cause Exacerbation of Airway Diseases

Exacerbations of asthma and COPD are major causes of morbidity, mortality, and health-care costs. Over the last decade, studies using new molecular diagnostic techniques have established that respiratory viruses are a major cause of exacerbations of both asthma and COPD. The most prevalent viruses detected during exacerbations are the rhinoviruses. Despite the burden of disease associated with exacerbations, little is known about the mechanisms of virus-induced exacerbations of airway diseases. Exacerbations are associated with increased airway inflammation in patients with both asthma and COPD, but many questions remain unanswered regarding the key inflammatory cells and mediators involved. Identifying the key inflammatory mediators involved in exacerbations holds the promise of developing diagnostic and prognostic markers of exacerbation. In addition, such studies can identify new therapeutic targets for the development of novel drugs for the prevention and treatment of exacerbations.

Airway fibrosis in a mouse model of airway inflammation

BALB/c mice were sensitized to ovalbumin by systemic injection and then exposed for up to 8 weeks to ovalbumin aerosols in whole body chambers. A pattern of airway inflammation, mucous cell hypertrophy and hyperplasia, and airway remodeling with submucosal fibrosis was observed as lesions evolved over time. Larger conducting airways were removed from the lungs by microdissection. Airway fibrosis was quantified by direct assay for collagen content, which was significantly increased after 4 and 8 weeks of exposure to ovalbumin aerosol. Based upon PCR analysis of mRNA levels in the airways, most of the newly synthesized collagen was Type I. Relaxin, administered by continuous infusion over the second half of a 4-week exposure to ovalbumin, was able to inhibit the accumulation of collagen in the airways of exposed mice. Thus, stimulation of collagen degradation by an activator of collagen breakdown by matrix metalloproteinases appears to be an effective therapeutic strategy in prevention of airway fibrosis in this animal model. Whole body plethysmography of unrestrained mice indicated functional changes in airway reactivity in the lungs of exposed animals occurring in conjunction with the reported structural changes. This result indicates that the ovalbumin-exposed mouse may be a suitable model for examining structure–function relationships in the lungs of animals with a predictable time course of airway inflammation, remodeling, and fibrosis and for testing potential new drugs for treatment of asthma or chronic bronchitis at a mechanistic level.

Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects

Background: An allergen challenge to the airways of sensitized mice causes eosinophilic airway inflammation and degranulation of goblet cells, which lead to airway obstruction. However, whether allergen challenge causes a similar pattern of airway inflammation and goblet cell degranulation in human beings is unknown. Objective: The purpose of this study was to determine whether allergen challenge increases airway inflammatory cells and causes goblet cell degranulation in human subjects with asthma. Methods: In bronchial biopsy specimens taken from 8 asthmatic subjects at 1 and 24 hours after allergen challenge, we measured eosinophil and neutrophil numbers as indicators of inflammation. We also measured goblet cell mucin stores and the amounts of secreted mucin in bronchial lavage as indicators of goblet cell degranulation. Results: Airway eosinophil numbers at both 1 and 24 hours after allergen challenge were twice as high as those after diluent challenge. Changes in neutrophil numbers were smaller and statistically insignificant. Goblet cell mucin stores measured in tissue stained with alcian blue/periodic acid-Schiff did not decrease significantly from baseline to 1 hour and actually tended to increase at 24 hours. This increase was significant in the subgroup of subjects with normal stored mucin levels at baseline. Mucin-like glycoprotein concentrations in bronchial lavage did not change significantly at either time point. Conclusion: Although allergen challenge in asthmatic subjects increases airway eosinophil numbers as early as 1 hour after challenge, this inflammatory response does not cause goblet cell degranulation. In fact, in subjects with normal baseline mucin stores, allergen challenge increases goblet cell mucin stores. (J Allergy Clin Immunol 2001;108:784-90.)

Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease.

The effect of bacterial colonization of the bronchi on the progress of airflow limitation is not well known. Therefore, the pattern of airway inflammation in smokers and patients with stable chronic obstructive pulmonary disease (COPD) and its relation to bronchial microbial colonization was assessed. Eight nonsmoking and 18 smoking controls as well as 52 patients with COPD (28 mild, 11 moderate and 13 severe) were studied. All subjects were investigated by means of flexible bronchoscopy including protected specimen brush and bronchoalveolar lavage (BAL) sampling. Differential cell counts, cytokine (interleukin (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha(TNF-alpha) concentrations and microbial patterns were determined in BAL fluid. Forced expiratory volume in one second (FEV1) % of the predicted value was inversely correlated with pack-yrs of cigarette smoking (r=-0.47, p<0.0001), the percentage of neutrophil (p=-0.56, p<0.0001) and IL-6 (p=-0.37, p=0.01) and IL-8 concentration (p=-0.43, p=0.004) in BAL fluid. Accordingly, pk-yrs of cigarette smoking (p=0.39, p=0.01) and IL-8 (p=0.69, p<0.0001) and TNFalpha (p=0.4, p<0.005) were positively correlated with the percentage of neutrophils in BAL fluid. Smoking controls and COPD patients were mainly colonized in the bronchial tree (33%) by community endogenous potentially pathogenic micro-organisms (PPMs). Colonization rates and patterns of PPMs were not affected by severity of airflow obstruction. The presence of PPMs was significantly associated with higher percentages of neutrophils (33.2+/-10.4% versus 10.1+/-3.5%, p=0.02) and TNF-alpha concentration (29.9+/-10.8 versus 6.3+/-2.1 pg x mL(-1), p=0.01) in BAL fluid. In conclusion, bronchial neutrophilia is a key inflammatory pattern in chronic obstructive pulmonary disease patients. Bronchial colonization with potentially pathogenic micro-organisms may represent an independent stimulus for additional airway inflammation.