Small Airway Inflammation Research Articles

The Role of Small Airways in Childhood Asthma

Over the last 10 to 15 years, the emerging role of distal or small-airway inflammation in the pathogenesis of asthma has been increasingly recognized. This review attempts to focus on the importance of small-airway dysfunction in asthma. Pathologic changes seen in the distal airways were highlighted using data obtained from biopsy studies, as well as changes seen in fatal asthma. Advances in the diagnostic evaluation of the distal airways were reviewed, specifically pulmonary function tests (including exhaled nitric oxide and impulse oscillometry), and newer imaging techniques. Finally, studies that have led to advances in therapeutic treatment of the small airways in childhood asthma were highlighted. The terms distal airways and small airways are used interchangeably throughout the article.

Differenzial analysis of antioxidative capacities in the alveolar compartment of diffuse parenchymal lung disorders and diseased controls

Diffuse parenchymal lung disorders (DPLDs) are a heterogeneous group of rare entities including granulomatous DPLDs like sarcoidosis, and idiopathic interstitial pneumonias like non specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). Common hallmarks of these entities are inflammation and fibrosis of lung interstitium and small airways. In the normal lung the antioxidant defense system protects the alveolar compartment from damaging effects of environmental oxidative influence. In DPLDs the regulation of antioxidants are thought to be disturbed. Searching for biomarkers to be used as support in differenzial diagnosis of interstitial DPLDs we analyzed low molecular weight antioxidants in the bronchoalveolar lavage fluids of patients with sarcoidosis, NSIP, and UIP compared to COPD and EAA as diseased controls. In a first approach we investigated glutathione (GSH), 8-isoprostane and superoxide dismutases (SOD) in the BALF of 147 individuals, namely 73 patients with sarcoidosis, 20 with UIP, 15 with NSIP, and as diseased controls 14 with EAA and 25 with COPD.. GSH was determined by a commercially available glutathione assay (Cayman Chemical). 8-isoprostane was detected using a competitive assay (Cayman Chemical 8-Isoprostane EIA Kit). The superoxide dismutases assay kit (Cayman Chemical) was used to quantify SOD in BALFs. Quantification of GSH revealed highest mean concentrations in BALFs of patients with Sarcoidosis (1.17µM) followed by UIP (1.02µM) and NSIP (0.87µM). Although GSH concentrations in DPLDs showed significant differences, diseased controls as COPD presented with significantly higher concentrations (2.06µM; up to p<0.0001 and EAA with significantly lower (0.61µM; p<0.05) GSH concentrations. Although not significant, highest amounts of 8-isoprostane were found in patients with sarcoidosis (8.20pg/ml) followed by NSIP (6.58pg/ml) and UIP (3.99pg/ml). This was also true for detection of SOD in BALFs (sarcoidosis 0.42U/ml; NSIP 0.37U/ml and UIP 0.31U/ml). To date preliminary data do not support the usage of GSH, 8-isoprostane or SOD as differenzial biomarkers in BALFs of patients with sarcoidosis, NSIP and UIP. However, analyses will be continued to improve the statistical power of this studies.

Clinical aspects of using exhaled NO in asthma diagnosis and management

Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FE(NO)) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FE(NO) reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FE(NO) can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes. The scope of this review is to provide an overview of the most important clinical studies using FE(NO) in asthma management and to summarise the implications of FE(NO) measurements in clinical practice. In several studies, FE(NO) measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FE(NO) can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.

Asthmatic Granulomatosis: A New Disease?

Severe asthma can manifest with both small airway inflammation and granulomatosis, representing a possibly new subset of the disease.

Mast Cell Infiltration Discriminates between Histopathological Phenotypes of Chronic Obstructive Pulmonary Disease

COPD is a complex disease with heterogeneous manifestations. Attempts have been made to define different phenotypes that could guide toward better disease understanding. We described before that smokers can develop either panlobular (PLE) or centrilobular emphysema (CLE). The latter has worse small airways remodeling and narrowing, which account for the airflow obstruction similar to asthma. Because of the small airways involvement in CLE similar to asthma, we hypothesized a role for mast cells in CLE but not in PLE. Hence, we investigated mast cell infiltration, along with overall inflammation, and their relation with hyperreactivity and emphysema type in COPD. We studied lung function, emphysema type, mast cells, and overall inflammation in small airways and alveolar walls, along with alveolar wall thickening in 67 subjects undergoing lung resection (59 smokers, 8 nonsmokers). Twenty-seven smokers had CLE, 24 had PLE, and 8 had no emphysema. Mast cells were significantly increased in CLE compared with PLE and control subjects. Especially relevant was the mast cell increase in airway smooth muscle in CLE, which related significantly to airway hyperreactivity. CD4(+)T cells, neutrophils, and macrophages, but not eosinophils and CD8(+)T cells, were significantly higher in CLE than PLE. Alveolar wall thickness was increased in all smokers, but significantly more in CLE. The pathological phenotypes of COPD CLE and PLE show important differences in their overall inflammation with a protagonism of mast cells, which are related to airway reactivity. These findings highlight the distinctness of these COPD phenotypes and the role of mast cells in the pathophysiology of COPD.

Lungenfunktionsdiagnostik der kleinen Atemwege

In the recent years growing interest has focused on the involvement of the distal airways (internal diameter < 2 mm) in obstructive lung diseases and other pulmonary conditions. Inflammation in the small airways seems to play a major role in severe and uncontrolled asthma as a major determinant of airflow obstruction. Thus, small airways represent an important target for inhalation therapy. Currently there is no accepted single lung function parameter to detect small airway dysfunction. Various invasive and non-invasive techniques have been described. In future, non-invasive lung function testing will gain more importance. Using spirometry or body plethysmography, lung function parameters such as the ratio of forced vital capacity to slow vital capacity (FVC/SVC) and the residual volume (RV) can provide information about air trapping in small airway disease. Recent data show that techniques such as impulse oscillometry, nitrogen washout testing and analysis of exhaled nitric oxide are promising tools to assess involvement of the small airways. Impulse oscillometry is a sensitive method to calculate peripheral airway resistance, nitrogen washout allows one to detect air trapping and inhomogeneous ventilation in the distal lung, and the alveolar nitric oxide concentration represents a marker of peripheral inflammation. Further studies are needed to validate these functional tests or their combination for diagnosis and assessment of treatment response in pulmonary diseases involving small airways.

Appraising the small airways in asthma

The small airways play an important yet poorly targeted role in asthma pathophysiology, leading to increased morbidity in asthma patients. Assessing inflammation and remodeling in these airways, determining the contribution of small airways to lung dysfunction and enhancing drug delivery to the distal regions of the lung remain challenging. The purpose of this review is to highlight recent advances in our understanding of small airways involvement in asthma. Inflammation in the small airways can be evaluated through exhaled gas measurements, most often nitric oxide. However, additional exhaled biomarkers have recently been described. Considerable infiltration of mast cells in the distal lung and extensive structural changes to the small airways have also been demonstrated. Advances have been made in the functional assessment of small airways, particularly in the measurement of small airway compliance and ventilation defects and in studies investigating the impact of small particle inhaled corticosteroid treatment on lung function. Experimental assessments of small airways inflammation, remodeling and function have provided novel insights into the importance of the distal regions of the lung in asthma pathology. Further advances in drug delivery to the small airways have the potential to improve asthma control.

P257 Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD

Introduction and ObjectivesAlveolar nitric oxide or (CANO), has been used as a surrogate marker of distal airway inflammation, which isimportant in COPD. Coarse particle inhaled corticosteroids (ICS) have been shown...

S9 Inhaled and systemic corticosteroid response in moderate-to-severe asthma assessed by extended exhaled nitric oxide and lung function

Introduction and ObjectivesAlveolar nitric oxide (CANO) has been proposed as a potential biomarker of small airway inflammation in severe asthma. We wished to investigate the effects on CANO of the...

Lipoxygenase-Derived Arachidonic Acid Metabolites in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by a persistence of inflammation in large and small airways. We hypothesized that this could be caused by the inability of an inflammatory process to resolve. In the resolution of inflammation, a switching of arachidonic acid metabolism from the production of proinflammatory leukotriene B(4) (LtB(4)) to the synthesis of anti-inflammatory lipoxins plays an important role. The aim of our study was to determine the content of lipoxin A(4) (LXA(4)) and LtB(4) in induced sputum of patients with exacerbated COPD and to compare it to healthy controls, as well as to analyze the relationship between proinflammatory and anti-inflammatory mediators and an inflammatory cell spectrum in induced sputum. Induced sputum from 17 COPD patients and 7 healthy controls were analyzed for LXA(4) and LtB(4) content and inflammatory cell spectrum. COPD patients had a significantly lower sputum LXA(4) concentration and LtB(4)/LXA(4) ratio compared with healthy controls. A significant negative correlation was found between the LXA(4) concentration and the relative neutrophil count and between the LtB(4)/LXA(4) ratio and the relative macrophage count. COPD patients during the late phase of exacerbation had a suppressed production of LXA(4) and an elevated LtB(4)/LXA(4) ratio in induced sputum demonstrating a proinflammatory imbalance. The correction of a balance between proinflammatory and anti-inflammatory eicosanoids by the administration of stable analogues of lipoxins could improve the treatment of chronic obstructive pulmonary disease in the future.

The Role of Bone Marrow-Derived Adult Stem Cells in a Transgenic Mouse Model of Allergic Asthma

Background: Asthmatic airway remodeling is an abnormal injury/repair process of the small airways caused by chronic inflammation in which the quantities of multiple cells increase dramatically. However, the origin of these proliferative cells is still undetermined. Objective: The aim of this study was to examine whether bone marrow (BM)-derived adult stem cells are responsible for the proliferative cells in asthmatic airway remodeling. Methods: Adult mice were durably engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. Using GFP BM chimera mice, an ovalbumin (OVA)-induced chronic asthma mouse model was established. The distribution of BM-derived GFP+ cells in the lungs of chronic asthma mice was detected by fluorescence microscopy. The phenotype of BM-derived GFP+ cells in the lung tissues of chronic asthma mice was analyzed by flow cytometry. Results: BM chimera mice were successfully generated, with no detectable radioactive inflammation observed. Using BM chimera mice, we established a mouse model of chronic asthma characterized by a significant increase in the thickness of the airway subepithelial basement membrane and smooth muscle layers. OVA treatment caused many GFP+ cells to appear at sites of small airway inflammation. The extravascular localization of some GFP+ cells and their morphology were not consistent with leukocytes. Flow cytometric analysis of lung cells revealed a significant increase in type I collagen (Col I)+GFP+ cells and α-smooth muscle actin (α-SMA)+GFP+ cells in OVA-treated GFP BM chimera mice. Conclusions: Considerable numbers of Col I- and α-SMA-producing cells originated from BM in the lung tissues of mice with OVA-induced chronic asthma.

Effect of inhaled corticosteroids on small airway inflammation in patients with bronchial asthma

Bronchial asthma is a chronic inflammatory disease affecting the bronchial mucosa. In asthma patients, the highest number of inflammatory cells, including eosinophils, are found in the small bronchi. According to the most recent 2006 report of the Global Initiative for Asthma, inhaled corticosteroids (ICS) remain the first-line treatment of chronic asthma. They are characterized by high lung deposition and good distribution in the small bronchi, which makes them particularly efficient in reducing chronic inflammatory infiltrate in the small airways. Good pulmonary distribution of ICS in patients with mild asthma is reflected by a better control of the disease, improvement in the quality of life, improvement in the results of pulmonary function tests, decreased levels of exhaled proinflammatory nitric oxide, lower number of inflammatory cells (including eosinophils) in the induced sputum, decrease in bronchial hyperreactivity, and decrease in exhaled air trapping observed in the computed tomographic scanning of the lungs.

Comparison of alveolar nitric oxide concentrations using two different methods for assessing small airways obstruction in asthma

Fractional exhaled nitric oxide (F(E) NO) is considered a potentially useful biomarker for airway inflammation. A two-compartment model (2CM) of pulmonary NO dynamics has been used for the evaluation of bronchial NO flux (J'awNO) and alveolar NO concentration (C(A) NO) in asthmatic patients. Recently, the trumpet shape of the airway tree and axial diffusion (TMAD) model has been reported as a modification of the 2CM. This study was designed to determine the validity of C(A) NO measurement using the TMAD model for assessing small airways inflammation in asthma. A total of 52 asthmatic patients and 12 normal control subjects were included in the study. Methacholine inhalation challenge and pulmonary function tests, sputum induction, and exhaled NO measurements at several flow rates were performed. J'awNO and C(A) NO were calculated using both the 2CM (C(A) NO( 2CM) , J'awNO( 2CM) ) and TMAD models (C(A) NO( TMAD) , J'awNO( TMAD) ). Both J'awNO (J'awNO( 2CM) and J'awNO( TMAD) ) and C(A) NO (C(A) NO( 2CM) and C(A) NO( TMAD) ) were significantly higher in asthmatic patients than in control subjects. C(A) NO( 2CM) was significantly correlated with FEV(1) /FVC (r = -0.35, P = 0.01), FEF(25-75) (r = -0.45, P < 0.001) and sputum eosinophils (r = 0.32, P = 0.02). In contrast, C(A) NO( TMAD) was significantly correlated with FEF(25-75) (r = -0.42, P = 0.002) but not with FEV(1) /FVC or sputum eosinophils. C(A) NO( TMAD) is more specific as an indicator of small airways obstruction than C(A) NO( 2CM) . Assessment of small airways obstruction using the TMAD model may clarify the role of the small airways in the pathogenesis of asthma.

Comparison of budesonide/formoterol Turbuhaler with fluticasone/salmeterol Diskus for treatment effects on small airway impairment and airway inflammation in patients with asthma

Background A course of combination therapy with an inhaled corticosteroid (ICS) and a long-acting β 2 agonist (LABA) for asthma can improve lung function, asthma symptoms and reduce exacerbations. Because both medicinal substance and inhalation devices are associated with clinical efficacy, each ICS/LABA combination may have different features. This study aimed to compare the effects of two widely available formulations, budesonide/formoterol (BUD/FM) delivered by a Turbuhaler ®, and fluticasone/salmeterol (FP/SM) delivered by a Diskus ®, on small airway function and airway inflammation. Methods Asthmatic patients ( n = 40) treated twice daily with FP/SM 250/50 μg with forced expiratory volume in 1 s values controlled above 80% of the predicted normal but with suspected persistent airway inflammation and small airway impairment were enrolled in the study. Patients were randomized into two groups, receiving either twice daily BUD/FM 320/9 μg or FP/SM 250/50 μg, and treatment efficacy was compared after 4 weeks. Outcomes included impulse oscillometry (IOS), fractional exhaled nitric oxide (FeNO), spirometry and Asthma Control Questionnaire (ACQ) scores. Results Patients in the BUD/FM group showed significant improvements in their IOS and spirometry parameters of small airway function, FeNO values and ACQ scores, compared with the FP/SM group. There were good correlations between IOS parameters, FeNO and ACQ score changes over the course of the treatment. Conclusions BUD/FM twice daily significantly improved small airway impairment and airway inflammation in asthmatic patients, leading to a reduction in asthma symptoms and achievement of good asthma control. In addition, improvement of small airway function may improve airway inflammation and/or lead to better controlled asthma.

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and ex-smoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.

Small airway function, exhaled NO and airway hyper-responsiveness in paediatric asthma

Asthma is a chronic inflammatory airway disorder known to involve the peripheral airways. Current guidelines state that diagnosis and treatment should be guided by symptoms and spirometry. FEV(1) is, however, a poor marker of small airway function and correlates poorly with asthma control and airway inflammation. To assess the contribution of small airway dysfunction and inflammation in paediatric asthma. A secondary aim was to study the associations between small airway dysfunction, airway inflammation and airway hyper-responsiveness (AHR). Small airway function was measured as LCI, S(cond) and S(acin), evaluated with the SF(6) multiple breath inert gas washout (MBW) technique, in 47 asthmatic children and 74 healthy controls. Exhaled NO at multiple exhalation flow rates including 50mL/s (FENO(50)) was assessed to calculate alveolar NO and bronchial NO flux (a surrogate for airway inflammation). AHR was evaluated with isocapnoic dry air hyperventilation challenge in the asthmatic children. S(cond) was elevated in 31 (66%) and S(acin) in 18 (38%) of the asthmatic subjects. LCI was increased and FEV(1) decreased in 7 (15%) of the subjects with asthma. Individuals with AHR had higher S(cond) (p=0.001) and FENO(50) (p<0.0001) than those without AHR. The levels of FENO(50) and bronchial NO flux were elevated in asthmatic subjects compared with healthy controls. In asthma, S(cond) correlated with FENO(50) (r(s)=0.42, p=0.003) and alveolar NO (r(s)=0.40, p=0.011), and S(acin) correlated with alveolar NO (r(s)=0.40, p=0.015). Dysfunction of small conducting airways is associated with airway inflammation and hyper-responsiveness in paediatric asthma.

Utility of Two-Compartment Models of Exhaled Nitric Oxide in Patients with Asthma

Two-compartment models provide more precise information about the contribution of the different portions of the airways to exhaled nitric oxide (NO). Airway wall concentration of NO (Caw,NO) and maximum flux of NO in the airways (J′aw,NO) reflect the tissue production rate of NO and they can be modified by corticosteroids. The airway wall diffusing capacity of NO (Daw,NO) depends on diverse physical and anatomical determinants of the airways, such as gas exchange surface area. Daw,NO can be modified by structural and physiological changes that are characteristic of airway remodeling, which take place over the long term. The alveolar concentration of NO (Calv,NO) represents the degree of small airway inflammation. The persistence of high Calv,NO in patients treated with inhaled corticosteroids could reflect the incapacity of these drugs to reach distal locations due to the heterogeneity of the acinar ventilation. In this review, we evaluate the parameters provided by the compartmentalized analysis of exhaled NO that could be useful in characterizing asthma patients.

The Pilot Study of Specific Biomarkers in Health Effects Among Engineered Nanoparticles Manufacturing Workers

PP-29-165 Background/Aims: Nanotechnology is being promoted rapidly. Although the industrial applications of nanomaterials are increasing daily, in vitro and animal in vivo studies have suggested nanoparticles may cause damage to cellular organelles, lung fibrosis, and granuloma through their ability to trigger the production of reactive oxygen species. However, limited epidemiologic study has been conducted to investigate the potential health effects in the industrial workers. The aim of this pilot study is to develop and identify sensitive and specific markers instead of investigation of health effects of nanoparticles exposure in manufacturing workers from cross-sectional and longitudinal design. Methods: This study conducted by using cross-sectional designs. We recruited 135 nanoparticle-exposed workers and 56 nonexposed workers from 13 plants in Taiwan. The biomarkers investigated include the following: (1) pulmonary inflammation markers, (2) cardiovascular disease markers, (3) genotoxicity comet assay, (4) oxidative stress markers, and (5) activity and polymorphism of antioxidant enzymes. Results: Most of exposed workers were male (84.2%) with the average of 35 years old. Of total, 79% of study subjects were graduated from university and only few had smoking (15.8%) or drinking habits (7.9%). The Clara cell protein (CC16 and NF-kB level (inflammation markers); the activity of MPO and aryl esterase (antioxidant markers); vascular cell adhesion molecule (VCAM) and Low frequency (LF); HF and LF/HF in frequency domain of heart rate variability (HRV) (cardiovascular markers) and FEV1, MMF, FEF50%, and FEF75% in pulmonary function test, and cortisol, aldosterone, and testosterone hormone levels showed higher values in the exposed workers than the nonexposed controls, either in cross-sectional study or in longitudinal repeated measurements study. No significant difference in oxidative damage, comet assay, and cardiovascular markers was found after adjusting for potential confounders. Control Banding from Nanotool Risk Level Matrix was adopted to categorize the exposure risk levels. CC16 and high-sensitive c-reactive protein (CRP) (hsCRP) were significantly increased in risk level (RL) 2 and RL3 and doses dependent. LF in HRV and VCAM were also marginally significantly increased in RL3, but not doses dependent. Conclusion: Biomarkers of small airway damage (CC16) and inflammation (hsCRP) as well as biomarkers of injuries to endothelium (VCAM) and sympathetic nerve activation (LF in HRV) may also be served as health effect markers of nanoparticles exposure. These cardiopulmonary injuries markers may be used for surveillance of health effects of nanoparticles exposure.

Particle size matters: diagnostics and treatment of small airways involvement in asthma

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large- and small-particle size AMP were assessed. After a 4-week run-in period using open-label fluticasone (100 μg b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 μm), large-particle (9.9 μm) and small-particle (1.06 μm) AMP. Subjects received 4-week ciclesonide (160 μg s.i.d.) or fluticasone (100 μg b.i.d.) treatment (double-blind and double-dummy) followed by large- and small-particle AMP provocation. Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV(1)) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV(1) (PC(20)) at the highest AMP dose. In those who did, ciclesonide improved small-particle AMP PC(20) by 1.74 doubling doses (DD) (p = 0.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC(20) significantly (1.32 DD; p = 0.03), whereas ciclesonide did not. Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC(20) with small- and large-particle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.

Increased levels ofNε-(carboxymethyl)lysine in epithelial lining fluid from peripheral airways in patients with chronic obstructive pulmonary disease: a pilot study

It has been reported that small airway inflammation is closely associated with the severity of airflow limitation in COPD (chronic obstructive pulmonary disease). We tested a new method of measurement of biochemical constituents in ELF (epithelial lining fluid) obtained separately from the central or peripheral airways using a bronchoscopic microsampling technique. The present study was designed to determine the validity of measuring CML [N(epsilon)-(carboxymethyl)lysine] levels in ELF for the assessment of small airway inflammation in COPD. Ten non-smokers, ten current smokers and 16 COPD patients were included in the present study. Concentrations of CML, 8-isoprostane and IL-8 (interleukin-8) were measured in ELF separately from the central or peripheral airways. CML levels in central airways did not differ significantly, but were markedly higher in peripheral than in central airways in the three groups. However, CML levels in peripheral airways of COPD patients were significantly higher than those in non-smokers and current smokers. In COPD patients, the CML level in peripheral airways was significantly correlated with FEV1 (forced expiratory volume in 1 s) (r=-0.82, P=0.002) and FEV1/FVC (forced vital capacity) (r=-0.57, P=0.03). Moreover, CML levels in peripheral airways were significantly correlated with levels of both 8-isoprostane (r=0.76, P=0.003) and IL-8 (r=0.67, P=0.01). In conclusion, these findings suggest that elevated levels of CML in ELF from peripheral airways were observed in COPD patients, and this parameter was correlated with the severity of airflow limitation.