key: cord-0684846-a9xcab8t
authors: Perng, Diahn-Warng; Chen, Pei-Ku
title: The Relationship between Airway Inflammation and Exacerbation in Chronic Obstructive Pulmonary Disease
date: 2017-09-04
journal: Tuberc Respir Dis (Seoul)
DOI: 10.4046/trd.2017.0085
sha: e14d8123b56a1b4825bf8aa262ff4f4d0f9549b4
doc_id: 684846
cord_uid: a9xcab8t

Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory response and airflow limitation. Acute exacerbation involves increased inflammatory burden leading to worsening respiratory symptoms, including dyspnea and sputum production. Some COPD patients have frequent exacerbations (two or more exacerbations per year). A substantial proportion of COPD patients may remain stable without exacerbation. Bacterial and viral infections are the most common causative factors that breach airway stability and lead to exacerbation. The increasing prevalence of exacerbation is associated with deteriorating lung function, hospitalization, and risk of death. In this review, we summarize the mechanisms of airway inflammation in COPD and discuss how bacterial or viral infection, temperature, air pollution, eosinophilic inflammation, and concomitant chronic diseases increase airway inflammation and the risk of exacerbation.

Chronic obstructive pulmonary disease (COPD) is defined as a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation caused by exposure to noxious particles or gases. The progressive airflow limitation is attributed to chronic inflammation leading to small airway obstruction and parenchymal Inflammation and Exacerbation

The airflow limitation in COPD is associated with abnormal inflammatory response. Progression of airflow limitation is associated with the increase in accumulation of mucus exudates in the lumen and infiltration of the small airway wall by inflammatory cells 5 . A variety of inflammatory cells are present in the airways of patients with COPD. Neutrophils, macrophages, eosinophils, mast cells, and CD8 + lymphocytes have been shown to play important roles in the inflammatory processes in COPD [6] [7] [8] [9] .

Neutrophils are one of the major inflammatory cell types in COPD 5 . Increased numbers of neutrophils in sputum were found to be correlated with a rapid decline in patients' forced expiratory volume in one second (FEV 1 ) in a 15-year period of observation 10 . In stable COPD patients, FEV 1 showed a significant inverse correlation with the number of neutrophils in induced sputum 11 and in the sub-epithelium from bronchial biopsies 12 , suggesting that neutrophilic inflammation of the airways may play an important role in the pathogenesis of COPD.

Macrophages can be activated by cigarette smoke to release inflammatory mediators and matrix metalloproteases (MMPs). The number of alveolar macrophages was correlated to the extent of emphysema formation 13 and to the severity of airway obstruction 12 . The MMPs, Zn 2+ -dependent proteases, and Ca 2+ -dependent proteases can degrade a broad range of connective tissue proteins and are involved in remodeling damaged tissue. Increased activity of MMP-8 (collagenase) and MMP-9 (gelatinase) was detected in induced sputum from patients with COPD, and this activity was correlated to the degree of airflow limitation 14 . In the animal model of knockout mice, MMP-12 deficiency can block the increase in macrophages in the lungs and the development of emphysema in response to long-term exposure to cigarette smoke 15 . In addition, MMP-12 mediates smoke-induced inflammation by releasing tumor necrosis factor α (TNF-α) from macrophages with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases 16 .

The role of eosinophils in COPD and the mechanism of eosinophil influx into airways remain to be clarified. Hogg et al. 5 reported that eosinophils do exist in the small airways of various severity of COPD. In a prospective clinical observation, nearly one third of COPD patients had sputum eosinophilia and the number of eosinophils was significantly correlated to the level of exhaled nitric oxide 17 . The degree of eosinophilic inflammation has been related to early changes in lung function and smoking habits. The higher counts of eosinophils in induced sputum is associated with higher pack-years and lower peak expiratory flow 25%-75% values 18 . In a retrospective analysis, FEV 1 reversibility was weakly correlated with the sputum eosinophil level. Patients with FEV 1 >0.4 L and >15% increment had higher sputum eosinophil levels whereas the level did not differ when dichotomized by FEV 1 increment >0.2 L and >12% 19 . The response to corticosteroids in COPD patients were better in a subset of patients presenting with more eosinophils and higher levels of eosinophil cationic protein 20 , suggesting that corticosteroids may be effective especially for patients with COPD with eosinophilic airway inflammation 21, 22 . In addition, we had reported that inhaled fluticasone (200 µg/day) can significantly suppress the numbers of eosinophils in the airways of COPD. Suppression of such eosinophilic inflammation was not associated with improvement in lung function. Brightling et al. 23 also reported that the improvement in FEV 1 is not associated with a reduction in the sputum eosinophil count in COPD with sputum eosinophilia.

Increased CD8 + T lymphocytes have been shown in the central and peripheral airways and lung parenchyma in COPD 12, 13, 24, 25 . The increased number of CD8 + T lymphocytes in the subepithelium has been correlated with the severity of airflow limitation 26 . Increased cytotoxic activity of CD8 + T cells was observed in induced sputum of patients with COPD compared to those of smokers without COPD and healthy subjects. The expression of perforins, a secreted molecule that causes cytolysis, was also high 27 . However, one in vitro study demonstrated that cytolytic activity of CD8 + T cells against alveolar epithelial cells is perforin-independent and is attributed entirely by TNF-α, which is expressed on CD8 + T cells 28 . However, the contribution of CD8 + T cell and the ratio of CD4 + /CD8 + cells to the pathogenesis of COPD as well as the cell recruitment to the airways are not clear.

Acute exacerbation is associated with increased inflam- matory burden leading to worsening respiratory symptoms including dyspnea and sputum production. In the ECLIPSE study, the exacerbation rates were 0.85, 1.34, and 2.0 (number/ yr/patient) for patients with Global Initiative for Obstructive Lung Disease (GOLD) stages 2, 3, and 4, respectively, during the first year of follow-up 4 . The exacerbation rates were significantly associated with post-bronchodilator FEV 1 , impairment in health status, history of reflux or heartburn, white blood cell count, and prior history of exacerbation. In addition, acute exacerbation of COPD had been found to be an independent factor of mortality, suggesting more exacerbations with higher mortality 29 . In a subgroup analysis in the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study, 39% and 36% of patients with or without inhaled corticosteroid treatment had no exacerbation in the first year of follow-up. During the three-year study period, 22% and 23% of patients respectively had no exacerbations 30 . In a retrospective observational study, 85.5%, 80.4%, 60.6%, and 48.1% of COPD patients with GOLD classification group A, B, C, and D had no acute exacerbation in the previous year before enrollment 31 .

Inflammation?

In a prospective observational study, 55% and 29% of COPD patients had bacteria or virus-associated exacerbations, respectively 32 . The most common causes of bacteria-associated exacerbations were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae 33 . The major viruses associated with COPD exacerbations were rhinovirus (common cold), coronavirus, influenza, and parainfluenza 34 . Papi et al. 35 reported that patients with infectious exacerbation (bacteria, virus, or coinfection) may have longer hospitalization and greater impairment of lung function compared to those noninfectious exacerbations. Sputum neutrophilia were observed in all exacerbations and was associated with disease severity. Sputum eosinophilia was observed during virus-associated exacerbations 35 .

Normally, the lower airways are sterile. Bacterial components such as flagella, lipoproteins, and lipopolysaccharides may initiate inflammatory reactions by releasing a variety of pro-inflammatory mediators and recruiting inflammatory cells 36 . For example, protein A from staphylococci can recognize TNF-α receptors in airway epithelium and induce production of IL-8, which is an important chemokine for neutrophils 37 . Pseudomonas aeruginosa flagella can activate airway epithelial cells to produce IL-8 through toll-like receptors 2 and 5 38 . In stable COPD patients, sputum neutrophils and IL-8 levels were higher than those in healthy subjects, which suggested ongoing neutrophilic inflammation in the airways 11 .

Sputum IL-8 levels were reported to be correlated with total bacterial count, and bacterial load in the airways was associated with increased exacerbation frequency 39 . Rhinovirus infection can increase the production of IL-8, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) from airway epithelial cells; IL-8 production was associated with viral replication 40 . In a study in mice, influenza virus infection resulted in influx of neutrophils, monocytes, lymphocytes, and eosinophils as well as various chemokines and cytokines 3 to 10 days after infection 41 .

Increased concentration of outdoor pollutants such as NO 2 , O 3 , SO 2 , particulate matter 2.5 (PM 2.5 ), and particulate matter 10 (PM 10 ) were associated with increased respiratory symptoms, acute exacerbations, and hospital admissions in COPD patients 42 . Inhalation of high concentration of NO 2 may correlate to acute epithelial damage 43 . Cultured human bronchial epithelial cells exposed to NO 2 could increase the expression of IL-1β, IL-8, GM-CSF, and TNF-α 44 . SO 2 can lead to airway edema, inflammation, and fibrosis in an animal model after 3-25 days' exposure to different levels of SO 2 45 . O 3 and PM 10 have been reported to increase the incidence of hospital admission for pneumonia and acute exacerbation of COPD in a meta-analysis based on city-specific regression models 46 . Short-term PM 2.5 exposure was associated with an increased risk of about 0.9% for COPD hospitalization 47 . In an epidemiologic study, for every 10 µg/m 3 increase in O 3 , NO 2 , and SO 2 concentrations, the risks of hospitalization for COPD increase to about 0.58%, 0.38%, and 0.44%, respectively 48 . Seasonal variations and temperature may affect the incidence of acute exacerbation of COPD. Tseng et al. 49 reported that a 1°C decrease in air temperature was associated with a 0.8% increase in the exacerbation rate on event-days. The cold temperature was reported to be linked to bronchoconstriction 50 and FEV 1 decrease 51 especially for COPD patients.

The gastroesophageal refluxate contains gastric acids, bile, and pepsin. Gastroesophageal reflux (GER) is a major cause of subacute and chronic cough. In a questionnaire-based prospective survey, the prevalence of GER disease (GERD) was 26.7% among stable COPD patients, and severe GERD symptoms were associated with more frequent exacerbations of COPD and hospitalization with crude relative risks of 3.42 and 3.66, respectively 51 . Casanova et al. 52 reported that severe COPD patients had high prevalence of GERD (62%) confirmed by esophageal 24-hour pH monitoring but 58% of them did not have any reflux symptoms. In addition, the annual rate of exacerbations of COPD was twice as high in patients with GER symptoms compared to those without GER Tuberc Respir Dis 2017;80:325-335

www.e-trd.org symptoms (3.2/yr vs. 1.6/yr, p=0.02) 53 . In our previous study, the amount of total bile acids in induced sputum was significantly higher in patients with GER and asthma-associated GER symptoms compared to that of healthy control subjects (p<0.005). Bile acid significantly induced transforming growth factor β1 (TGF-β1) production from airway epithelial cells, which in turn enhanced fibroblast proliferation 54 and altered alveolar epithelial permeability, which may contribute to the pathogenesis of lung injury 55 . Airway epithelium exposed to bile acids could induce fibrosis via production of connective tissue growth factor (CCN2). CCN2 is essential for TGF-β1induced fibrogenesis and functions as a downstream mediator of TGF-β1 action on fibroblasts 56 . The major bile acid, chenodeoxycholic acid, stimulated alveolar epithelial cells to increase IL-8 production through p38 and c-Jun N-terminal kinase activation. This may enhance neutrophilic inflammation in chronic airway disorders 57 . How to intervene and attenuate GER-related inflammation and fibrogenesis in chronic airway disorders is worth further investigation.

The prevalence of bronchiectasis in COPD varies according to COPD severity. In a prospective observational study, 50% of moderate to severe COPD patients had significant detectable bronchiectasis on high-resolution computed tomography scanning. Lower lobe bronchiectasis was associated with bacterial colonization quantified by sputum sampling 58 . Martinez-Garcia et al. 59 reported that the prevalence of bronchiectasis in moderate and severe COPD patients was 34.7% and 72.5%, respectively. Patients with bronchiectasis had more chronic expectoration, more exacerbation indices, more severe airflow obstruction, and greater positive cultures of potentially pathogenic microorganism. Haemophilus influenzae and Pseudomonas aeruginosa were the most common microorganisms isolated from sputum 59 . In addition, moderate-to-severe COPD patients with bronchiectasis was associated with increased all-cause mortality (37.4%) compared to COPD patients without bronchiectasis (9.3%) 60 .

Eosinophilic airway inflammation is a characteristic feature of atopic asthma and exists in a subgroup of COPD. Bafadhel et al. 32 reported that 28% of cases of acute exacerbation of COPD were associated with sputum eosinophilia. In our previous study, 32% of naïve COPD patients had sputum eosinophilia and tended to have higher serum IgE levels and positive allergen tests 17 . Patients with asthma-COPD overlap syndrome may present with more respiratory symptoms, worse lung function, and increased risk of exacerbation and hospitalization (prevalence ratio, 2.11 and 4.11, respectively) compared to patients with COPD alone 61 . Hardin et al. 62 reported that patients with asthma and COPD overlap syndrome (ACOS) were more likely to experience frequent exacerbations (odds ratio, 3.55) and have had a severe exacerbation in the past years. In a prospective randomized study, a reduction in eosinophilic airway inflammation was associated with a reduction in severe exacerbation of COPD 63 . Sputum eosinophilia and high blood eosinophil counts are associated with increased responsiveness to steroids in COPD patients 22, 23, 64, 65 . Accordingly, the detection of eosinophilic inflammation is a crucial step to make a precise treatment in COPD patients.

In an epidemiologic study for COPD, the risk of obstructive sleep apnea (OSA) assessed by questionnaire was 29.5% among COPD patients 66 . The prevalence was reported to be 65.9% for moderate to severe COPD confirmed by polysomnography 67 . Marin et al. 68 showed that COPD patients with OSA overlap syndrome without continuous positive airway pressure (CPAP) treatment had higher mortality rates and were more likely to have a severe COPD exacerbation leading to hospitalization (relative risk, 1.70; 95% confidence interval [CI], 1.21-2.38) compared to patients with COPD alone. OSA exacerbated airway inflammation by increasing neutrophil proportion and levels of IL-8 and TNF-α in bronchoalveolar lavage fluid samples from moderate to severe COPD patients. The augmentation of inflammation can be curbed by treatment with CPAP 69 . The mechanisms of how OSA exacerbates airway inflammation in COPD remain to be elucidated.

The significant predictors or factors that are associated with increased risk of acute exacerbation in COPD is summarized in Table 1 .

Long-acting bronchodilators such as long-acting muscarinic antagonist (LAMA) and long acting β 2 -adrenergic receptor agonist (LABA) are the major pharmacological drugs for COPD to improve airflow limitation, respiratory symptoms, and quality of life as well as reduce exacerbations 70, 71 . The mechanisms of long-acting bronchodilators in reducing exacerbation either by improving hyperinflation or targeting inflammation remain controversial. The combination of LABA and corticosteroids can reduce the numbers of macrophages 72 , neutrophils 73 , and CD8 + T lymphocytes 72, 73 in bronchial biopsy tissue and in induced sputum from patients with COPD. We had reported that the combination of inhaled salmeterol and fluticasone caused a significant reduction in IL-8 and MMP-9 in induced sputum from COPD patients compared to levels in those who received treatment with tiotropium alone 74 . Tiotropium can www.e-trd.org inhibit airway inflammation and remodeling 75 and attenuate neutrophilic inflammation as well as associated mediators LTB 4 , IL-6, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1, MIP-2, and TNF-α in the animal model 76 . In clinical studies, the odds ratio for tiotropium in reducing exacerbations compared to placebo was 0.74 (95% CI, 0.66-0.83) and hospitalizations 0.69 (95% CI, 0.55-0.87) 77 . Indacaterol and formoterol can suppress neutrophilassociated mediators such as reactive oxygen species, LTB 4 , and elastase in a dose-dependent manner 78 . In a prospective, randomized, blinded, and double-dummy study, it was found that tiotropium was superior to indacaterol in terms of annualized exacerbation rate (0.61 vs. 0.79) for severe COPD 79 . A combination of indacaterol and glycopyrronium significantly reduced the annual rate of moderate to severe exacerbations versus glycopyrronium alone by 12%, suggesting that the combination of indacaterol/glycopyrronium was superior in preventing moderate to severe exacerbations compared to glycopyrronium alone 80 . Roflumilast, a]' phosphodiesterase-4 (PDE 4 ) inhibitor, has been reported to significantly reduce moderate to severe exacerbations by 17% compared to placebo for severe COPD patients with chronic bronchitis and frequent exacerbation phenotype 81 . PDE 4 inhibitors were associated with a reduced likelihood of COPD exacerbation with odds ratio 0.77 (95% CI, 0.71-0.83) in a pooled analysis 82 . Choosing the optimal LABA, LAMA, dual bronchodilator, PDE 4 inhibitor, inhaled corticosteroids, or specific combination of different drugs for COPD patients with various severity and phenotype is challenging in our clinical practice.

Pneumococcal and influenza vaccinations have been recommended for patients with COPD as a preventive strategy 1 . A recent meta-analysis showed that pneumococcal vaccination can provide significant protection against community-acquired pneumonia (CAP) and reduce the likelihood of a COPD exacerbation 83 . By contrast, Sehatzadeh 84 reported that the time to the first episode of CAP due to pneumococcus or of unknown etiology was not significantly different between the vaccine and control groups. Nevertheless, hospital admission rates and median lengths of hospital stay were lower in the vaccine group but were not statistically significant 84 . For influenza vaccination, it was found that the vaccine group had fewer episodes of influenza-related acute respiratory illnesses in all severities (mild, moderate, and severe) of COPD, fewer hospitalizations, and fewer requirements for mechanical ventilation 84 .

It is necessary to promote and conduct research on ambient air pollution as a COPD risk factor. It is necessary to form a partnership with government institutions such as the Environmental Protection Agency (EPA) and academic institutions to investigate the detrimental effect of environmental exposure and occupational hazards as well as to apply prevention strategy and patient education. The U.S. EPA has recommended that time and intensity of outdoor activity should be regulated by air quality index since 2009. The N95 respirator was reported to be able to provide excellent protection against airborne particles 85 .

Aspiration of gastroesophageal refluxate can trigger exacerbation of COPD and enhance airway inflammation and fibrosis as we discussed earlier. Among COPD patients with GERD, those who did not use acid inhibitory treatment regularly had a significantly increased risk of COPD exacerbation with a hazard ratio (HR) of 2.7 as compared to those who were treated regularly with an HR of 1.2 86 . In moderate to severe asthma patients with GERD and nocturnal respiratory symptoms, taking proton pump inhibitors significantly improved morning and evening peak expiratory flow over those taking palcebo 87 . The ability to identify COPD patients who are at risk for GERD or GER-related chronic cough is essential to COPD management. It is worth conducting randomized trials to investigate the efficacy of anti-acid and anti-reflux therapy on COPD patients with GERD and whether these treatments can decrease respiratory symptoms, improve lung function, and quality of life as well as reduce exacerbation.

In a prospective study, the incidence of bacterial colonization in bronchiectasis was as high as 64%. The risk factors included diagnosis of bronchiectasis before the age of 14 years (odds ratio [OR], 3.92), FEV 1 <80% predicted (OR, 3.91) and presence of varicose or cystic bronchiectasis (OR, 4.8) 88 . Bacterial infection can cause airway inflammation, which can subsequently result in exacerbation. COPD patients with bronchiectasis have more respiratory symptoms, more exac-erbations, and worse prognosis. Azithromycin 250 mg taken daily for 1 year, decreased the frequency of exacerbations (HR, 0.73; p<0.001) and improved the quality of life among COPD patients 89 . The clinical efficacy on hospitalization, urgent care visit, and intubation was similar between both groups and the adverse reaction (hearing impairment) was more common in the azithromycin group. Uzun et al. 90 reported that azithromycin 500 mg taken 3 times a week for 12 months resulted in a significant reduction in the exacerbation rate versus placebo (HR, 0.58; p=0.001) among COPD patients who had 3 or more exacerbations in the previous year. A small study demonstrated that inhaled tobramycin reduced the inflammatory impact of Pseudomonas aeruginosa in a multiresistant Pseudomonas-colonized patient with severe COPD after 2-week treatment. A 42% reduction in exacerbation rate was observed in the 6-month follow-up 91 . The ability to select patients, choose appropriate antibiotics, decide the duration of treatment are the major concerns for treatment strategy for frequent exacerbations of COPD with bacterial colonization.

Whether eosinophilic inflammation in COPD is attributable to ACOS or is a specific phenotype of COPD is still controversial. However, the response of eosinophilic inflammation to treatment would be more important than the delineation of the differences between these two terms. Early detection of characteristic features of asthma or eosinophilic airway inflammation in COPD patients is necessary before starting treatment. Zanini et al. 92 reported that COPD patients with bronchial hyper-responsiveness (BHR) had higher sputum eosinophils than those without BHR. The change in FEV 1 was positively correlated with sputum eosinophils while patients had bronchial reversibility 19, 92 . The prevalence of elevated serum IgE had been reported to be 47.3% in COPD patients 93 . Serum IgE levels were associated with COPD severity 94 and sputum eosinophilia 17 . The levels of eosinophils in sputum samples were significantly correlated with exhaled nitric oxide level (eNO) 17 . The eNO, blood eosinophils, and antigenspecific IgE were significantly higher in ACOS than in COPD alone according to a cross-sectional study in Japan 95 . Blood eosinophils were proposed to be a surrogate marker for airway eosinophilia in stable COPD 96 and a marker of response to inhaled corticosteroids 97 . COPD patients with blood eosinophils ≥2% treated with inhaled corticosteroid/LABA had significantly fewer exacerbations than those treated with LAMA (relative risk [RR], 0.75; p=0.006, INSPIRE study) or placebo (RR, 0.63; p<0.001) 98 . It is warranted to conduct a prospective study to determine which marker is better in predicting corticosteroid response in COPD with eosinophilic airway inflammation. www.e-trd.org

CPAP is considered to be the standard treatment for OSA patients. The benefit of CPAP treatment on reducing airway inflammation in COPD is barely discussed. CPAP may reduce oxidative stress by decreasing plasma malondialdehyde in OSA 99 and significantly reduce urinary norepinephrine levels and blood pressure in patients with severe OSA 100 . Briefly, OSA may exacerbate airway inflammation in COPD and CPAP is the optimal choice to reverse the inflammatory process so far.

Though airway inflammation in COPD varies based on severity, there is still a gap between inflammation and exacerbation. Bacterial or viral infection, air pollution, GERD, bronchiectasis with bacterial colonization, and eosinophils may breach the airway stability and lead to overwhelming inflammation and acute exacerbation. The application of antiinflammatory agents and vaccines, prevention strategies for air pollution, early detection of GERD, reduction of bacterial load in bronchiectasis, and measurement of biomarkers that can predict response to corticosteroids are becoming the therapeutic goals to minimize the risks of acute exacerbation. We still need more evidence and clinical studies to achieve these endpoints and improve health-related quality of life among COPD patients.

No potential conflict of interest relevant to this article was reported.

Global Initiative for Chronic Obstructive Lung Disease: global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO workshop report, publication No. 2701. Bethesda, MD: National Institutes of Health; National Heart, Lung, and Blood Institute

Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease

COPD exacerbations. 2: aetiology

Susceptibility to exacerbation in chronic obstructive pulmonary disease

The nature of small-airway obstruction in chronic obstructive pulmonary disease

Eosinophilic inflammation in stable chronic obstructive pulmonary disease: relationship with neutrophils and airway function

The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a doubleblind, placebo-controlled biopsy study

Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease

The cellular composition of induced sputum in chronic obstructive pulmonary disease

Airways obstruction, chronic expectoration, and rapid decline of FEV 1 in smokers are associated with increased levels of sputum neutrophils

Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment

Severity of airflow limitation is associated with severity of airway inflammation in smokers

Alveolar inflammation and its relation to emphysema in smokers

Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD

Requirement for macrophage elastase for cigarette smokeinduced emphysema in mice

Macrophage metalloelastase mediates acute cigarette smokeinduced inflammation via tumor necrosis factor-alpha release

Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD

Eosinophils in induced sputum from asymptomatic smokers with normal lung function

Post-bronchodilator reversibility of FEV 1 and eosinophilic airway inflammation in COPD

Corticosteroid reversibility in COPD is related to features of asthma

Eosinophilic inflammation in the airway is related to glucocorticoid reversibility in patients with pulmonary emphysema

Sputum eosinophilia and shortterm response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial

Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease

CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease

Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema

Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV 1

Perforin expression and cytotoxic activity of sputum CD8+ lymphocytes in patients with COPD

Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand

Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease

Inhaled Steroids in Obstructive Lung Disease in Europe Study Investigators. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations

Factors associated with the prescription of inhaled corticosteroids in GOLD group A and B patients with COPD: subgroup analysis of the Taiwan obstructive lung disease cohort

Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers

Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review

Role of viruses in exacerbations of chronic obstructive pulmonary disease

Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations

Airway epithelial cell signaling in response to bacterial pathogens

Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1

Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as tolllike receptor 5

Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations

Infection of a human respiratory epithelial cell line with rhinovirus: induction of cytokine release and modulation of susceptibility to infection by cytokine exposure

Time-dependent airway epithelial and inflammatory cell responses induced by influenza virus A/PR/8/34 in C57BL/6 mice

Air pollution and chronic obstructive pulmonary disease

Janssen-Heininger YM. Nitrogen dioxide induces death in lung epithelial cells in a density-dependent manner

Effect of nitrogen dioxide on synthesis of inflammatory cytokines expressed by human bronchial epithelial cells in vitro

Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD)

The effect of ozone and PM10 on hospital admissions for pneumonia and chronic obstructive pulmonary disease: a national multicity study

Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases

Effect of exposure to O 3 , NO 2 , and SO 2 on chronic obstructive pulmonary disease hospitalizations in Tabriz

The effect of cold temperature on increased exacerbation of chronic obstructive pulmonary disease: a nationwide study

Bronchoconstriction due to cold weather in COPD. The roles of direct airway effects and cutaneous reflex mechanisms

Prospective evaluation of the relationship between acute exacerbations of COPD and gastroesophageal reflux disease diagnosed by questionnaire

Increased gastro-oesophageal reflux disease in patients with severe COPD

Role of gastroesophageal reflux symptoms in exacerbations of COPD

Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation

Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2, cyclooxygenase-2, prostaglandin E2 and junctional proteins

Bile acids induce CCN2 production through p38 MAP kinase activation in human bronchial epithelial cells: a factor contributing to airway fibrosis

Bile acid aspiration in suspected ventilator-associated pneumonia

Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease

Factors associated with bronchiectasis in patients with COPD

Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease

Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma

The clinical features of the overlap between COPD and asthma

Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial

Inhaled fluticasone and salmeterol suppress eosinophilic airway inflammation in chronic obstructive pulmonary disease: relations with lung function and bronchodilator reversibility

Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis

Predictive factors warrant screening for obstructive sleep apnea in COPD: a Taiwan National Survey

High prevalence of obstructive sleep apnea in patients with moderate to severe chronic obstructive pulmonary disease

Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome

Obstructive sleep apnea exacerbates airway inflammation in patients with chronic obstructive pulmonary disease

Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators

Drugs for chronic obstructive pulmonary disease

Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial

Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease

Antiinflammatory effects of salmeterol/fluticasone, tiotropium/ fluticasone or tiotropium in COPD

Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD

Tiotropium bromide exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD

Role of tiotropium in the treatment of COPD

The beta-2-adrenoreceptor agonists, formoterol and indacaterol, but not salbutamol, effectively suppress the reactivity of human neutrophils in vitro

Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallelgroup study

Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study

Pharmacological strategies to reduce exacerbation risk in COPD: a narrative review

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Pneumococcal vaccines for preventing pneumonia in chronic obstructive pulmonary disease

Influenza and pneumococcal vaccinations for patients with chronic obstructive pulmonary disease (COPD): an evidence-based review

Performance of N95 respirators: filtration efficiency for airborne microbial and inert particles

Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease

Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial

Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors

Azithromycin for prevention of exacerbations of COPD

Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial

Tobramycin nebulizer solution in severe COPD patients colonized with Pseudomonas aeruginosa: effects on bronchial inflammation

Bronchial hyperresponsiveness, airway inflammation, and reversibility in patients with chronic obstructive pulmonary disease

The prevalence of increased serum IgE and Aspergillus sensitization in patients with COPD and their association with symptoms and lung function

Association of severity of COPD with IgE and interleukin-1 beta

Inflammatory biomarkers in asthma-COPD overlap syndrome

Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD

Blood eosinophils as a marker of response to inhaled corticosteroids in COPD

Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD

Effects of nasal positive airway pressure treatment on oxidative stress in patients with sleep apnea-hypopnea syndrome

Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea