Inflammation In Chronic Obstructive Pulmonary Disease Patients Research Articles

Impacts of event-specific air quality improvements on total hospital admissions and reduced systemic inflammation in COPD patients

There is limited evidence linking the impacts of reduced air pollution on hospital admissions. The potential biological mechanisms are still not completely understood. This study examined the effects of mitigated ambient pollution on hospital admissions and inflammatory biomarker levels in chronic obstructive pulmonary disease (COPD) COPD patients. Daily hospital admissions were compared over 51 days associated with the Asian Games period (Nov 1-Dec 21, 2010) with the identical calendar dates of baseline years (2004–2009 and 2011–2013). A three-year cohort study was conducted with 36 COPD patient participants. The daily particulate matter (PM10) decreased from 65.86 μg/m3 during the baseline period to 62.63 μg/m3 during the Asian Games period; the daily NO2 level decreased from 51.33 μg/m3 to 42.63 μg/m3. Between the baseline period and the Asian Games, daily hospital admissions from non-accidental diseases decreased from 116 to 93, respectively; respiratory diseases decreased from 20 to 17, respectively; and cardiovascular diseases decreased from 11 to 9 during the Asian Games period, respectively. No statistically significant reductions were seen in the remaining months of 2010 in Guangzhou, during the the Asian Games period in the control city, and two other control diseases. Furthermore, we identified significant improvement in CRP and fibrinogen by -20.4% and -15.4% from a pre-Asian game period to a during-Asian game period, respectively. For CRP, we found significant increases in NO2 at lag1-3 days after-Asian game period and significant increases in PM10 at lag1-2 days. Similar effects were also seen with fibrinogen. This discovery provides support for efforts to diminish air pollution and improve public health through human air pollutants intervention. Improved air pollution during the 2010 Asian games was correlated with decreases in biomarkers associated with systemic inflammation in COPD patient participants.

Systemic inflammation in patients of chronic obstructive pulmonary disease with metabolic syndrome.

Context:India has 18% of the global population and an increasing burden of chronic respiratory diseases. The prevalence of Metabolic syndrome (MS) was found to be as high as 39.7% among Indian population. Metabolic syndrome is found to be more common in Chronic Obstructive Pulmonary Disease (COPD) when compared to the general population. This study was done to assess the prevalence of metabolic syndrome in COPD and the association of systemic inflammation in COPD patients with metabolic syndrome.Methodology:This study enrolled 150 consecutive consenting patients of stable COPD attending the outpatient pulmonology department. Detailed history, clinical examination, spirometry, and relevant routine laboratory investigations including complete blood count, fasting blood sugar, and lipid profile were done. In addition, hsCRP, Serum lactate and Vitamin D level was assessed in all patients. Diagnosis of COPD and Metabolic syndrome was done according to GOLD guidelines, 2018 and the International Diabetes Federation criteria respectively.Result:The prevalence of metabolic syndrome was found to be 27.3% in our COPD patients. The frequency of metabolic syndrome in GOLD stage I, II, III, and IV was 75%, 32%, 17%, and 13.5%, respectively. Logistic regression analysis showed a significant relationship of blood leucocyte count (OR = 0.342, CI = 0.171-0.686), hs-CRP (OR = 0.020, CI = 0.003-0.122), pack years (OR = 1.083, CI = 1.026-1.14) and vitamin D levels (OR = 1.219, CI = 1.093-1.359) with metabolic syndrome in COPD patients.Conclusion:Metabolic syndrome is a co-morbidity that is very often overlooked in patients of COPD. Systemic inflammation which is a common characteristic of both COPD and Metabolic syndrome has been found to be an important contributor towards cardiovascular morbidity and mortality.

Serum Cystatin C Levels in COPD: Potential Diagnostic Value and Relation between Respiratory Functions.

SummaryBackgroundThe aim of this study was to determine the level of serum cystatin C (CysC) in patients with Chronic Obstructive Pulmonary Disease (COPD) during exacerbation and stable periods and to investigate its potential diagnostic value and the relationship between CysC levels and the pulmonary function test (PFT).MethodsOne hundred twenty-six patients with COPD (68 in stable periods, 58 during exacerbation periods) and 50 healthy subjects were included in the study. PFT, body mass index (BMI), white blood cell counts, C-reactive protein (CRP), serum urea and creatinine levels were evaluated in both groups of patients. CysC levels were measured in all participants.ResultsSerum CysC levels were statistically higher in both COPD groups than the control group (p<0.001 for both) although there was no statistically significant difference between COPD groups (p>0.05). CysC levels showed negative correlation with forced expiratory volume in 1 second (FEV1) and a positive correlation with C-reactive protein (CRP) levels in patients with stable COPD. There was a positive correlation between serum CysC levels and serum urea, creatinine, CRP levels in patients with COPD exacerbation (r=0.333, p=0.011; r=0.260, p=0.049; r=0.414, p<0.01 respectively). When stable COPD and control groups were evaluated, serum CysC had an area under the curve (AUC) in the receiver operating characteristic (ROC) curve of 0.951 (0.909–0.994 95% CI: p<0.001).ConclusionsOur results showed that CysC levels increased in both COPD groups. Increased CysC levels may be related with lung function decline and inflammation in COPD patients. In addition, CysC levels may be a potential indicator for the diagnosis of COPD.

Downregulation of Sfrp5 in insulin resistant rats promotes macrophage-mediated pulmonary inflammation through activation of Wnt5a/JNK1 signaling

BackgroundInsulin resistance (IR), a common co-morbidity of chronic obstructive pulmonary disease (COPD), aggravates airway inflammation in COPD patients, but its mechanism is unclear. Sfrp5, a novel anti-inflammatory adipocytokine, inhibits macrophage-mediated inflammation of adipose tissue and abrogates IR. However, few studies have been conducted on the regulatory role of Sfrp5 in lung inflammation. MethodsIn the present study, 30 SD rats were divided into two groups: the normal food (NF) group and the high-fat diet (HFD) group. Oral glucose tolerance test (OGTT) and insulin release test were performed to assess whether a successful IR rat model was established. The expression of Sfrp5 and key downstream moleculars of Wnt5a/JNKl signaling was detected. Lung tissue pathomorphology and macrophage activation were observed. In addition, we counted the number of inflammatory cells and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In vitro, rat lung macrophages were isolated and treated with Wnt5a, Sfrp5, and/or JNK inhibitor SP600125. JNK activity and inflammatory cytokines expression were examined. ResultsWe found that in a rat model of IR, Sfrp5 expression of lung tissue was downregulated, while the Wnt5a/JNKl pathway was activated and the lung inflammatory response was enhanced. Meanwhile, Sfrp5 significantly suppressed Wnt5a/JNKl-induced macrophage activation. ConclusionsCollectively, IR reduces Sfrp5 expression of lung tissue and activates the Wnt5a/JNK1 pathway, promoting macrophage activation and contributing to the lung's inflammatory response. In contrast, Sfrp5 suppresses the inflammatory response by inhibiting the Wnt5a/JNKl pathway, which could be a target of treatment of COPD.

Increased Kynurenine Plasma Concentrations and Kynurenine-Tryptophan Ratio in Mild-To-Moderate Chronic Obstructive Pulmonary Disease Patients

Since an increase in kynurenine (Kyn) plasma concentrations has been proposed as marker of immune system activation, we studied the associations between the Kyn levels and presence and severity of chronic obstructive pulmonary disease (COPD). Plasma Kyn, tryptophan (Trp) and Kyn/Trp ratio were measured in 43 COPD patients with clinically defined mild (n=29) or moderate (n=14) disease and 43 age- and sex-matched healthy controls. When compared with controls, COPD patients had significantly higher plasma Kyn concentrations and Kyn/Trp ratios. In multiple logistic regression analysis, after adjusting for clinical and demographic confounders, the Kyn/Trp ratio was independently associated with COPD severity. Kyn and Kyn/Trp ratio might represent a new, sensitive, biomarker of systemic inflammation in COPD patients.

Role of neutrophil to lymphocyte ratio in prediction of acute exacerbation of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lung. Some of the inflammatory markers such as C-reactive protein (CRP), leukocyte count are associated with COPD. The aim of this study is to evaluate the role of neutrophil-to-lymphocyte ratio (NLR) as new inflammatory marker in COPD patients in comparison with the other well-known inflammatory markers. We prospectively evaluated neutrophil-to-lymphocyte ratio, CRP and ESR in 60 patients with stable COPD and 68 COPD patients during acute exacerbation and 60 sex- and age-matched healthy controls. We found that NLR values during acute exacerbation of the disease were significantly higher than those during stable period (P<0.001). NRL values of the stable COPD patients were significantly higher than those of the controls (P<0.001). NLR values were also positively correlated with serum CRP levels, ESR, and WBC. ConclusionNLR can be used as a new inflammatory marker for assessment of inflammation in COPD patients. It is a good predictor for exacerbation of COPD. It is a quick, cheap, easily measurable marker with no need for a special request.

The impact of smoking on inflammatory biomarkers in patients with chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by airflow limitation that is not fully reversible (Nillawar et al., 2012). The pathophysiology of COPD is not completely understood. Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Elevated CRP has been increasingly used as a surrogate marker of systemic inflammation in diverse conditions. TNF-α, a powerful pro-inflammatory cytokine primarily produced by activated macrophages, is thought to play a critical role in the pathogenesis of COPD (Higashimoto et al., 2008; Churg et al., 2002). The aim of the workTo evaluate the impact of smoking on inflammatory biomarkers and relations between these biomarkers and the decline of lung function in COPD patients. MethodsThis case–control observational prospective study was conducted on fifty-eight clinically stable COPD patients (26 non-smokers and 32 current smokers; at different stages ranged from mild to very severe), their mean age 53.1±14.25 and 53.9±5.95years respectively), recruited from Chest Department, Assiut University Hospitals. All patients met the Global Initiative for Obstructive Lung Disease (GOLD) (Battaglia et al., 2007). All participants were subjected to thorough history taking, full clinical examination, anthropometric measurements with spirometry and chest X-ray. Peripheral hemogram, liver function tests, kidney function tests, high sensitivity C-reactive protein (hs CRP) and serum level of TNF-α were measured for both patients and controls. ResultsThe concentrations of circulating hs-CRP and TNF-α, were highly significantly elevated in patients with COPD in comparison to the control group (3.74±0.2 vs. 1.30±0.14 for hs-CRP; 33.88±5.97 vs. 8.79±0. 57 for TNF-α with p<0.0001 for each) and the levels of measured TNF-α were significantly increased with the increased degree and severity of COPD and increased severity of smoking status. Regarding the smoking status of COPD patients, there was a highly significant difference for the measured TNF-α (53. 74±9.52 versus 12.73±1.20 with p<0.0001) with no significant difference for the measured hs-CRP (3.87±0.29 versus 3.58±0.27 with p>0.05). Interestingly, there were significant negative correlations between the levels of TNF-α and hs-CRP, and FEV1 in stages II, III, and IV of COPD. ConclusionsThe circulating levels of the inflammatory markers hs-CRP and TNF-alpha are significantly elevated in patients with stable COPD and these biomarkers could be used as predictor factors for severity of inflammation in COPD patients. Longitudinal studies evaluating the effects of smoking cessation on bronchial and systemic inflammation are needed to allow better understanding of these relationships and their consequences.

Effects of Low-Dose and Long-Term Treatment with Erythromycin on Interleukin-17 and Interleukin-23 in Peripheral Blood and Induced Sputum in Patients with Stable Chronic Obstructive Pulmonary Disease.

Objective. To study the effects of low-dose and long-term treatment with erythromycin on IL-17 and IL-23, in peripheral blood and induced sputum, in patients with stable chronic obstructive pulmonary disease (COPD). Methods. Patients were randomly divided into placebo-treated group, group A (12 months of additive treatment with erythromycin, N = 18), and group B (6 months of additive treatment with erythromycin followed by 6 months of follow-up, N = 18). Inflammatory cells in induced sputum, pulmonary function, and the 6-minute walk distance (6MWD) were analyzed. Concentrations of IL-17 and IL-23 in peripheral blood and sputum were measured using enzyme-linked immunosorbent assays. Results. After treatment, sputum and peripheral blood concentrations of IL-17 and IL-23 significantly decreased in groups A and B compared with placebo-treated group. There were no significant differences after erythromycin withdrawal at months 9 and 12 in group B compared with placebo-treated group. An increase in 6MWD was observed after treatment. Conclusions. Erythromycin was beneficial and reduced airway inflammation in COPD patients. Underlying mechanisms may involve inhibition of IL-17 and IL-23 mediated airway inflammation. COPD patients treated with erythromycin for 6 months experienced improved exercise capacity. Finally, treatment for 12 months may be more effective than treatment for 6 months.

Chronic bronchitis leads to accelerated hyperinflation in COPD patients during exercise.

It is not known whether patients with chronic obstructive pulmonary disease (COPD) have a different exercise capacity with (CB(+) ) or without accompanying chronic bronchitis (CB(-) ). We conducted spirometry, a 6-min walk distance test and cardiopulmonary exercise test in 50 age-matched healthy control subjects, 45 COPD patients without CB (CB(-) ) and 37 COPD patients with CB (CB(+) ). A multiple regression model was established to identify factors independently associated with peak oxygen consumption ( V ˙ O 2 ). Patients with and without CB had similar forced expiratory volume in 1 s (FEV1 ). CB(+) patients had a lower V ˙ O 2 . CB(+) and CB(-) participants had similar increases in tidal volume at peak exercise; however, CB(+) patients had an increased respiratory rate (RR). These patients reached the peak value for ratio of end-expiratory lung volume to total lung capacity (TLC) at a lower work load. A stepwise multiple linear regression analysis identified chronic bronchitis, FEV1 , diffusing capacity for carbon monoxide, the ratio of residual volume to TLC and serum tumour necrosis factor-α as independent predictors of peak V ˙ O 2 . CB significantly lowers exercise capacity in COPD patients because of dynamic hyperinflation during exercise. The accelerated dynamic hyperinflation may contribute to increased airway and systemic inflammation in COPD patients.

Levels of CMV-reactive antibodies correlate with the induction of CD28(null) T cells and systemic inflammation in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is characterized by chronic irreversible inflammation and progressive decline in lung function. While smoking and other environmental agents (e.g., air pollutants) are common causes of COPD, the major challenges in managing this condition are the persistent inflammation and functional deterioration which are not reversed by removal of precipitating agents (e.g., smoking cessation) or treatment with anti-inflammatory agents. We hypothesized that the reactivation of latent CMV infection may trigger expansion of pro-inflammatory CD28null T cells and hence promote sysmetic inflammation in patients with COPD. This study presents novel data showing increased levels of CMV-reactive IgM and IgG in COPD patients compared to controls. This paralleled observed increases in markers of sytemic inflammation ex vivo and proportions of circulating CD28null T cells. This mechanism may explain the persistent inflammation in COPD patients.

A study of oxidative stress, antioxidant status and TNF- and #945; in chronic obstructive pulmonary disease

Background: Nearly all smokers show some evidence of lung and systemic cellular and/or humoral inflammation, only a few will experience an amplified response and develop chronic obstructive pulmonary disease (COPD). Several studies have shown systemic inflammation in COPD patients with increased neutrophil, macrophage and T lymphocyte numbers, and high concentrations of inflammatory mediators in peripheral blood (C-reactive protein, interleukin (IL)-6, IL-8, and tumor necrosis factor- (TNF-)). Aims and Objective: To study oxidative stress, antioxidant status, and TNF- levels in patients with COPD. Materials and Methods: Forty-four COPD patients along with an equal number of ageand sex-matched controls were included in study. The levels of malondialdehyde (MDA; by thiobarbituric acid assay), assay of TNF- (by TNF-), and total antioxidant were measured. Results: Malondialdehyde level was found to be significantly higher in all cases, and it was statistically significant in COPD patients with Global Initiative on Obstructive Lung Disease (GOLD) classification grades 2 and 3. Total antioxidant level was significantly lower in all the patients with COPD and was statistically significant in GOLD grades 2 and 3. Like MDA, TNF level was also significantly higher in all the cases with statistically significant increase in GOLD grades 2 and 3. Conclusion: To better understand the role of these trace elements and oxidative stress in the pathogenesis and complications of COPD, it is recommended to carry out further clinical studies.

Air Pollution and Biomarkers of Systemic Inflammation and Tissue Repair in COPD Patients

The origin(s) of systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the impact of exposure to ambient air pollution on systemic biomarkers of inflammation (C-reactive protein (CRP), tumour necrosis factor-α, interleukin (IL)-6, IL-8 and fibrinogen) and tissue repair (hepatocyte growth factor (HGF)) in 242 clinically stable COPD patients (mean age 67.8 years and forced expiratory volume in 1 s 71.3% predicted) in Barcelona, Spain, in 2004-2006. A spatiotemporal exposure assessment framework was applied to predict ambient nitrogen dioxide (NO2) and levels of particles with a 50% cut-off aerodynamic diameter of 2.5 μm (PM2.5) at each participant's home address during 10 periods of 24 h (lags 1-10) and 1 year prior to the blood sampling date. We used linear regression models to estimate associations between biomarkers and exposure levels. An interquartile range (IQR) increase in NO2 exposure in lag 5 was associated with 51%, 10% and 9% increases in CRP, fibrinogen and HGF levels respectively. We also observed 12% and 8% increases in IL-8 associated with an IQR increase in NO2 exposure in lag 3 and over the year before sampling, respectively. These increases were larger in former smokers. The results for PM2.5 were not conclusive. These results show that exposure to ambient NO2 increases systemic inflammation in COPD patients, especially in former smokers.

The Role of Nf-Κappa and HDCA and Implication of Oxidative Stress in Airway Inflammation of Chronic Obstructive Pulmonary Disease

Oxidative stress has been implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD), due to its effect on proinflammatory gene transcription. Oxidants/antioxidants imbalance is responsible for disease development. The study was designed to assess oxidative stress and inflammation in COPD patients. The level of TNF-α and IL-8 in sputum and BAL were compared. NF-κB and HDAC were measured in BAL leucocytes. Oxidative stress was evaluated by assessment of MDA levels in BAL and antioxidant markers: TAS, GSH, GSH-Px activity, vitamin E and vitamin C in BAL and uric acid in serum. Design and Methods. Sixty patients with COPD were recruited from Medical Biochemistry Department, in collaboration with the Chest hospital, Ain Shams University and compared to 20 control (smokers and nonsmokers) subjects. The patients were divided to three groups (GOLD stage II, III and IV) according to the severity of disease. Results. Concentrations of TNF-α and IL-8 were significantly elevated in both sputum and BAL compared to controls. MDA level increased while antioxidants (TAS, GSH, GSH-Px, vitamin E, vitamin C and uric acid) decreased in patients compared to the controls. Oxidants stress also alters the activity of HDAC and NF-κB. There was a significant negative correlation between MDA and all antioxidant markers (p<0.000), also HDAC and NF-κB (p<0.000). Conclusion. There is evidence of increased oxidative stress in the airways of patients with COPD. Understanding the mechanisms of TNF-α inhibition, NF-κB regulation, histone acetylation/deacetylation balance may support the development of novel therapies that limit lung inflammation and injury.

Impaired CTLA-4 responses in COPD are associated with systemic inflammation

Systemic inflammation is a feature of chronic obstructive pulmonary disease (COPD). Defects in T cell-mediated anti-inflammatory pathways such as cytotoxic T lymphocyte antigen-4 (CTLA-4) may promote damaging inflammation. This study provides novel data implicating the impaired induction of an anti-inflammatory molecule, CTLA-4 in the elevated inflammation observed in COPD patients. Low induction of CTLA-4 in COPD patients paralleled increased markers of systemic inflammation ex vivo and increased T-cell responses to a bacterial superantigen, staphylococcal enterotoxin-B (SEB) in vitro. This mechanism may explain the increased inflammation in COPD patients.

Air pollution and biomarkers of systemic inflammation and tissue repair in COPD patients.

The origin(s) of systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the impact of exposure to ambient air pollution on systemic biomarkers of inflammation (C-reactive protein (CRP), tumour necrosis factor-α, interleukin (IL)-6, IL-8 and fibrinogen) and tissue repair (hepatocyte growth factor (HGF)) in 242 clinically stable COPD patients (mean age 67.8 years and forced expiratory volume in 1 s 71.3% predicted) in Barcelona, Spain, in 2004-2006. A spatiotemporal exposure assessment framework was applied to predict ambient nitrogen dioxide (NO2) and levels of particles with a 50% cut-off aerodynamic diameter of 2.5 μm (PM2.5) at each participant's home address during 10 periods of 24 h (lags 1-10) and 1 year prior to the blood sampling date. We used linear regression models to estimate associations between biomarkers and exposure levels. An interquartile range (IQR) increase in NO2 exposure in lag 5 was associated with 51%, 10% and 9% increases in CRP, fibrinogen and HGF levels respectively. We also observed 12% and 8% increases in IL-8 associated with an IQR increase in NO2 exposure in lag 3 and over the year before sampling, respectively. These increases were larger in former smokers. The results for PM2.5 were not conclusive. These results show that exposure to ambient NO2 increases systemic inflammation in COPD patients, especially in former smokers.

Advance in the pathogenesis of chronic obstructive pulmonary disease

Currently,the high morbidity and mortality of chronic obstructive pulmonary disease (COPD) is the main reason to cause huge worldwide economic and social burden.The pathogenesis of COPD is complex.Inflammation,oxidative stress,Protease-antiprotease imbalance,and apoptotic are the key link of the pathogenesis of COPD.Infection is a major cause of acute exacerbation and progression of COPD.Autoimmunity may be the main reason for the persistence of inflammation in COPD patients after smoking cessation.Lung damage caused by cigarette smoke eventually form a continuous process of selfamplified,which lead to clinical symptoms and pathological changes. Key words: Chronic obstructive pulmonary disease; Pathogenesis; Emphysema; Oxidative stress; Apoptosis

Adiponectin: An Attractive Marker for Metabolic Disorders in Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease which may be complicated by development of co-morbidities including metabolic disorders. Metabolic disorders commonly associated with this disease contribute to lung function impairment and mortality. Systemic inflammation appears to be a major factor linking COPD to metabolic alterations. Adipose tissue seems to interfere with systemic inflammation in COPD patients by producing a large number of proteins, known as “adipokines”, involved in various processes such as metabolism, immunity and inflammation. There is evidence that adiponectin is an important modulator of inflammatory processes implicated in airway pathophysiology. Increased serum levels of adiponectin and expression of its receptors on lung tissues of COPD patients have recently highlighted the importance of the adiponectin pathway in this disease. Further, in vitro studies have demonstrated an anti-inflammatory activity for this adipokine at the level of lung epithelium. This review focuses on mechanisms by which adiponectin is implicated in linking COPD with metabolic disorders.

Neutrophil-to-Lymphocyte Ratio in Chronic Obstructive Pulmonary Disease: A Retrospective Study

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lung with a high mortality and morbidity rate. Some of the inflammatory markers such as C-reactive protein (CRP), leukocyte count are associated with COPD. In this study, we aimed to evaluate the role of neutrophil-to-lymphocyte ratio (NLR) in COPD patients comparing with the other well-known inflammatory markers. We retrospectively enrolled the laboratory results of 269 COPD patients of which 178 patients at stable period and 91 patients during acute exacerbation and 50 sex- and age- matched healthy controls. We found that NLR values of the stable COPD patients were significantly higher than those of the controls (P < 0.001). During acute exacerbation of the disease there was a further increase compared to stable period (P < 0.001). NLR values were also positively correlated with serum CRP levels and red cell distribution width (RDW) and negatively correlated with mean platelet volume (MPV) in both COPD groups. In conclusion, NLR could be considered as a new inflammatory marker for assessment of inflammation in COPD patients with its quick, cheap, easily measurable property with routine complete blood count analysis.

Predicting Sputum Eosinophilia in Exacerbations of COPD Using Exhaled Nitric Oxide

Fractional exhaled nitric oxide (FENO) may be a pulmonary biomarker in chronic obstructive pulmonary disease (COPD). In this prospective study, the relationship between FENO and airway inflammation was assessed in COPD exacerbations. FENO and lung function were measured, and sputum was collected from 49 ex-smoking COPD patients, first at the time of hospital admission and again at discharge following treatment. There was a significant positive correlation between the percentage of sputum eosinophils and FENO concentrations, both at exacerbation (r = 0.593, p < 0.001) and discharge (r = 0.337, p = 0.044). The increase in forced expiratory volume in one second (FEV(1)) after treatment was greater in patients with sputum eosinophilia (ΔFEV(1) 0.35 ± 0.12 vs. 0.13 ± 0.04 L, p = 0.046), and FENO was a strong predictor of sputum eosinophilia (area under the receiver operating characteristic curve, 0.89). The optimum cut point was 19 parts per billion (sensitivity: 90 %; specificity: 74 %). Our data suggest that FENO is a good surrogate marker of eosinophilic inflammation in COPD patients with exacerbations.

The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD

Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a two-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A more severe degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and the large amounts of reactive oxygen species and reactive nitrogen species released from inflammatory cells are likely to induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely to be activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterised by mutually reinforcing inflammation and DNA damage, may cause the inflammation in COPD patients to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer.