Association of interleukin-8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. lnterleukin 8 (IL-8) is a potent proinflammatory cytokine which interacts with the IL-8 receptor alpha (IL8RA, CXCR1) and beta (IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single-strand conformation polymorphism analysis in 50 COPD patients and identified three exchanges (M31R, S276T and R335C). These three polymorphisms were subsequently genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma as well as 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (P=0.0073 and 0.023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.     

Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that causes damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. Although COPD shares some clinical features with asthma, another prevalent airway inflammatory disease, there are distinct differences in the phenotypic characteristics of airway inflammation between COPD and asthma. The eosinophil is the most prominent inflammatory cell in asthma, with mast cells, lymphocytes, and macrophages playing important but less prominent roles. In COPD the cellular composition of the airway inflammatory infiltrate differs, with neutrophils, macrophages, and lymphocytes assuming prominence and the eosinophil playing a minor role, except in the setting of exacerbations. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy.     

Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages.

Chronic obstructive pulmonary disease (COPD) is considered to be caused in part by smoking-induced inflammation, but it is unknown which inflammatory cells within the small airways are associated with the obstruction. We investigated the inflammatory infiltrate in the small airways of 16 current or ex-smokers with COPD (FEV1 < or = 75% predicted) and 15 without COPD (FEV1 > or = 85% predicted) in pneumectomy specimens that were removed for lung cancer. Mast cells, macrophages, neutrophils, eosinophils, T cells, and B cells were identified using immunohistochemistry on formalin-fixed, paraffin-embedded specimens. These cells were quantified in the epithelium and the remainder of the airway wall. The number of mast cells and macrophages in the epithelium, but not in the remainder of the airway wall, was significantly increased in patients with COPD. Neutrophil and T cell numbers did not differ between the groups. Only few B cells and eosinophils were present in both groups. Smoking history, perioperative steroid usage, tumor localization, or reversibility in the FEV1 to salbutamol could not account for the observed differences. We conclude that the number of epithelial mast cells and macrophages is increased in the bronchioli in smokers with airflow limitation, suggesting a role in development of COPD.     

Outpatient treatment of chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that cause damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy. The outpatient treatment of COPD differs from the approach used in asthma and can be divided into 3 subgroups: health care maintenance, drug therapy, and nondrug therapy. Smoking cessation, regular spirometry, and immunization are important components of health care maintenance. Drug therapy consists of optimal bronchodilator therapy supplemented, when necessary, with either inhaled corticosteroids or theophylline. Nondrug therapies include pulmonary rehabilitation, supplemental oxygen, and surgery.     

Long-term NO2 exposure induces pulmonary inflammation and progressive development of airflow obstruction in C57BL/6 mice: a mouse model for chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, development of emphysema and irreversible airway obstruction. Macrophages, neutrophils and CD8+ T cells and their products have been shown to play an important role in the initiation and maintenance of these processes. In contrast, the mechanisms underlying COPD pathogenesis still remain uncertain. This article focuses on the generation of an animal model that mirrors some features of human COPD in association with a progredient airflow limitation.     

Evaluation of Pregnancy-Associated Plasma Protein-A Levels in Patients with Chronic Obstructive Pulmonary Disease and Associations with Disease Severity

Chronic obstructive pulmonary disease (COPD) represents a systemic disorder characterized by chronic airflow limitation and an increased inflammatory response of the airways. Comorbidities are frequent in COPD and it is crucial to predict these in early stage for adequate management of COPD. Recent studies have reported that elevated levels of pregnancy-associated plasma protein-A (PAPP-A), a zinc-binding metalloproteinase, detected in patients with asthma, lung cancer, and pulmonary embolism and independently associated with cardiovascular events. We aimed to assess serum PAPP-A levels in COPD and the associations between disease severity. The study population consisted of 75 COPD patients and 35 healthy subjects as a control group. PAPP-A levels were measured by using ultrasensitive enzyme-linked immunosorbent assay. Elevated levels of PAPP-A were observed in patients with COPD on comparison with the controls (p?=?0.000). The levels in stage 1 (34.73?±?22.97) and stage 2 (48.29?±?53.35) were significantly higher than stage 3 (20.58?±?22.98) and stage 4 (27.36?±?21.46) (p?=?0.049). Increased PAPP-A levels may be a useful marker in management of COPD that seeks to prevent the development of comorbidities such as adverse cardiovascular diseases.     

Differences in airway remodeling between asthma and chronic obstructive pulmonary disease

The functional consequence of asthma and chronic obstructive pulmonary disease (COPD) is airflow limitation, which is mostly reversible in asthma and not fully reversible in COPD. In both diseases, inflammatory conditions are associated with cellular and structural changes, referred to as remodeling, and these structural changes may lead to thickening of the airway wall, thereby promoting airway narrowing and airflow limitation. However, the pattern of infilatrated cells and the pattern of structural changes occur differently in the two diseases. In asthma, CD4+, T lymphocytes, eosinophils, and mast cells are the predominant cells involved, whereas COPD, CD8+, T lymphocytes, and macrophages are predominantly involved. In severe cases of asthma and COPD, neutrophil infiltration becomes evident. Regarding structural changes, epithelial injury and early thickening of reticular basement membrane are highly characteristic of the airway wall of asthmatics. Increases in airway smooth muscle mass occur in large airways of severe asthmatics and in small airways of patients with COPD. Thickening of the airway wall, golblet cell hyperplasia, mucous gland hypertrophy, and the luminal obstruction caused by inflammatory exudates and mucous are features of both asthma and COPD. Squamous epithelial metaplasia and airway wall fibrosis are commonly observed characteristics of COPD. Destruction and fibrosis of the alveolar wall occur in COPD but not in asthma. The remodeling processes accompanied by chronic inflammatory infiltrates interact in a complex fashion and contribute to the development of airflow limitation in both asthma and COPD.     

Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2

Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltration into tissues can lead to chronic inflammation. In the lung, such diseases include chronic obstructive pulmonary disease (COPD), a debilitating, respiratory condition characterized by progressive and largely irreversible airflow limitation for which cigarette smoking is the major risk factor. COPD is associated with an increased inflammatory cell influx including increased macrophage numbers in the airways and tissue. Alveolar macrophages develop from immigrating blood monocytes and have the capacity to cause the pathological changes associated with COPD. This study addressed the hypothesis that increased macrophage numbers in COPD are a result of increased recruitment of monocytes from the circulation. Chemotaxis assays of peripheral blood mononuclear cells (PBMC)/monocytes from nonsmokers, smokers, and COPD patients demonstrated increased chemotactic responses for cells from COPD patients when compared with controls toward growth-related oncogene (GRO)alpha and neutrophil-activating peptide (NAP)-2 but not toward monocyte chemoattractant protein, interleukin-8, or epithelial-derived NAP(ENA)-78. The enhanced chemotactic response toward GROalpha and NAP-2 was not mediated by differences in expression of their cellular receptors, CXCR1 or CXCR2. Receptor expression studies using flow cytometry indicated that in COPD, monocyte expression of CXCR2 is regulated differently from nonsmokers and smokers, which may account for the enhanced migration toward GROalpha and NAP-2. The results highlight the potential of CXCR2 antagonists as therapy for COPD and demonstrate that an enhanced PBMC/monocyte response to specific CXC chemokines in these patients may contribute to increased recruitment and activation of macrophages in the lungs.     

The role of miR-155 in cigarette smoke-induced pulmonary inflammation and COPD

Chronic obstructive pulmonary disease (COPD) is a highly prevalent respiratory disease characterized by airflow limitation and chronic inflammation. MiR-155 is described as an ancient regulator of the immune system. Our objective was to establish a role for miR-155 in cigarette smoke (CS)-induced inflammation and COPD. We demonstrate increased miR-155 expression by RT-qPCR in lung tissue of smokers without airflow limitation and patients with COPD compared to never smokers and in lung tissue and alveolar macrophages of CS-exposed mice compared to air-exposed mice. In addition, we exposed wild type and miR-155 deficient mice to CS and show an attenuated inflammatory profile in the latter. Alveolar macrophages were sorted by FACS from the different experimental groups and their gene expression profile was analyzed by RNA sequencing. This analysis revealed increased expression of miR-155 targets and an attenuation of the CS-induced increase in inflammation-related genes in miR-155 deficient mice. Moreover, intranasal instillation of a specific miR-155 inhibitor attenuated the CS-induced pulmonary inflammation in mice. Finally, elastase-induced emphysema and lung functional changes were significantly attenuated in miR-155 deficient mice. In conclusion, we highlight a role for miR-155 in CS-induced inflammation and the pathogenesis of COPD, implicating miR-155 as a new therapeutic target in COPD.     

Evaluation of Oxidative Stress and Antioxidant Status in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a common respiratory condition involving the airways and characterized by airflow limitation. Gaseous and noxious particles play an important role in this process. Antioxidants are the substances that may protect cells from the damage caused by unstable molecules known as free radicals. The increased oxidative stress in patients with COPD is the result of an increased burden of inhaled oxidants, as well as increased amounts of reactive oxygen species (ROS) generated by various inflammatory, immune and epithelial cells of the airways. A total of 150 subjects with COPD and 100 healthy controls subjects were enrolled in this study from the period October 2015 to January 2016. The investigation included measurements of plasma superoxide dismutase activity (SOD), catalase activity (CAT), glutathione content (GSH) reduced form, (GPx) glutathione peroxidase, glutathione reductase (GR) and lipid peroxidation (LPO). Absorbance was measured by UV spectrophotometer. The estimated values of SOD, catalase, GPx, GSH and GR were found to be significantly (P = 0.0001) lower among the cases compared with controls. But, the levels of MDA were higher (P = 0.0001) in cases as compared to control group and there was significant difference in the oxidative stress parameters among the various stages of COPD. The post hoc analysis revealed that SOD was significantly (P < 0.01) lower among the mild, moderate and severe patients compared with very severe patients. The catalase was also observed to be significantly (P = 0.01) lower among mild, moderate and severe patients than very severe patients. The GPx was found to be significantly (P = 0.002) lower among the mild, moderate and severe patients compared with very severe patients. MDA was observed to be significantly higher in mild, moderate and severe patients compared with very severe (P = 0.001). GR was significantly (P = 0.003) lower among mild, moderate and severe patients than very severe patients. However, there was no significant difference in GSH among severity of COPD patients. This study suggests that oxidant and antioxidant imbalance plays an important role in various stages of severity of COPD. These results revealed the presence of an oxidative stress in subjects with COPD, and it is proportionate to the severity of disease.     

Chemotactic activity of neutrophils to fMLP and IL-8 in patients with severe asthma with reversible and irreversible airflow obstruction and in patients with chronic obstructive pulmonary disease

Asthma is a chronic inflammatory disease of the airways in which many cell types play a role. Although the most important cells are eosinophils, there are suggestions that also neutrophils may play a role in asthma. The aim of the study was to measure and compare chemotactic activity of neutrophils in patients with severe asthma and with COPD. We examined 49 patients with severe asthma and 23 patients with COPD. The mean number of neutrophils in peripheral blood of 20 asthmatics with irreversible airflow obstruction was 3.96 x 10(6)/ml. The chemotactic activity of neutrophils to FMLP was 2.69 SEM +/- 0.4, to IL-8 in concentration 10-7 microg/ml - 1.64, SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.17, SEM +/- 0.1. The mean number of neutrophils in 29 asthmatics with reversible airflow obstruction was 3.08 x 10(6)/ml. Their chemotactic activity to fMLP was 1.7, SEM +/- 0.1 to IL-8 in concentration 10-7 microg/ml - 1.51. SEM +/- 0.2, and to IL-8 in concentration 10-8 microg/ml - 1.08, SEM +/- 0.1. The mean number of neutrophils in COPD patients was 4.05 x 10(6)/ml and their chemotactic activity to FMLP was 1.9, SEM +/- 0.1 to IL-8 - 1.35, SEM +/- 0.1. All asthmatic patients were treated with inhaled corticosteroids and some of them with oral corticosteroids. Despite of that treatment the number of neutrophils isolated from patients with asthma with irreversible airflow obstruction was almost the same like in COPD patients and chemotactic activity of neutrophils in this group was the highest. We concluded that corticosteroids treatment did not diminished chemotactic activity of neutrophils isolated from patient suffering from asthma with irreversible airflow obstruction.     

Role of small airways in asthma: investigation using high-resolution computed tomography

BACKGROUND: Small airways may have an important role in asthma but are more difficult to assess pathologically than central airways. Computed tomographic indices of lung density are assumed to reflect air trapping and may be a useful noninvasive measure of small airways disease, but their pathophysiological relevance remains undetermined. OBJECTIVE: To evaluate lung density on high-resolution computed tomography and examine its correlations with clinical and physiologic variables in 29 patients with stable asthma. METHODS: Both lungs were scanned at full-inspiratory and full-expiratory phases to quantify percentage of lung field occupied by low attenuation area (LAA%; < -960 Hounsfield units) and mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were evaluated. RESULTS: The mean lung density increased and LAA% decreased in all patients at expiratory phase compared with inspiratory phase. The inspiratory density indices and expiratory mean lung density correlated only with FEV(1)/forced vital capacity (FVC). Expiratory LAA% correlated more strongly than other variables with FEV(1)/FVC and with indices of peripheral airflow obstruction. Expiratory/inspiratory ratios of LAA% and mean lung density correlated, the former more strongly, with disease severity, residual volume/total lung capacity, and airway sensitivity, as well as with indices of global (FEV(1) and FEV(1)/FVC) and peripheral airflow obstruction. CONCLUSION: Expiratory/inspiratory high-resolution computed tomography is useful for assessing small airways disease in asthma. Small airways involvement is associated with airflow obstruction, airway hypersensitivity, and more severe disease. CLINICAL IMPLICATIONS: Small airways are an important therapeutic target in asthma.     

Role of viral infections in asthma and chronic obstructive pulmonary disease

Substantial evidence implicates common respiratory viral infections in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Children who experience recurrent virally induced wheezing episodes during infancy are at greater risk for developing asthma. In addition, respiratory viral infections are a major trigger for acute exacerbations of both asthma and COPD. Despite the importance of viral infections in asthma and COPD, the mechanisms by which viruses predispose to, or cause exacerbations of, these diseases remain poorly understood. It is clear that viral infections lead to enhanced airway inflammation and can cause airways hyperresponsiveness. The epithelial cell is the principal site of viral infection in the airways and plays a central role in viral modulation of airway inflammation via release of a variety of cytokines, chemokines, and growth factors. The mechanisms by which viral infections modulate epithelial function, therefore, is a topic of intense investigation. The epithelium also contributes to the host innate defense response to viral infection by releasing products that are antiviral and/or can lead to increased recruitment of dendritic cells and lymphocytes. Some evidence supports a role for the epithelial cell in specific immunity, although the response of more conventional cells of the immune system to viral infections is likely the dominant factor in this regard. Although current therapies may help combat virally induced disease exacerbations, they are less than ideal. A better understanding of the mechanisms underlying viral modulation of these diseases, therefore, may lead to new therapeutic approaches.     

CD8+ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure

BACKGROUND: Persistent macrophage accumulation and alveolar enlargement are hallmark features of chronic obstructive pulmonary disease (COPD). A role for CD8(+) lymphocytes in the development of COPD is suggested based on observations that this T cell subset is increased in the airways and parenchyma of smokers that develop COPD with airflow limitation. In this study, we utilize a mouse model of COPD to examine the contributions of CD8(+) T cells in the persistent macrophage accumulation and airspace enlargement resulting from chronic irritant exposure. METHODS: We analyzed pulmonary inflammation and alveolar destruction in wild-type and Cd8-deficient mice chronically exposed to acrolein, a potent respiratory tract irritant. We further examined cytokine mRNA expression levels by RNase protection assay, matrix metalloproteinase (MMP) activity by gelatin zymography, and epithelial cell apoptosis by active caspase3 immunohistochemistry in wild-type and Cd8-deficient mice exposed chronically to acrolein. RESULTS: These studies demonstrate that CD8(+) T cells are important mediators of macrophage accumulation in the lung and the progressive airspace enlargement in response to chronic acrolein exposures. The expression of several inflammatory cytokines (IP-10, IFN-gamma, IL-12, RANTES, and MCP-1), MMP2 and MMP9 gelatinase activity, and caspase3 immunoreactivity in pulmonary epithelial cells were attenuated in the Cd8-deficient mice compared to wild-type. CONCLUSIONS: These results indicate that CD8(+) T cells actively contribute to macrophage accumulation and the development of irritant-induced airspace enlargement.     

Remodeling in asthma

Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.     

Infection-induced airway fibrosis in two rat strains with differential susceptibility.

Chronic infections play a significant role in the morbidity and mortality of patients with chronic airflow limitation. By stimulating airway inflammation, persistent infection has the potential to cause airway fibrosis. However, in patient this condition is most typically found in lungs damaged by other factors, such as smoking, abnormal secretions, or barotrauma. We report the characterization of Mycoplasma pulmonis infection-induced lung fibrosis in two immunocompetent rat strains with no preexisting lung disease. The fibrosis was predominantly in the airways, as demonstrated by the findings for infected animals of increased airway inflammation, airway fibrosis, and airway wall thickness, which correlated with the collagen content of the lungs. Also, the physiological alterations were the opposite of those found in interstitial fibrosis, with a positive correlation between lung compliance and collagen content. The airway fibrosis was noted earlier and to a greater extent in Lewis rats than in Fisher rats, and this result apparently was related to regulation of the inflammatory response. Airway wall thickness, airway inflammation, and airway fibrosis are commonly reported in tissue specimens from patients with chronic airway diseases and have been shown to correlate with airflow limitation in patients with chronic obstructive pulmonary disease. Thus, this model may be useful in furthering our understanding of the role of chronic infection and airway inflammation in airflow obstruction.     

MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients

Aims:  Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups.
Methods and results:  Bronchial rings from 10 non-smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid–Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5–31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5–17.5%); P  < 0.05] and non-smoking subjects [2% (0.4–6.2%); P  < 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25–92%) epithelial area] compared with non-smoking subjects [15% (2.7–32%); P  < 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack-years.
Conclusions:  COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.     

Airway inflammation in asthma and chronic obstructive pulmonary disease with special emphasis on the antigen-presenting dendritic cell: influence of treatment with fluticasone propionate

Asthma is a chronic inflammatory disorder of the airways characterized by variable airflow limitation and airway hyperresponsiveness. The type of inflammatory response in asthma is compatible with a major contribution of professional antigen-presenting cells. The airways in chronic obstructive pulmonary disease (COPD) are also markedly inflamed; however, the predominant types of inflammatory cells and the main anatomical site of the lesion appear to differ from those in asthma. COPD is characterized by reduced maximum expiratory flow and slow forced emptying of the lungs. Steroids are the most prominent medication used in the treatment of asthma and COPD; however, the beneficial effect of steroid treatment in COPD is subject of debate. We investigated the efficacy of fluticasone propionate (FP) treatment in atopic asthmatics and in COPD patients with bronchial hyperreactivity who smoke. The effect of the treatment on bronchial hyperreactivity and indices of the methacholine dose–response curve were analysed, as well as indices of inflammation of the airway mucosa with special emphasis on the antigen presenting dendritic cell. Treatment of allergic asthmatic patients resulted in improvement of lung function (FEV₁), a decrease in bronchial hyperresponsiveness and a decrease of maximal airway narrowing. During the FP-treatment of COPD patients, FEV₁ remained stable, while FEV₁ deteriorated significantly in the placebo group. Therefore, steroid treatment may have a beneficial effect in COPD patients with bronchial hyperresponsiveness (BHR). Since immunohistochemical analysis of bronchial biopsy specimens from asthma and COPD patients show disease-specific aspects of inflammation, the anti-inflammatory effect of FP is obtained through modulation of different cell populations in asthma and COPD.     

No evidence of chromosome damage in chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in industrialized countries. It is characterized by a progressive airflow limitation resulting from an abnormal inflammatory response of the lungs to inhaled gases and particles. Since oxidative stress is thought to play a role in COPD, and since increased oxidative stress is associated with chromosomal instability in several diseases, we investigated whether such relationship also exists in COPD. Whole blood lymphocytes from 49 COPD patients and 48 age- and sex-matched controls were cultivated in vitro and cytogenetic damage was evaluated by micronucleus (MN) and sister-chromatid-exchange (SCE) assays. In patients with COPD, MN frequency was not significantly different from that of controls. Similarly, SCE frequency did not differ in the two groups suggesting no disturbance in DNA replication. Unlike other diseases characterized by oxidative stress, COPD does not appear to be associated with DNA damage.