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Objectives: To compare the distribution of lung volume at total lung capacity (TLC) among adult men and women known to have normal lung function or chronic obstructive disease or restrictive lung disease (RLD)., Design: Five-year retrospective study., Setting: Review of available clinical pulmonary function testing (PFT) reports and chest radiographs., Patients: Sixty-four patients presenting with normal PFT and chest radiograph findings (normal subjects), 26 patients with severe COPD and increased TLC (COPD group), 29 patients with cystic fibrosis (CF) and increased TLC (CF group), and 19 patients with RLD with a clinical diagnosis of pulmonary fibrosis and a reduced TLC (RLD group)., Measurements: Average posteroanterior rib cage diameter (PAave), average lateral rib cage diameter (LAave), and average vertical height of the diaphragm (HDIave) were measured using radiography. Normal prediction equations were generated based on stature, body mass index (BMI), age, and sex as independent variables and then used in between-group comparisons., Results: PAave correlated positively with BMI and age but not with height, whereas LAave correlated positively with BMI and height but not with age. HDIave correlated positively with height and age but negatively with BMI. PAave and LAave were smaller and HDIave was greater in women than men having the same stature. In the COPD group and in male CF group patients, BMI was low and only HDIave was greater than in sex-, age-, and height-matched normal subjects, but in female CF group patients, only the rib cage diameters were greater than normal. In the RLD group, PAave and HDIave were smaller than predicted and inversely related to each other, but LAave was normal., Conclusion: Variations in maximum lung volume caused by gender, growth, or by lung diseases are nonisotropic and entail substantial changes in chest wall shape.

Endotoxin is one of the principal components of grain dust that causes acute reversible airflow obstruction and airway inflammation. To determine whether endotoxin responsiveness influences the development of chronic grain dust-induced airway disease, physiological and airway inflammation remodeling parameters were evaluated after an 8-wk exposure to corn dust extract (CDE) and again after a 4-wk recovery period in a strain of mice sensitive to (C3H/HeBFeJ) and one resistant to (C3H/HeJ) endotoxin. After the CDE exposure, both strains of mice had equal airway hyperreactivity to a methacholine challenge; however, airway hyperreactivity persisted only in the C3H/HeBFeJ mice after the recovery period. Only the C3H/HeBFeJ mice showed significant inflammation of the lower airway after the 8-wk exposure to CDE. After the recovery period, this inflammatory response completely resolved. Lung stereological measurements indicate that an 8-wk exposure to CDE resulted in persistent expansion of the airway submucosal cross-sectional area only in the C3H/HeBFeJ mice. Collagen type III and an influx of cells into the subepithelial area participated in the expansion of the submucosa. Our findings demonstrate that subchronic inhalation of grain dust extract results in the development of chronic airway disease only in mice sensitive to endotoxin but not in mice that are genetically hyporesponsive to endotoxin, suggesting that endotoxin is important in the development of chronic airway disease.

Induced sputum is increasingly used to detect and monitor airway inflammation in respiratory diseases. However, the processing of sputum has been rather laborious for clinical practice. The aim of this study was to improve the practicality of induced-sputum studies by simplifying sample processing. Eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), neutrophil lipocalin (HNL) and myeloperoxidase (MPO) were used as biochemical markers of airway inflammation and the results of the study method were compared with a previously validated (reference) method. Induced sputum was obtained from 42 healthy controls, 10 subjects with acute respiratory infection, eight patients with chronic obstructive pulmonary disease (COPD) and 17 asthmatics. The sputum sample was divided into two parts and treated either: (i) by the reference method (released markers), where sputum was homogenized with dithiotreitol and centrifuged to yield cell-free supernatant and a cell pellet, or (ii) by the study method (total markers), where the cells were lysed after homogenization so that cell-associated markers were released and solubilized. For comparison, the four biochemical markers were measured in sputum supernatant and in sputum lysate. The differential cell count was performed from the cell pellet in the reference method. Repeatability was assessed in a group of 16 subjects. The effect of reagents and the recovery of assays were also evaluated. Released and total markers correlated well (ECP r(s)=0.80, P<0.0001; EPO r(s)=0.49, P<0.0001; HNL r(s)=0.87, P<0.0001; MPO r(s)=0.71, P<0.0001). Incubation with dithiotreitol and lysis reagent had no negative influence on marker assays. The within-subject variability of total ECP, MPO and HNL in both methods was small in two measurements taken I week apart. The study method, measuring total inflammatory markers, gave comparable results to the reference method, measuring released markers. In the study method the sputum processing was simplified, which may improve its applicability.

The therapy of chronic obstructive pulmonary disease has been comprehensively reviewed in a number of international treatment guidelines. There is consensus about what elements should be included, but the purposes of therapy and the timing of its introduction remain poorly defined. Major factors limiting effective treatment beyond those associated with the biology of the condition itself are poor diagnostic methodology, failure to identify relevant co-morbidities and reluctance to devote appropriate resources to maximizing patient gain. Too many patients are identified at the end-stages of their illness when treatment is relatively limited. Most therapy is directed at reducing the impact of the disease in terms of symptoms, exercise performance and exacerbations on the individual and only smoking cessation modifies the evolution of the disease. Treatment of hypoxaemic patients with domiciliary oxygen improves mortality and slows the development of pulmonary hypertension. Effective smoking cessation is relevant at all stages of the disease. It depends on the willingness of the individual to participate, and quit rates can be improved by the use of nicotine replacement therapy and possibly bupropion. Inhaled bronchodilator drugs palliate symptoms and improve exercise performance in pharmacologically predictable ways. In patients with severe disease, reduction in operating lung volumes is more important than 'bronchodilitation' and is better sustained by long acting beta agonists and anticholinergics. Inhaled corticosteroids reduce exacerbation rates and improve health status in established disease but do not modify disease evolution. Pulmonary rehabilitation improves exercise performance and health status without changing underlying pulmonary mechanics. Whether hospitalizations and exacerbations can be modified is still to be established. Nutritional therapy is in its infancy but calorie supplementation alone is insufficient to improve patient well being. Selected individuals can undergo lung volume reduction surgery with benefits extending up to two years but the risks are dependent on the skill of the operators and the appropriateness of patient selection. Lung transplantation is symptomatically helpful but does not modify the natural history of the disease. Hospitalization due to exacerbations of disease is frequent and their treatment with bronchodilators, antibiotics and corticosteroids now have a basis in randomized trial data. Mortality reflects the incidence of respiratory acidosis and noninvasive ventilation has a role in safely managing patients outside of the intensive care unit. Effective prevention of exacerbation should be possible with newer antiviral agents but data are presently lacking.

There is no uniform consensus on the dose of bronchodilator to be used in the bronchodilator test (BDT). The objective of the study was to determine the dose of inhaled terbutaline that can safely achieve a greater number of positive BDT in patients with chronic obstructive pulmonary disease (COPD). The study was prospective and single blinded. One-hundred and fifty patients with stable COPD were included. Their mean (+/-SD) age was 67.4 (8.8) years. Their mean forced expiratory volume in the first second (FEV1) was 1.14 (0.48) l (41% of the predicted value). A baseline spirometry was performed and a second 20 min after the inhalation of placebo. Three consecutive doses of 500 microg of inhaled terbutaline were administered and a new spirometry was performed after each one. A multivariate analysis based on the comparison of the repeated means was performed in order to analyse the spirometric changes achieved after the different doses of bronchodilator. The increase of FEV1 and forced vital capacity (FVC) with the two first doses of terbutaline was statistically significant; the increase of the peak expiratory flow (PEF) was significant after the three doses administered. The number of positive BDT were 40, 47 and 60 after each dose of terbutaline (P=0.004). The higher dose of terbutaline was more useful in identifying patients with significant bronchoreversibility and, moreover, was well tolerated. We suggest that this dose (1500 microg) should be routinely used in performing the BDT.

A cigarette smoke-induced inflammatory process underlies the pathogenesis of the majority of pathologic lesions associated with chronic obstructive pulmonary disease (COPD). In chronic bronchitis, this process is located in the mucosa, gland ducts and glands of intermediate sized bronchi with an internal diameter of 2-4 mm. The mucus-containing exudate produced by the inflammatory response overpowers the normal clearance mechanisms, resulting in the cough and expectoration that characterize chronic bronchitis. In some cases of chronic bronchitis, the inflammatory process extends to smaller bronchi and bronchioles less than 2 mm in internal diameter. In this location, the inflammatory process thickens the wall, narrows the lumen and destroys the parenchymal support of the airways. These changes progressively increase peripheral airways resistance and eventually reduce the patient's ability to empty their lungs to a degree that can be measured by a reduction in FEV1 (forced expiratory volume in one second). The reduction in lung surface area produced by parenchymal inflammation contributes to the decline in FEV1 by reducing lung elastic recoil, which is the major force driving air out of the lung. It also contributes to the reduction in diffusing capacity by reducing the lung capillary bed. The purpose of this presentation is to review the quantitative aspects of these pathological changes and attempt to provide insight into factors which result in progression of these lesions.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Since flow is the result of a driving pressure that promotes flow and of an opposing resistance that contradicts it, the reduction in flow observed in COPD has two main components: increased resistance, which is due to airway obstruction, and a loss of the elastic recoil pressure of the lung, which is due to parenchymal destruction. Although it has long been known that the major site of increased resistance in COPD is the peripheral airways, recent studies have shown that central airways are involved in the disease as well. The purpose of this review is to describe the major structural and cellular changes present in peripheral airways, central airways and lung parenchyma of patients with COPD, and to underline the possible mechanisms contributing to airflow limitation in these subjects., (Copyright 2001 S. Karger AG, Basel)

This paper reports a case of a 71-year-old pulmonary emphysema patient with neuropsychological impairments that were markedly improved 6 months after he underwent lung volume reduction surgery (LVRS). He also underwent pulmonary rehabilitation before and after surgery. He was suspected of having memory impairment and attention disorder when he was referred for rehabilitation. The neuropsychologic test showed a general cognitive impairment, attention disorder, and verbal memory impairment. Magnetic resonance imaging showed moderate atrophy of the left hippocampal area, cortex, and lacunae infarction in the periventricular area. Interestingly, scores of the neuropsychologic test, as well as severity of dyspnea and lung function, remarkably improved 6 months after LVRS. These results suggested that the neuropsychological impairments in pulmonary emphysema patients can be improved after lung reduction surgery.

Background: Patients with more frequent exacerbations of chronic obstructive pulmonary disease (COPD) may have increased bronchial inflammation. Airway inflammation was measured in patients who had been thoroughly investigated with full pulmonary function testing, thoracic HRCT scanning, and sputum microbiology to examine further the relationship between exacerbation frequency and bronchial inflammation., Methods: Airway inflammation (spontaneous sputum sol phase myeloperoxidase (MPO), elastase, leukotriene (LT)B(4), interleukin (IL)-8, secretory leukoprotenase inhibitor (SLPI), protein leakage) and serum levels of C reactive protein (CRP) were compared in 40 patients with stable, smoking related COPD, divided into those with frequent (> or =3/year) or infrequent (< or =2/year) exacerbations according to the number of primary care consultations during the preceding year. The comparisons were repeated after excluding eight otherwise clinically indistinguishable patients who had tubular bronchiectasis on the HRCT scan., Results: Patients with frequent (n=12) and infrequent (n=28) exacerbations were indistinguishable in terms of their clinical, pulmonary function, and sputum characteristics, CRP concentrations, and all of their bronchial inflammatory parameters (p>0.05). The patients without evidence of tubular bronchiectasis (n=32) were equally well matched but the sputum concentrations of SLPI were significantly lower in the frequent exacerbators (n=8) in this subset analysis (p<0.05)., Conclusions: There are several clinical features that directly influence bronchial inflammation in COPD. When these were carefully controlled for, patients with more frequent reported exacerbations had lower sputum concentrations of SLPI. This important antiproteinase is also known to possess antibacterial and antiviral activity. Further studies are required into the nature of recurrent exacerbations and, in particular, the regulation and role of SLPI in affected individuals.

We studied 16 patients with stable COPD in a double blind, double dummy, placebo-controlled, within patient study to see if formoterol could be used as a rescue drug. We compared the of onset of bronchodilation obtained with formoterol 12 microg (metered dose corresponding to 9 microg delivered dose) and formoterol 24 microg (metered dose corresponding to 18 microg delivered dose), both delivered via Turbuhaler, with that of salbutamol 400 microg and salbutamol 800 microg delivered via pressurized metered-dose inhaler (pMDI). Patients inhaled single doses of placebo, formoterol and salbutamol on five separate days. FEV1 was measured in baseline condition and 3, 6, 9, 12, 15, 18, 21, 24, 30, 40, 50, and 60 min after inhalation of each treatment. We examined two separate criteria for deciding if a response was greater than that expected by a random variation of the measurement: (1) a rise in FEV1 of at least 15% from the baseline value; (2) an absolute increase in FEV1 of at least 200 ml. Formoterol 12 microg (15.2 min; 95% CI 9.5-21.0) and formoterol 24 microg (15.1 min; 95% CI 8.9-21.2) caused a rise in FEV1 of at least 15% from the baseline value almost rapidly as salbutamol 400 microg (13.6 min; 95% CI 7.1-20.1) and salbutamol 800 microg (14.5 min; 95% CI 7.1-21.9). No significant difference (P=0.982) in onset of action was seen between the four active treatments. According to Criterion 2, the mean time to 200 ml increase in FEV1 was 11.1 min (95% CI: 7.0-15.2) after salbutamol 400 microg, 13.0 min (95% CI: 7.9-18.1) after salbutamol 800 microg, 14.7 min (95% CI: 7.1-22.4) after formoterol 12 microg, and 12.7 min (95% CI: 7.4-18.0) after formoterol 24 microg. Again, there was no significant difference (P= 0.817) between the four active treatments. Formoterol Turbuhaler 12 microg and 24 microg caused bronchodilation as rapidly as salbutamol 400 microg and 800 microg given via pMDI.

It is arguable that more biologic insight has been gained from the study of COPD than from any other pulmonary disorder. A vast knowledge of the biology of extracellular matrix proteins, proteinases, and proteinase inhibitors has largely stemmed from the elastase:anti-elastase hypothesis for the pathogenesis of emphysema. An equally compelling case could be made that interest in, and funding for, COPD research has been woeful, and investigators have made no significant medical breakthroughs in the treatment of this disorder, which, unfortunately, is becoming epidemic worldwide. Indeed, it cannot be argued that physicians have very little treatment to offer to the many patients with COPD. Humankind is rapidly approaching a time when all human genes will be sequenced, and genetic engineering will allow determination of the function of these proteins in vivo. Expression profiling and bioinformatics will allow clinicians to assess the spectrum of genes and proteins regulated in biologic processes, no longer limiting study to naïve candidate genes. These advances will allow investigators to decipher precise pathways of complex diseases, identify genetic and environmental interactions, and ultimately lead to specific (pre)diagnoses and rational treatment. Answers to the question as to why only a subset of smokers develop COPD will enhance the understanding of the disease process. Fortunately, there has been a resurgence of interest in COPD, led largely by the pharmaceutical industry, which has discovered the potential of this unmet need. Consequently, these state-of-the-art scientific techniques are being directly applied to COPD, lending hope for the future. Of even greater importance, the tide seems to be turning on the cigarette industry. Although difficult to imagine, perhaps cigarettes will disappear in this lifetime or at least the next generation won't be fooled by this deadly habit! Well ... the rational therapy thing could work.

We investigated the relationship between the reversibility of airflow limitation, the concentration of nitric oxide (NO) in exhaled air, and the inflammatory cells in the sputum of patients with stable chronic obstructive pulmonary disease (COPD). We examined nine normal healthy control subjects and 20 nonatopic patients with COPD. Ten patients had no reversibility of airflow limitation (increase in FEV(1) of < 12% and < 200 ml after 200 microg of inhaled salbutamol), and 10 patients had partial reversibility of airflow limitation (increase in FEV(1) of < 12% but > 200 ml after 200 microg of inhaled salbutamol). Exhaled NO levels were higher in COPD patients with partial reversibility of airflow limitation than in those with no reversibility of airflow limitation (median 24 [interquartile range 15.3 to 32] ppb versus 8.9 [4.6 to 14.7] ppb; p < 0.01). Compared with healthy control subjects, only COPD patients with partial reversibility of airflow limitation had increased concentrations of sputum eosinophils. We conclude that, in patients with stable COPD, even a partial bronchodilator response to inhaled salbutamol is associated with increased exhaled NO and sputum eosinophilia, suggesting that these patients may have a different response to treatment than do those without reversible airflow limitation.

In patients with advanced chronic obstructive pulmonary disease (COPD) diaphragm function may be compromised because of reduced muscle fibre length. Diaphragm length (L(Di)) can be estimated from measurements of transverse diameter of the rib cage (D(Rc)) and the length of the zone of apposition (L(Zapp)) in healthy subjects, but this method has not been validated in patients with COPD. Postero-anterior chest radiographs were obtained at total lung capacity (TLC), functional residual capacity (FRC) and residual volume (RV) in nine male patients with severe COPD (mean [S.D.]; FEV(1), 23 [6] %pred.; FRC, 199 [15] %pred.). Radiographs taken at TLC were used to identify the lateral costal insertions of the diaphragm (L(Zapp) assumed to approach zero at TLC). L(Di) was measured directly and also estimated from measurements of L(Zapp) and D(Rc) using a prediction equation derived from healthy subjects. The estimation of L(Di) was highly accurate with an intraclass correlation coefficient of 0.93 and 95% CI of approximately +/-8% of the true value. L(Di) decreased from 426 (64) mm at RV to 305 (31) mm at TLC. As there were only small and variable changes in D(Rc) across the lung volume range, most of the L(Di) changes occurred in the zone of apposition. Additional studies showed that measurements of L(Di) from PA and lateral radiographs performed at different lung volumes were tightly correlated. These results suggest that non-invasive measurements of L(Zapp) in the coronal plane (e.g. using ultrasonography) and D(Rc) (e.g. using magnetometers) can be used to provide an accurate estimate of L(Di) in COPD patients.

Background: Some patients with chronic obstructive pulmonary disease (COPD) respond to corticosteroid therapy. Whether these patients have different airway pathology from other COPD patients is unclear. We tested the hypothesis that response to prednisolone is related to the presence of eosinophilic airway inflammation., Methods: We did a randomised, double-blind, crossover trial. Patients who had COPD treated with bronchodilators only were assigned placebo and 30 mg prednisolone daily for 2 weeks each, in a random order, separated by a 4-week washout period. Before and after each treatment period, we assessed patients with spirometry, symptom scores, the chronic respiratory disease questionnaire (CRQ), incremental shuttle walk test, and induced sputum. Analysis was done by intention to treat., Findings: 83 patients were recruited, of whom 67 were randomised. The geometric mean sputum eosinophil count fell significantly after prednisolone (from 2.4% to 0.4%; mean difference six-fold [95% CI 3.1-11.4]) but not after placebo. Other sputum cell counts did not change. After stratification into tertiles by baseline eosinophil count, postbronchodilator forced expiratory volume in 1 s (FEV1) and total scores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophilic tertile, compared with placebo. The mean change in postbronchodilator FEV1, total CRQ score, and shuttle walk distance with prednisolone compared with placebo in the highest tertile was 0.19 L (0.06-0.32), 0.62 (0.31-0.93), and 20 m (5-35), respectively., Interpretation: Our findings suggest that eosinophilic airway inflammation contributes to airflow obstruction and symptoms in some patients with COPD and that the short-term effects of prednisolone are due to modification of this feature of the inflammatory response. The possibility that sputum eosinophilia identifies a subgroup of patients who particularly respond to long-term treatment with inhaled corticosteroids should be investigated.

We evaluated the levels of 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE] and the expression of 15-lipoxygenase (15-LO) mRNA in induced sputum obtained from 10 control and 15 chronic bronchitis subjects. 15(S)-HETE was evaluated by reverse phase high-performance liquid chromatography separation followed by specific RIA. 15-LO mRNA expression was determined by primed in situ labeling. The levels of both soluble and cell-associated 15(S)-HETE resulted significantly higher in chronic bronchitis than in control subjects. The percentage of cells expressing 15-LO mRNA was significantly higher in chronic bronchitis than in control subjects (P < 0.01). Double staining for specific cell type markers and 15-LO mRNA showed macrophages and neutrophils positive for 15-LO, whereas similar staining of peripheral blood neutrophils did not show evidence for 15-LO expression, suggesting that expression of 15-LO in neutrophils takes place on migration into the airways. Because 15(S)-HETE inversely correlated with the percentage of neutrophils in sputum of chronic bronchitis subjects, we studied the effect of 15(S)-HETE on leukotriene B(4) (LTB(4)) production in vitro and evaluated the concentration of LTB(4) in induced sputum and the contribution of LTB(4) to the chemotactic activity of induced sputum samples ex vivo. The results obtained indicate that macrophages and neutrophils present within the airways of chronic bronchitis subjects express 15-LO mRNA; increased basal levels of 15(S)-HETE may contribute to modulate, through the inhibition of 5-lipoxygenase metabolites production, neutrophil infiltration and airway inflammation associated with chronic bronchitis.

The airflow limitation that characterises chronic obstructive pulmonary disease (COPD) has two main components: an increased resistance, which is due to airway obstruction, and a loss of the elastic recoil pressure of the lung, which is due to parenchymal destruction. Although it has long been known that the major site of increased resistance in COPD is the peripheral airways, recent studies have shown that central airways are involved in the disease as well. The purpose of this review is to describe the major structural and cellular changes present in peripheral airways, central airways and lung parenchyma of patients with COPD, and to underline the possible mechanisms contributing to airflow limitation in these subjects.

The seroprevalence of Chlamydia pneumoniae is increased in chronic obstructive pulmonary disease (COPD), and subjects with COPD are more likely to have a positive polymerase chain reaction for C. pneumoniae in their sputum. It has been suggested that C. pneumoniae may have a role in the pathogenesis of COPD. We undertook immunohistochemistical staining for C. pneumoniae in archival tissue from subjects who had undergone lobectomy for bronchial carcinoma. There were 16 subjects with COPD (FEV(1) = 64 +/- 8% [mean +/- SD] predicted) and 21 subjects with normal lung function (FEV(1) = 95 +/- 11% predicted). There was no difference between the two groups in age or smoking history. Tissues from all of the subjects stained positively for C. pneumoniae, but in the subjects with COPD there were 14.5 positive cells per field (magnification x400), as compared with 9.3 cells per field in the control subjects (p = 0.02). Fifty-four percent of the macrophages from the subjects with COPD stained positively for C. pneumoniae, as compared with 29% from the control subjects (p < 0.001). A second control group consisted of 18 younger individuals (mean age: 32 yr) who died accidentally. Only 44% of these subjects had positive staining for C. pneumoniae, and the mean number of cells per field was 0.4. These findings suggest that persistent infection with C. pneumoniae is common, and that there is increased immunostaining for C. pneumoniae in COPD. Further studies are necessary to determine whether chronic infection with C. pneumoniae is important in the pathogenesis of COPD.

Both abnormalities in high energy phosphate metabolism and a decreased oxidative enzyme capacity have been reported in skeletal muscle of stable chronic obstructive pulmonary disease (COPD) patients. The first aim of this study was to investigate whether these findings are present in anterior tibialis muscle and whether or not they are associated. Abnormalities in mitochondrial structure and function as well as signs of myopathy have been found during corticosteroid treatment. The second aim of this study, therefore, was to investigate whether in COPD patients prolonged use of low dose prednisolone has effects on muscle energy metabolism and qualitative morphology. In a cross-sectional study 15 COPD patients (forced expiratory volume in one second (FEV1) 33+/-9 (mean+/-SD) % predicted) who were steroid-naive (CORT-) were compared with 10 healthy control subjects (HC) and with 14 COPD patients (FEV1 30+/-11 % pred), who had been using oral prednisolone for at least 1 yr (CORT+). It was found that adenosine triphosphate (ATP)/adenosine diphosphate was lower in CORT- compared to HC (5.7 versus 6.2, p=0.03). Inosine monophosphate was detected in 13 of 15 CORT- compared to 3 of 10 HC (p=0.004). However, although indications were found for an imbalance in production and utilization of ATP, comparing CORT- and HC, no differences in oxidative (citrate synthase and 3-hydroxy-acyl-coenzyme A dehydrogenase) and glycolytic (hexokinase, lactate dehydrogenase and phosphofructokinase) enzyme capacities were found. When, comparing steroid-treated and steroid-naive patient subgroups, no differences in the above mentioned parameters of muscle energy metabolism and of muscle qualitative morphology were found.

The role of infection in exacerbations of COPD remains controversial and incompletely understood. Although some investigators believe that bacteria are not important for patients with exacerbation, we disagree and believe that patients with at least two of the three cardinal symptoms of exacerbation should receive antibiotic therapy. With an open-minded view of the area, we review the data, showing that bacteriologic studies, pathologic investigations, and clinical trials all support roles for bacteria and antibiotic therapy in this disease. Still, many questions remain, and future studies will be needed to better define the mechanisms of bacterial invasion in the bronchitic patient and to develop effective vaccines to prevent exacerbations. In the meantime, we must rely on antibiotic therapy, and we will need prospective studies to corroborate preliminary findings showing that different patients may require different therapies; thus, patient subsetting may be vital in the selection of antibiotic therapy for exacerbations of COPD.

Neutrophil activation is a multistep process. In vitro activation of neutrophils with semiphysiological activators is optimal only after preactivation or priming with cytokines, chemotaxins, and/or bacterial products. Until now, no antibodies have been developed that can distinguish between resting and (cytokine) primed neutrophils with a sufficient dynamic range necessary for screening clinical samples. We have isolated two human phage antibodies, designated MoPhab A17 and A27, from a synthetic bacteriophage antibody library. These phage antibodies recognize epitopes that are upregulated on neutrophils present in whole blood treated with low priming concentrations of cytokines, such as GM-CSF and TNF-alpha. This induction was time- and concentration-dependent and optimal at concentrations that are sufficient for priming functional responses in neutrophils: GM-CSF (10 pM) and TNF-alpha (100 IU/ml). PMNs, isolated from the peripheral blood of chronic obstructive pulmonary disease (COPD) patients with a clinical exacerbation, exhibited a partial in vivo primed phenotype. These antibodies promise to be an ideal tool to monitor disease activity in whole blood of patients with inflammatory diseases.

COPD is the most common chronic condition in the UK and it varies in severity from mild through to disabling and severe disease with respiratory failure. The treatment of the disease is tailored to the severity of the symptoms and the cornerstones are stopping smoking, inhaled bronchodilator and inhaled corticosteroid therapy. Preoperative assessment of patients with COPD needs to be thorough; remember that these patients may have concomitant ischaemic heart disease. Patients with severe COPD are at particularly high risk when given intravenous sedatives, opiates or general anaesthetics.

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. Oxidative stress is thought to play an important role in the pathogenesis of a number of lung diseases, not only through direct injurious effects, but by involvement in the molecular mechanisms that control lung inflammation. A number of studies have shown an increased oxidant burden and consequently increased markers of oxidative stress in the airspaces, breath, blood, and urine in smokers and in patients with COPD. The presence of oxidative stress has important consequences for the pathogenesis of COPD. These include oxidative inactivation of antiproteinases, airspace epithelial injury, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of proinflammatory mediators. With regard to the latter, oxidative stress has a role in enhancing the inflammation that occurs in smokers and patients with COPD, through the activation of redox-sensitive transcriptions factors such as nuclear factor-kappaB and activator protein-1, which regulate the genes for proinflammatory mediators and protective antioxidant gene expression. The sources of the increased oxidative stress in patients with COPD are derived from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Antioxidant depletion or deficiency in antioxidants may contribute to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants, and hence dietary supplementation may be a beneficial therapeutic intervention in this condition. Antioxidants that have good bioavailability or molecules that have antioxidant enzyme activity may be therapies that not only protect against the direct injurious effects of oxidants, but may fundamentally alter the inflammatory events that play an important part in the pathogenesis of COPD.

Background: Chronic obstructive pulmonary disease (COPD) is often accompanied by bronchial hyperresponsiveness (BHR). Measurement of BHR may give information about airway inflammation., Objective: To investigate the role of airway inflammation in hyperresponsiveness to adenosine 5'-monophosphate (AMP) in COPD., Methods: We investigated inflammatory indices in induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies in subjects with COPD with and without hyperresponsiveness to AMP. Twelve nonatopic subjects with COPD with hyperresponsiveness to AMP (mean +/- SD, age 63 +/- 8 years, FEV1% predicted 56 +/- 13%), six without BHR (age 60 +/- 6 years, FEV1% predicted 65 +/- 11%) and 11 healthy nonatopic controls without BHR (age 58 +/- 8 years, FEV1% predicted 104 +/- 11%) participated in the study., Results: Subjects with COPD with BHR had significantly higher numbers of mucosal CD8 + and higher percentages of sputum eosinophils than those without BHR (median, 550 cells/mm2; range, 30-1340 vs 280 cells/mm2; range, 110-450, P = 0.045; and median, 2.7%; range, 0.5-8.5 vs 0.6%; range, 0-0.8 %, P = 0.0036, respectively). No differences were observed in BAL fluid., Conclusion: We conclude that hyperresponsiveness to AMP in COPD is associated with airway inflammation that is characterized by increased numbers of mucosal CD8 + cells and percentages of sputum eosinophils. Hyperresponsiveness to AMP may be used as a marker of airway inflammation in COPD, but its significance in the clinical course remains to be determined.

Objectives: In South Africa chronic obstructive airway disease (COAD), which could be due to working in a dusty atmosphere in scheduled mines or works, is a compensatable disease. Miners are compensated for in-life respiratory disability and for findings at autopsy of COAD, which includes emphysema, bronchitis assessed by mucus gland hyperplasia in the main bronchus, and bronchiolitis assessed by goblet cell metaplasia. The question arises as to whether the autopsy findings correlate with in-life impairment. The objectives of the study were: (1) to determine whether autopsy COAD outcomes relate to lung function and to respiratory symptoms and signs; and (2) to quantify the individual contributions of emphysema, bronchiolitis and bronchitis to lung function impairment., Methods: On 724 gold miners, pathological findings of COAD--emphysema, bronchitis and bronchiolitis-- were related to lung function measurements and respiratory symptoms and signs observed within 5 years prior to death., Results: Emphysema diagnosed at autopsy was the main determinant of airflow impairment. The emphysema score categories 0-5, 5-35, 35-65 and > 65 were associated with decreased forced expiratory volume in 1 s, expressed as percentage predicted (FEV1%) as follows: 78.8%, 66.2%, 52.0% and 46.0%, respectively. The score was also associated with increasing frequency of dyspnoea. After adjustment for emphysema, the bronchitis and bronchiolitis were not related to significant lung function loss, and in subjects without emphysema, the presence of moderate or marked bronchitis was associated with a mild impairment only. Bronchitis at autopsy was associated with increased frequency of rhonchi, sputum and cough, whereas bronchiolitis was associated with increased sputum only. Silicosis found at autopsy was associated with some obstructive and restrictive lung function impairment. Tobacco smoking was associated with all the COAD outcomes.

A common feature of COPD and other chronic lung diseases is hypersecretion of mucus into the airways, causing peripheral airway plugging and further airflow obstruction. The mucus is secreted by goblet cells, which are present in excessive numbers in COPD. This review describes how neutrophils in the airways of COPD patients stimulate the goblet cells to secrete their products. Recent findings on the mechanisms of neutrophil stimulation of goblet cell degranulation are discussed. These implicate the proteolytic enzyme elastase and cell surface adhesion molecules, and provide a basis for the investigation of potential novel therapies.

Emphysema is an almost constant finding in the lungs of chronic obstructive pulmonary disease patients. Several types of emphysema are recognized by pathologists, but only the centrilobular (CLE) and panlobular (PLE) emphysemas are found in association with smoking. In this review, the morphological and functional differences between CLE and PLE are described, and it is suggested that they could arise as different abnormalities as a result of the same insult, cigarette smoke. In CLE: 1) the destruction of the lung is uneven and originates around the airways; 2) the membranous bronchioles are thicker, narrower and more reactive than in PLE; 3) lung compliance is low or normal and does not relate to the extent of the emphysema; and 4) the decrease in flow is related mainly to the degree of airway abnormality and not to the losses of elastic recoil. In contrast, in PLE: 1) the destruction of the lung is even; 2) the small airways appear less narrowed and less inflammed than in CLE; 3) the compliance of the lung is increased and related to the extent of the emphysema; and 4) the decrease in flow is related mainly to the loss of elastic recoil and not to the abnormalities in the airways. The authors would propose that centrilobular emphysema and panlobular emphysema are distinct entities, centrilobular emphysema an airborne disease related to airway reactivity, panlobular emphysema a blood-borne disease related to abnormalities in lung protective mechanisms against inflammatory insults.

It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model. Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance. The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients. The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients.

Background: Interleukin 10 (IL-10) is a cytokine that downregulates inflammation, in part by reducing the production of the proinflammatory cytokines IL-1beta and IL-8. It has been suggested that an inability to produce IL-10 might predispose preterm infants to develop chronic lung disease., Aim: To measure IL-10, IL-1beta, and IL-8 in bronchoalveolar lavage fluid from ventilated preterm infants in a prospective cohort study., Patients: 17 consecutive newborn infants < or = 29 weeks' gestational age (median, 25; 9 boys) who were ventilated from birth underwent daily bronchoalveolar lavage sampling., Results: 102 samples were collected, of which 57 contained IL-10 in amounts that were comparable with those found previously in ventilated term infants with respiratory failure. Chronic lung disease developed in 9 of the 11 survivors and all 9 infants had produced IL-10. IL-1beta and IL-8 were detected in nearly all samples and were raised throughout the course of sample collection., Conclusion: IL-10 is readily detectable in early bronchoalveolar lavage samples from ventilated preterm infants, although it remains unclear whether this cytokine has any influence on the development of chronic lung disease.

Background: A central feature in the pathogenesis of COPD is the inflammation coexisting with an abnormal protease/antiprotease balance. However, the possible role of different serine and metalloproteinases remains controversial., Patients and Measurements: We examined the expression of gelatinases A and B (matrix metalloproteinase [MMP]-2 and MMP-9); collagenases 1, 2, and 3 (MMP-1, MMP-8, and MMP-13); as well as the presence of apoptosis in lung tissues of 10 COPD patients and 5 control subjects. In addition, gelatinase-A and gelatinase-B activities were assessed in BAL obtained from eight COPD patients, and from six healthy nonsmokers and six healthy smoker control subjects., Setting: Tertiary referral center and university laboratories of biochemistry, and lung cell kinetics., Results: Immunohistochemical analysis of COPD lungs showed a markedly increased expression of collagenases 1 and 2, and gelatinases A and B, while collagenase 3 was not found. Neutrophils exhibited a positive signal for collagenase 2 and gelatinase B, whereas collagenase 1 and gelatinase A were revealed mainly in macrophages and epithelial cells. BAL gelatin zymography showed a moderate increase of progelatinase-A activity and intense bands corresponding to progelatinase B. In situ end labeling of fragmented DNA displayed foci of positive endothelial cells, although some alveolar epithelial, interstitial, and inflammatory cells also revealed intranuclear staining., Conclusion: These findings suggest that there is an upregulation of collagenase 1 and 2 and gelatinases A and B, and an increase in endothelial and epithelial cell death, which may contribute to the pathogenesis of COPD through the remodeling of airways and alveolar structures.

To quantify the number of goblet cells and inflammatory cells in the epithelium of peripheral airways in smokers with both symptoms of chronic bronchitis and chronic airflow limitation, we examined surgical specimens obtained from 25 subjects undergoing lung resection for localized pulmonary lesions: 10 smokers with symptoms of chronic bronchitis and chronic airflow limitation, six asymptomatic smokers with normal lung function, and nine nonsmoking control subjects. Peripheral airways were examined with histochemical methods to identify goblet cells and with immunohistochemical methods to identify total leukocytes (CD45(+) cells), neutrophils, macrophages, CD4(+) and CD8(+) cells in the epithelium. When compared with nonsmokers, smokers with both symptoms of chronic bronchitis and chronic airflow limitation had an increased number of goblet cells (p < 0.01), CD45(+) cells (p < 0. 01), macrophages (p < 0.05), and CD8(+) cells (p < 0.01) in the epithelium of peripheral airways. When all the smokers were grouped together, they showed an increased number of neutrophils (p < 0.05) along with an increased number of goblet cells, CD45(+) cells, macrophages and CD8(+) cells (p < 0.05) compared with nonsmokers. In conclusion, smokers with both symptoms of chronic bronchitis and chronic airflow limitation have an increased number of goblet cells and inflammatory cells in the epithelium of peripheral airways.

Previous work has shown an increase in CD8+ T-cells, neutrophils and eosinophils in small airway subepithelium in smokers. The authors have now investigated whether similar changes occur in the large airways. Immunohistochemistry on frozen sections of bronchial biopsies were obtained at bronchoscopy in 11 nonsmokers, eight asymptomatic smokers and 11 smokers with chronic bronchitis and chronic obstructive pulmonary disease (COPD). There was an increase in the number of CD8+ cells infiltrating the bronchial subepithelium in the COPD group compared to the asymptomatic smokers (305 (109-400) versus 92 (41-550) cells x mm(-2), p=0.030). There was a negative correlation between the number of CD8+ cells and the forced expiratory volume in one second (FEV1) %predicted (p=0.005, r=-0.62), and a positive correlation between the number of CD8+ cells and the number of pack years smoked (p=0.017, r=0.42). There was a negative correlation between the activated/total eosinophils ratio and the FEV1 % pred (p=0.017, r=-0.51). There was a negative correlation between pack years smoked and the number of neutrophils (p=0.022, r=-0.36). Smokers who develop chronic obstructive pulmonary disease have increased numbers of CD8+ T-cells in large airways when compared to asymptomatic smokers. Airway obstruction was associated with an increase in the proportion of eosinophils that were activated.

Background: An obstructive defect is usual in bronchiectasis, but the pathophysiological basis of airflow obstruction remains uncertain. High resolution computed tomographic (CT) scanning now allows quantitation of static morphological abnormalities, as well as dynamic changes shown on expiratory CT scans. The aim of this study was to determine which static and dynamic structural abnormalities on the CT scan are associated with airflow obstruction in bronchiectasis., Methods: The inspiratory and expiratory features on the CT scan of 100 patients with bronchiectasis undergoing concurrent lung function tests were scored semi-quantitatively by three observers., Results: On univariate analysis the extent and severity of bronchiectasis, the severity of bronchial wall thickening, and the extent of decreased attenuation on the expiratory CT scan correlated strongly with the severity of airflow obstruction; the closest relationship was seen between decreased forced expiratory volume in one second (FEV(1)) and the extent of decreased attenuation on the expiratory CT scan (R(s) = -0.55, p<0. 00005). On multivariate analysis bronchial wall thickness and decreased attenuation were consistently the strongest independent determinants of airflow obstruction. The extent of decreased attenuation was positively associated with the severity of bronchial wall thickness, but was not independently linked to gas transfer levels. Endobronchial secretions seen on CT scanning had no functional significance; the severity of bronchial dilatation was negatively associated with airflow obstruction after adjustment for other morphological features., Conclusions: These findings indicate that airflow obstruction in bronchiectasis is primarily linked to evidence of intrinsic disease of small and medium airways on CT scanning and not to bronchiectatic abnormalities in large airways, emphysema, or retained endobronchial secretions.

Objective: To correlate clinical score, intrapleural pressure, cytologic findings of bronchoalveolar lavage fluid (BALF), and histologic lesions of pulmonary tissue in horses affected with summer pasture-associated obstructive pulmonary disease (SPAOPD)., Animals: 8 adult horses affected with SPAOPD and 6 adult horses without evidence of respiratory tract disease., Procedure: Clinical score, change in intrapleural pressure (deltaPpl) during tidal breathing, results of cytologic examination and bacteriologic culture of BALF, and results of histologic examination of pulmonary parenchyma were evaluated., Results: Clinical scores for SPAOPD-affected horses (median, 5.75; range, 4.0 to 7.5) were significantly greater, compared with clinically normal horses (median, 2.0; range, 2.0 to 3.0). Cytologic examination of BALF from SPAOPD-affected horses revealed predominantly nondegenerate neutrophils. Histologic lesions were identified throughout pulmonary tissue and included severe accumulation of mucus and neutrophils within the small airways, metaplasia of bronchiolar goblet cells, and mild peribronchial infiltrate. Histologic examination of specimens collected via percutaneous biopsy was predictive of disease and corresponded to findings at postmortem examination. Clinical score and deltaPpl were highly correlated with mucus accumulation in the airways of affected horses. Peribronchial inflammatory infiltrate correlated with percentage of neutrophils in BALF of affected horses., Conclusions and Clinical Relevance: Clinical scoring and deltaPpl provided valid estimates of disease severity. Findings from cytologic examination of BALF of SPAOPD-affected horses varied, although, in most instances, it was diagnostically useful. Severe mucus accumulation in the airways was the most remarkable histopathologic finding in SPAOPD-affected horses. Examination of biopsy specimens collected from pulmonary parenchyma was consistently useful in diagnosing SPAOPD.

Products of the prostaglandin H synthase (PGHS) metabolic pathway are thought to play a role in the pathogenesis of asthma. We determined the level of expression of the constitutive (PGHS-1) and inducible (PGHS-2) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma, patients with chronic obstructive pulmonary disease (COPD), and unaffected control subjects by immunocyto- and immunohistochemistry. Immunoreactivity for PGHS-2 was significantly greater in the induced sputum of patients with asthma and patients with COPD compared with unaffected control subjects. The level of PGHS-2 was greater in asthma than in COPD. Immunoreactivity for PGHS-1 increased in cells in the induced sputum of patients with asthma and patients with COPD compared with that of unaffected control subjects. Immunostained cells included macrophages, eosinophils, and neutrophils. Greater PGHS-2 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects. In summary, we demonstrate an induction of PGHS-2 in asthma, suggesting increased formation of prostanoids, which may contribute to the inflammatory process.

Background: Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke., Methods: Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV(1)) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV(1) 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed., Results: Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm(2), p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm(2), p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p = 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV(1)/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils)., Conclusions: Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.

Background and Objectives: We evaluated the size and configuration of the trachea in patients with chronic obstructive pulmonary disease (COPD; n = 35) on high-resolution computed tomography (HRCT) images and compared them with those of healthy volunteers (n = 24)., Methods: Using a newly developed computed method for analyzing the digital data of HRCT, the size and configuration of the trachea were automatically evaluated., Results: The size of the trachea of the COPD subjects was the same as that of the control subjects; however, the configuration was more distorted in the COPD patients. There was no difference in the tracheal index (TI), which is the ratio of the coronal to the sagittal length, between these two groups; however, the ratio of the short to the long radius (SR/LR) was significantly smaller in the COPD group than in the control group. There was a significant correlation between SR/LR and airflow limitation as assessed by pulmonary function tests in the COPD group., Conclusions: The SR/LR is a better index of tracheal deformity than the classical TI. This deformity is not a consequence secondary to hyperinflation or emphysematous change of the lung, because the low attenuation area of the lung was not correlated with SR/LR., (Copyright 2000 S. Karger AG, Basel)

Negative-pressure casting techniques have been used for obtaining silicone rubber casts of the avian respiratory system, which contains minute air capillaries, noncompressible hollow bones, and highly flexible air sacs. The possibilities of this technique for the study of human airway diseases, which present technical difficulties similar to those of avian lungs, are investigated here. Left lungs from patients with various obstructive lung diseases or with normal lungs were fixed at autopsy under 25 cm H2O airway pressure with 2.5% phosphate-buffered glutaraldehyde. Cannulated, isolated lobes were placed in a vacuum chamber, and Dow Corning 734 RTV silicone elastomer, diluted with 10% low-viscosity silicone oil, was introduced into the airways at--10 kPa. Following complete polymerization, the tissue was microdissected to reveal the lung cast in situ, and histological sections were obtained for correlative studies. The tissue was then macerated in 5.25% sodium hypochlorite. The total time from fixation to finished cast was 3-4 days. Linear shrinkage of the elastomer was less than 1% in glutaraldehyde or water and between 1 and 2% in bleach. The negative-pressure injection technique enabled complete and accurate filling of airways to the alveolar duct level at physiological pressures and provided good delineation of blind cavities such as obstructed airways or ecstatic mucous gland ducts. The technique proved useful for the study of obstructive lung disease and should also prove useful for modelling aerosol deposition in diseased lungs.

It is unclear how cellular and soluble inflammatory markers in induced sputum relate to markers in lavage fluid and biopsies in chronic obstructive pulmonary disease (COPD). This was investigated and also the possible differences between subjects with COPD and healthy controls assessed. Eighteen nonatopic subjects with COPD and 11 healthy controls were studied. Sputum was induced by inhalation of hypertonic saline. The airways were lavaged, using the first 50 mL for bronchial wash (BW) and the subsequent 150 mL for bronchoalveolar lavage (BAL), and biopsies were taken from subsegmental carinae. Neutrophils were the predominant cell type in sputum in COPD (median 77.3%) but not in BW (5.5%) and BAL fluid (1.7%). Differential cell counts in sputum did not correlate with the counts in BW or BAL fluid or biopsies, whereas sputum eosinophil cationic protein (ECP) levels correlated with BW fluid ECP levels (p=0.66, p=0.007) and sputum interleukin-8 (IL-8) concentration with BAL fluid IL-8 concentration (p= 0.52, p=0.026). Subjects with COPD had a higher percentage of sputum neutrophils and eosinophils and higher concentrations of ECP and IL-8 than healthy controls. The higher percentages of eosinophils and concentrations of ECP were also seen in BW and BAL fluid. Finally, higher numbers of macrophages and eosinophils were found in biopsies. In conclusion, induced sputum is derived from a different compartment from BW and BAL fluid and biopsies. Induced sputum may be useful for studying the contribution of luminal neutrophils and eosinophils in chronic obstructive pulmonary disease.

The effects of oral doxofylline (400 mg BID) on bronchial airway mucosa were investigated in 14 patients with chronic obstructive bronchitis. The eligible patients had to have forced expiratory volume in 1 second > 60% of the predicted value and oxygen partial tension > 55 mm Hg. At the onset and the end of the study, bronchial biopsies were performed via a flexible fiberoptic bronchoscope. Chronic inflammation of the airways was graded according to absence of lesions = 0, involvement of 1-10% = 1, 10-50% = 2 and > 50% = 3. After three months of treatment, 57% of patients in the doxofylline group presented absence of lesions, while the remaining 43% exhibited advanced lesions. In the control group, absence of lesions was observed in 14%, while lesions of grade 1, 2 and 3 were visible in 14%, 29% and 43%, respectively. At histological examination, a significant difference in the degree of structural changes was observed in the doxofylline group between baseline and the end of the study (p < 0.03). In conclusion, doxofylline may induce favorable effects on inflammatory changes and altered cell proliferation of the airway mucosa in patients with chronic obstructive bronchitis.