No abstract

There are little data describing noncellular changes in bronchial inflammation during exacerbations of chronic bronchitis. The relationship between sputum colour and airway inflammation at presentation has been assessed during an exacerbation in patients with chronic bronchitis and a primary care diagnosis of chronic obstructive pulmonary disease.Sputum myeloperoxidase, neutrophil elastase, leukotriene B 4 (LTB 4 ), interleukin-8 (IL-8), sol:serum albumin ratio and serum C-reactive protein were measured in patients presenting with an exacerbation and mucoid (n~27) or purulent sputum (n~42).Mucoid exacerbations were associated with little bronchial or systemic inflammation at presentation, and sputum bacteriology was similar to that obtained in the stable state. Purulent exacerbations were associated with marked bronchial and systemic inflammation (pv0.025 for all features) and positive sputum cultures (90%). Resolution was related to a significant reduction in LTB 4 (pv0.01), but no change in IL-8, suggesting that LTB 4 may be more important in neutrophil recruitment in these mild, purulent exacerbations. In the stable state, IL-8 remained higher in patients who had experienced a purulent exacerbation (2pv0.02).The presented results indicate that exacerbations of chronic bronchitis, defined by sputum colour, differ in the degree of bronchial and systemic inflammation. Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B 4 concentrations.

Neutrophils recruited to the airways in chronic obstructive pulmonary disease (COPD) are thought to mediate tissue destruction. Neutrophil recruitment is increased during bacterial exacerbations. The inflammatory process was studied in patients with an acute exacerbation of COPD in order to ascertain the role of leukotriene B 4 (LTB 4 ).The sputum of eight subjects with a bacterial exacerbation of COPD was analysed for neutrophil products (myeloperoxidase, elastase) and chemoattractants (interleukin-8 (IL-8) and LTB 4 ). The contribution of LTB 4 to the chemotactic activity of the sputum sol phase was determined using the LTB 4 receptor antagonist LY293111. The concentrations of the serum acute phase proteins a 1 -proteinase inhibitor, a 1 -antichymotrypsin and C-reactive protein were measured. All patients received appropriate broad-spectrum antibiotic treatment for 7±14 days.Initially, the sputum myeloperoxidase activity was high, indicating neutrophil influx; this was associated with high levels of IL-8 and LTB 4 . All these concentrations fell with treatment (p<0.01). The chemotactic activity of the sputum was raised on presentation and fell with treatment (p<0.01). LTB 4 contributed~30% of the total chemotactic activity on presentation; this diminished with therapy. All acute phase proteins were raised on presentation and fell with therapy (p<0.01).These findings suggest that leukotriene B 4 contributes to neutrophil influx into the airway in chronic obstructive pulmonary disease and may influence disease progresgression. Eur Respir J 2000; 15: 274±280.

Many of the features of bronchial disease are believed to be caused by damage to the airways by elastase released by recruited neutrophils. There have been few studies of the mechanisms involved and the interrelationships between components of the inflammatory process. We studied secretions from patients with chronic bronchitis in the stable state. We assessed the presence of neutrophils by measuring myeloperoxidase (MPO) activity and active neutrophil elastase (NE). These results were compared with the chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)), the bronchial inhibitor secretory leukoprotease inhibitor (SLPI), and protein leak (sputum/serum albumin ratio). MPO correlated with NE activity (r = 0.68, p < 0.001) and both IL-8 (r = 0.52, p < 0.001) and LTB(4) (r = 0.41, p < 0.001) indicating an association with the chemoattractants. Elastase activity correlated with IL-8 (r = 0.55, p < 0.001) and LTB(4) (r = 0.41, p < 0.001) but negatively with SLPI (r = -0.49, p < 0.001). NE also correlated positively with protein leak (r = 0.36, p < 0.001), suggesting a cause and effect. MPO and protein leak correlated negatively with FEV(1) (percentage of predicted) only in patients with chronic obstructive pulmonary disease (COPD) without alpha(1)-antitrypsin deficiency (r = -0.37, p < 0.001; r = -0.42, p < 0.01, respectively). These complex interactions provide a template for future studies with specific inhibitors or agonists which will clarify the role of individual factors.

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.

COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling.

Background: Recent studies of the role of bacteria in chronic bronchitis have shown that bacterial colonisation is associated with enhanced inflammation and that purulent acute exacerbations of chronic bronchitis (AECB) are associated with bacteria and characterised by increased inflammation. Changes in bronchial inflammation in response to the success or failure of bacterial eradication following AECB were therefore studied. Methods: Bacterial quantitative culture and sputum markers of inflammation (myeloperoxidase (MPO), neutrophil elastase, leukotriene B4 (LTB4), sol:serum albumin ratio, and secretory leukoprotease inhibitor) were measured in patients presenting with culture positive purulent AECB and repeated 10 days and 2 months later. 41 patients provided sputum sufficient for both bacteriology and assessment of inflammation at baseline and day 10, and 46 provided sufficient sample for bacteriology, 40 of which could also be analysed for inflammation at 2 months (when clinically stable). Results: At day 10, 17 of the 41 patient samples had a positive bacterial culture. In the stable state, 18 of the 46 samples had a positive culture, but with a significantly lower bacterial load than at presentation. Although there was no difference between the groups at presentation, the concentration of MPO was lower (p<0.05) in those in whom bacteria were eradicated by day 10 than in those with persisting bacteria. The LTB4 concentration was similarly lower (p<0.001) in those in whom bacteria were eradicated than in those with persistent bacteria. In the stable clinical state the concentrations of both MPO and LTB4 were lower in those in whom bacteria were eradicated than in patients with persisting bacteria. Conclusion: Resolution of bronchial inflammation following AECB is related to bacterial eradication. Those in whom bacteria continue to be cultured in their sputum have partial resolution of inflammation which may reflect continued stimulation by the reduced bacterial load.

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. 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 aVected individuals. (Thorax 2001;56:36-41) Keywords: chronic obstructive pulmonary disease; inflammation; secretory leukoprotease inhibitor (SLPI) Chronic obstructive pulmonary disease (COPD) comprises a heterogeneous group of conditions, characterised by varying degrees of expiratory airflow limitation, related to combinations of abnormalities in the large and small airways and to alveolar destruction. The patients have a reduced state of health that is (loosely) related to the degree of physiological abnormality.