Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of alpha(1)-antitrypsin deficiency and the role of leukotriene B(4) and interleukin 8.

摘要

BACKGROUND: Neutrophil recruitment to the airway is thought to be an important component of continuing inflammation and progression of chronic obstructive pulmonary disease (COPD), particularly in the presence of severe alpha(1)-antitrypsin (alpha(1)-AT) deficiency. However, the chemoattractant nature of secretions from these patients has yet to be clarified. METHODS: The chemotactic activity of spontaneous sputum from patients with stable COPD, with (n=11) and without (n=11) alpha(1)-AT deficiency (PiZ), was assessed using the under-agarose assay. The contribution of leukotriene B(4) (LTB(4)) and interleukin 8 (IL-8) to the chemotactic activity was examined using an LTB(4) receptor antagonist (BIIL 315 ZW) and an IL-8 monoclonal antibody, respectively. RESULTS: Sputum neutrophil chemotactic activity (expressed as % n-formylmethionyl leucylphenylalanine (fMLP) control) was significantly higher in patients with alpha(1)-AT deficiency (mean (SE) 63.4 (8.9)% v 36.7 (5.5)%; mean difference 26.7% (95% CI 4.9 to 48.4), p<0.05). The mean (SE) contribution of both LTB(4) and IL-8 (expressed as % fMLP control) was also significantly higher in alpha(1)-AT deficient patients than in patients with COPD with normal levels of alpha(1)-AT (LTB(4): 31.9 (6.3)% v 18.0 (3.7)%; mean difference 13.9% (95% CI -1.4 to 29.1), p<0.05; IL-8: 24.1 (5.2)% v 8.1 (1.2)%; mean difference 15.9% (95% CI 4.7 to 27.2), p<0.05). When all the subjects were considered together the mean (SE) contribution of LTB(4) (expressed as % total chemotactic activity) was significantly higher than IL-8 (46.8 (3.5)% v 30.8 (4.6)%; mean difference 16.0% (95% CI 2.9 to 29.2), p<0.05). This difference was not significantly influenced by alpha(1)-AT phenotype (p=0.606). CONCLUSIONS: These results suggest that the bronchial secretions of COPD patients with alpha(1)-AT deficiency have increased neutrophil chemotactic activity. This relates to the increased levels of IL-8 and, in particular LTB(4), which accounted most of the sputum chemotactic activity in the patients with COPD as a whole. Increased chemotactic activity, together with inhibitor deficiency, may contribute to the more rapid disease progression seen in alpha(1)-AT deficiency via increased neutrophil recruitment and release of neutrophil elastase.