Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of α1–antitrypsin deficiency and the role of leukotriene B4 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 α1–antitrypsin (α1–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) α1–AT deficiency (PiZ), was assessed using the under-agarose assay. The contribution of leukotriene B4 (LTB4) and interleukin 8 (IL-8) to the chemotactic activity was examined using an LTB4 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 α1–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 LTB4 and IL-8 (expressed as % fMLP control) was also significantly higher in α1–AT deficient patients than in patients with COPD with normal levels of α1–AT (LTB4: 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 LTB4 (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 α1–AT phenotype (p=0.606). >Conclusions: These results suggest that the bronchial secretions of COPD patients with α1–AT deficiency have increased neutrophil chemotactic activity. This relates to the increased levels of IL-8 and, in particular LTB4, 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 α1–AT deficiency via increased neutrophil recruitment and release of neutrophil elastase.