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Veruno, Italy
Dr. Di Stefano is Research Biologist, Dr. Capelli is Respiratory Physician, and Dr. Donner is Chief, Division of Pulmonary Disease, Salvatore Maugeri Foundation IRCCS, Scientific Institute of Veruno.
Correspondence to: Claudio F. Donner, MD, FCCP, Divisione di Pneumologia, Fondazione S. Maugeri, IRCCS, Istituto Scientifico di Veruno, Via per Revislate, 13, 28010 Veruno (NO), Italy; e-mail: cdonner{at}fsm.it
In the last decade, the role of inflammation and of proinflammatory cytokines in the pathogenesis of COPD has been extensively investigated. Studies1 performed in bronchial biopsy specimens and in the peripheral airways of COPD patients have shown that a mononuclear cell infiltration, consisting predominantly of T lymphocytes and macrophages, is prevalent in patients with mild disease, while neutrophils and macrophages have become the prevalent inflammatory cells in patients with more severe states of the disease. Although the role of neutrophils in the pathogenesis of COPD still has not been fully clarified, it is likely that neutrophil accumulation in the airways of patients with COPD is driven by an increased release of cytokines exerting a chemotactic effect on these cells. This pattern of inflammatory cell prevalence is accompanied by increased levels of intercellular adhesion molecule-1, macrophage inflammatory protein-1
, and interleukin (IL)-8 in the epithelium, and of endothelial adhesion molecule-1 in the submucosal endothelium of severely diseased patients,123 and by increased levels of phospho-signal transducer and activator of transcription-4, interferon-
, and nuclear factor-
B in bronchial biopsy specimens from patients with mild-to-moderate disease.45 Total inflammatory cell infiltration was reported to be decreased in association with increased fibrotic modifications in the airways of patients with severe disease, compared to those with the mildest forms of COPD.1
An analysis of BAL and sputum samples has also shown increased levels of IL-8, leukotriene B4,6 and monocyte chemotactic protein-1 in patients with mild-to-moderate COPD,789 suggesting that the migration of neutrophils and mononuclear cells from the bronchial wall to the lumen could be increased through IL-8 and monocyte chemotactic protein-1 release, even in patients with the mildest forms of the disease.
Studies of cultured bronchial epithelial cells obtained from patients with moderate COPD have shown that constitutive10 and tumor necrosis factor (TNF)--stimulated IL-8 release1011 is higher in COPD patients compared to that in healthy smokers and control subjects. Some recent studies of patients with COPD exacerbations has shown an up-regulation of gene expression for IL-8 and epithelial-derived neutrophil attractant-78 in intubated patients with severe exacerbations,12 and a significant correlation between increased levels of systemic IL-8 and enhanced peripheral muscle weakness.13
These data highlight the potential of novel therapeutic approaches that not only are focused on the symptomatic management of COPD but also confront the basic pathophysiologic mechanisms underlying the disease (ie, they are aimed at suppressing chronic neutrophilic inflammation in patients with COPD). They also raise the question of whether a specific treatment of patients directed against a single proinflammatory cytokine may influence the state of the disease.
Some recent studies14 have investigated the ability of a new selective phosphodiesterase 4 inhibitor to inhibit the release of neutrophil chemoattractants such as TNF-, IL-8, and granulocyte-macrophage colony-stimulating factor, showing a significant inhibition for TNF- and granulocyte-macrophage colony-stimulating factor, but not for IL-8. Since IL-8 develops chemotactic activity for neutrophils and CD8+ cells, and activates neutrophils by increasing degranulation and neutrophil elastase release, attention has been focused on the possible efficacy of monoclonal neutralizing antibodies against IL-8 when administered to COPD patients. ABX-IL8 is a monoclonal antibody recognizing IL-8, and previous studies1516 have observed the role of this antibody in the inhibition of angiogenesis, and in the growth of human melanoma and bladder cancers through the down-regulation of matrix metalloproteinases 2 and 9 modulating the nuclear factor-B expression and transcriptional activity.
In this issue of CHEST (see page 926), Mahler and coauthors show that IV infusion of ABX-IL-8, administered monthly for a 3-month period, improved symptoms of dyspnea, as indicated by the significant and clinically relevant increase in the transition dyspnea index total scores during the treatment in the group with moderate-to-severe COPD (average FEV1, 42% predicted) compared to those of the group treated with placebo. Relief of dyspnea was evident at 2 weeks after the first infusion and persisted for a 2-month period. The authors did not observe significant differences in lung function, health status, 6-min walking distance, and number of adverse events between the two groups examined. The pilot study of Mahler et al shows that treatment with ABX-IL-8 is safe and well-tolerated, and that the number of adverse events were similar between the treatment and placebo groups. This study represents the first report of a trial of monoclonal antibody therapy targeted against an important chemokine in patients with COPD, providing preliminary support for further investigation and opening up new perspectives for therapeutic intervention. These data, however, need to be confirmed in a larger case series, as markers and the mechanism of action of biological agents in COPD patients were not elucidated. The investigation of these factors certainly would contribute to a better selection of patients appropriate for targeting: investigating the optimal dose to achieve sufficient concentration in the airway; evaluating the benefit/safety profile of the treatment over a longer time period (at least 1 year); and selecting the most adequate outcome measures. Furthermore, the following question remains open: since measurements of IL-8, IL-8 receptors, and neutrophils in biological samples (ie, from sputum, BAL, and bronchial biopsies) were not performed in this study, how does ABX-IL-8 treatment influence these inflammatory markers?
From this perspective, we can conclude that a better understanding of the inflammatory pathogenesis of COPD and, in particular, of the mechanisms leading to airway neutrophilia may contribute to a more effective therapeutic approach to this progressive and very disabling disease. Several chemoattractants may act as targets for future antiinflammatory agents, insofar as they are able to potentially reduce the rate of decline in lung function in COPD patients by reducing neutrophil-mediated lung tissue destruction.
References
B. Clin Cancer Res 2003;9,3167-3175This article has been cited by other articles:
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  S Rao and J Grigg New insights into pulmonary inflammation in cystic fibrosis. Arch. Dis. Child., September 1, 2006; 91(9): 786 - 788. [Abstract] [Full Text] [PDF]
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