© 2003 American Thoracic Society
Neutrophil Chemokines in Severe Exacerbations of Chronic Obstructive Pulmonary DiseaseFatal Chemo-Attraction?Department of Clinical and Experimental Medicine Section of Respiratory Diseases University of Padova Padova, Italy Chronic obstructive pulmonary disease (COPD) is a public health problem around the world, being a major cause of chronic morbidity and mortality. It is characterized by fixed airflow limitation and progressive decline of lung function, which is punctuated by exacerbations. These can be so severe as to cause admission to hospital or the intensive care unit (1). Smokers with stable COPD have an inflammatory response involving the entire tracheobronchial tree, characterized by an increase of macrophages and CD8 T lymphocytes in the airway wall and of neutrophils in the airway lumen (2). This cellular pattern changes during severe exacerbations, with neutrophils becoming the major component of the inflammatory response (3). While the cellular mechanisms in mild and moderate exacerbations of COPD have been extensively investigated (3), little is known about severe exacerbations. In particular, the mechanisms underlying neutrophil recruitment and accumulation within the airway wall in critically ill patients requiring intubation for acute severe exacerbations of COPD has not been reported. In this issue of the Journal, Qiu and coworkers (4) report that these patients exhibit airway neutrophilia in association with upregulation of two important neutrophil chemoattractants (cysteine-x-cysteine ligands, CXCL5 and CXCL8) and the receptors on which these ligands act (cysteine-x-cysteine receptors, CXCR1 and CXCR2). Why is it important to investigate the cellular mechanisms underlying severe exacerbations? As lung function worsens, patients with COPD become increasingly prone to exacerbations, which are associated with a major health and economic burden and a markedly increased mortality (1). The results of a large multicenter study (5) clearly reveal that hospital admission for severe exacerbations of COPD is associated with a mortality rate of 49% at two years, a dramatic figure resembling that of lung cancer. Therefore, a better understanding of the mechanisms involved in neutrophil recruitment might help to prevent or treat severe exacerbations, and hopefully to improve the otherwise inexorable clinical outcome of these patients. One finding of Qiu and coworkers is especially intriguing: the dominant neutrophil chemoattractant was CXCL5 and not CXCL8, as suggested by most previous reports (6, 7). By showing that the expression of CXCL5 is three times higher than that of CXCL8, the investigators identify a new potential target for anti-inflammatory strategies aimed at impeding neutrophil recruitment in these severe patients. An added bonus in this study is that, in contrast with other reports of sputum and bronchoalveolar lavage (3, 6, 7), the investigators examined bronchial biopsies. The data provide direct information on airway tissue, where the structural changes occur. These changes are probably crucial in a chronic disorder such as COPD. In this context, the pro-angiogenic activity of CXCL5, demonstrated in other lung diseases (8), may deserve further attention. Although the study is focused primarily on patients with severe exacerbations of COPD, the investigators also studied patients with stable disease and nonsmoking subjects as control groups. As such, the study also provides insight into neutrophil recruitment and the pattern of chemokines in stable COPD (9, 10). The findings are especially interesting because these patients with stable COPD had a remarkable degree of airflow limitation (average FEV1 51% predicted); little has been published on chemokine patterns in bronchial biopsies of patients with this degree of severity. None of the examined chemokines, their receptors, or the number of neutrophils were upregulated in the submucosa. The findings indicate that tissue neutrophilia is not a feature of stable COPD, even when lung function is quite impaired. Moreover, the findings suggest that neutrophil recruitment during an exacerbation does not arise from enhancement of a pre-existing mechanism, but is instead the result of new activation of CXCL5 and CXCL8 signaling—possibly driven by a bacterial or viral agent. In addition to being a common trigger of exacerbations, growing evidence implicates viral infections in stable COPD through enhancing the inflammatory response (11). It is surprising that Qiu and coworkers did not find viruses in patients with stable COPD. Other investigators detected respiratory viruses in approximately 20% of such patients (12). Firm conclusions cannot be drawn from this study, however, because it was not specifically designed to examine the role of viral infections in different manifestations of the disease. We should be careful when interpreting the findings of Qiu and coworkers for several reasons. First, the three groups of subjects were not well matched. Patients with severe exacerbations were intubated and mechanically ventilated before biopsy sampling, whereas subjects in the two control groups were not. Moreover, only the patients with exacerbations were treated with intravenous corticosteroids. Both of these factors can potentially enhance airway neutrophilia (13, 14). Second, this study was focused on the central airways and not the peripheral airways, the site at which chronic airflow limitation develops in smokers (15). It is still unknown to what extent bronchial biopsies capture pathology at this more peripheral location. Finally, it was a cross-sectional study. Without longitudinal data, we cannot rule out the possibility that these patients already had neutrophilia even when stable and before the severe exacerbations. It should be acknowledged, however, that these problems are somewhat unavoidable in this type of study, especially in patients with disease of this severity. There is no doubt that the study by Qiu and coworkers improves our understanding of the cellular mechanisms underlying severe COPD, and may provide the basis for new antiinflammatory strategies. The study also raises two key questions that are unanswered. "Do neutrophils play a causal role in the clinical outcome of a severe exacerbation of COPD"? And, more importantly, "If we successfully eradicate neutrophilic inflammation, will it necessarily improve clinical outcome"? FOOTNOTES Conflict of Interest Statement: M.S. has been reimbursed by various pharmaceutical companies (GlaxoSmithkline; AstraZeneca; and Merck, Sharpe & Dome) for attending several conferences and has participated as a speaker in scientific meetings or courses organized and financed by GlaxoSmithkline; AstraZeneca; and Merck, Sharpe & Dome. S.B. and R.Z. have no declared conflict of interest. REFERENCES
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