© 2007 American Thoracic Society doi: 10.1164/rccm.200706-820ED
Airway Inflammation in COPDFriend or Foe?Università di Genova Genova, Italy
Centro di Fisiopatologia Respiratoria e dello Studio della Dispnea Azienda Ospedaliera S. Croce e Carle Cuneo, Italy A disease expected to rank third in prevalence and fifth for disability by 2020, with increasing mortality, morbidity, hospitalization rates, and which results in absence from work, and has high social cost, becomes a global and unsustainable social health problem if remedies are not taken soon. This appears to be the case for chronic obstructive pulmonary disease (COPD), a disease well known to be caused by long-term exposure to cigarette smoke, environmental pollution, or both. The knowledge of risk factors certainly makes COPD a preventable disease, but relatively poor knowledge of its pathophysiology makes it difficult to treat. A current pathogenetic theory is based on the hypothesis that COPD is sustained by a perpetuating "burning" process mediated by inflammatory cells, proinflammatory cytokines, and abnormally high oxidative stress (1). In an attempt to confront the noxious gases and particles, the respiratory system reacts with innate and adaptive responses mostly at the level of its smallest and most delicate airways. Airway remodeling is the consequence of such an inflammatory process, and would represent the major cause of airway narrowing. Based on this putative mechanism, inhaled steroids were first used in clinical practice and then included in the international guidelines after a series of multicenter trials (2–5) documented clinical benefit, such as reduced symptoms, improved disease-specific health status, and, in some cases, decreased numbers of exacerbations. It has been suggested that steroidal medications may even have the potential to reduce the risk of cardiovascular disease through a decrease in systemic inflammation (6). In this issue of the Journal (pp. 454–459), Hogg and coworkers (7) investigated the relationship between small airway pathology and long-term mortality in 101 patients with COPD who had undergone lung volume reduction surgery. Interestingly, they found that the only parameter significantly related to survival was the severity of small airway occlusion by exudates containing mucus, but not other indexes of airway inflammation. In the history of COPD, mucus secretion has always been given a secondary role. Since the seminal study of Fletcher and Peto in 1977 (8) and again in the work by Vestbo and Lange (9) 25 years later, reanalyzing the data from the Copenhagen City Heart Study (9), mucus was dismissed as a factor unimportant with respect to the decline of lung function. In contrast, a recent study has brought mucus production back in the limelight by documenting that the presence of chronic cough and phlegm doubles the risk of COPD (10). If mucus production is so important in COPD, then how can we explain its role in the development and progression of the disease and eventually leading to death? The question is perhaps still without a definitive answer, but Hogg and coworkers propose that mucus could increase in the small airways either because it is produced in excess by goblet cells stimulated by neutrophil elastase or oxygen free radicals, or because it is incapable to flow out as a result of impaired mucus clearance. However, we also believe that mucus could stick to airway walls, thus contributing to luminal occlusion and lung function decline by virtue of its viscosity. Another intriguing hypothesis is that the initial event in the pathogenesis of COPD may be the differentiation of airway stem cells into secretory cells as a part of an injury-repair process (11). Be that as it may, all of these findings lead to a new hypothesis that airway inflammation and mucus production in COPD are somewhat dissociated, with the latter representing the most important prognostic factor. As a secondary, yet not minor, finding, Hogg and colleagues observed a significant negative relationship between steroid therapy and the percentage of airways containing lymphoid follicles. The results are straightforward but appear to go countercurrent to the dominant pathogenetic theory of the disease. As mentioned above, a popular view of the pathogenesis and treatment of COPD is that airway wall inflammation is the primary mechanism through which the disease develops, and steroids are of definite clinical benefit because they reduce such inflammation. The data by Hogg and coworkers do suggest that treatment with systemic and, to a lesser extent, inhaled steroids blunts the adaptive immune response in severe COPD while leaving mucus secretion unaltered. The authors raise the hypothesis that long-term therapy with steroids can suppress the host immune response, thus facilitating lower respiratory tract infections. This would explain the findings of clinical studies showing that steroid treatment in COPD is associated with increased risk of pneumonia from opportunistic fungi (12), hospitalization for pneumonia, and death in elderly patients (13).
The pathologic findings from this study, in conjunction with results of large clinical trials, challenge the idea that airway inflammation is invariably a foe to the patient with COPD. Other considerations may help strengthen this idea. For instance, what the trials on COPD treatments (14) taught us is that the effects of antiinflammatory treatments alone are few, if any, and benefits can only be obtained when bronchodilator agents are given either alone or in combination with inhaled steroids. Moreover, it is known that smoking cessation is the only intervention able to reduce decline in lung function, yet it leaves airway inflammation basically unaltered (15). Finally, in addition to inflammation, small airway remodeling in COPD has been shown to be directly caused by cigarette smoke through an increase in transforming growth factor- FOOTNOTES
Conflict of Interest Statement: V.B. received REFERENCES
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