Airway Obstruction in Chronic Obstructive Pulmonary Disease
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《新英格兰医药杂志》
To the Editor: In their article on small-airway obstruction in patients with chronic obstructive pulmonary disease (COPD), Hogg and colleagues (June 24 issue)1 report that the progression of COPD is associated with the luminal accumulation of exudates and inflammatory-cell infiltration. However, the role of hypersecretion and retention of mucus in airway narrowing has not been addressed in detail. Retention of mucus is likely to lead to a major debilitating symptom of COPD. No specific therapy is available to date,2 but a new molecular treatment option that inhibits mucus matrix-forming protein mucin 5AC has recently been proposed.3 Mucin 5AC is present and is increased in expression in the bronchiolar epithelium and lumen in patients with COPD (Figure 1). Mucin 5AC and mucin 5B are the major mucins that are secreted into the lumen in both COPD and asthma.4,5 An assessment of the mucous composition at all stages of COPD should be part of the description of the nature of small-airway obstruction.
Figure 1. Immunohistochemical Analysis Showing Respiratory Mucin 5AC–Positive Airway Mucus in Epithelial Goblet Cells from a Patient with COPD.
The scale bar represents 100 μm.
K. Fan Chung, M.D., D.Sc.
Imperial College
London SW3 6LY, United Kingdom
f.chung@imperial.ac.uk
Gaetano Caramori, M.D.
Universita di Ferrara
44100 Ferrara, Italy
David A. Groneberg, M.D.
Charité School of Medicine
D-13353 Berlin, Germany
References
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653.
Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004;350:2689-2697.
Singer M, Martin LD, Vargaftig BB, et al. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat Med 2004;10:193-196.
Groneberg DA, Eynott PR, Lim S, et al. Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 2002;40:367-373.
DiGregorio C, Caramori G, Carlstedt I, et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 2004;45:311-319.
To the Editor: In his Perspective article, Barnes (June 24 issue)1 discusses the findings by Hogg et al. and points out that the inflammatory response in the airways of patients with COPD does not resolve on cessation of smoking. However, this point is not addressed in the work of Hogg et al. We think that this statement does not correlate well with two clinical observations. First, it has been proved that cessation of smoking is the only measure that slows the rate of decline in the forced expiratory volume in one second (FEV1) in patients with COPD. In such patients, the annual decrease in FEV1 changes notably before and after the cessation of smoking.2 Second, patients with COPD who quit smoking have clinical improvement in terms of cough and sputum production.3 These observations suggest that even though both chronic inflammation and tissue remodeling and repair persist, a decrease in the acute inflammatory response might explain the clinical improvement in patients with COPD after they stop smoking.
Joaquín Lamela, M.D.
Complejo Hospitalario Universitario de Orense
32005 Orense, Spain
jlamela@separ.es
Francisco Vega, M.D., Ph.D.
Baylor College of Medicine
Houston, TX 77030
José Blanco, M.D.
Complejo Hospitalario Universitario de Orense
32005 Orense, Spain
References
Barnes PJ. Small airways in COPD. N Engl J Med 2004;350:2635-2637.
Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977;1:1645-1648.
Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med 1999;106:410-416.
Dr. Hogg replies: My colleagues and I agree with Lamela et al. that cessation of smoking is beneficial for patients with COPD, and we did not mean to imply that the patients in our study did not benefit from quitting. Our point is that the inflammatory reaction in the small airways persisted after a prolonged period of smoking cessation, and this point has been made by other authors.1,2
We also agree with Chung et al. that we did not study in detail the mucus contained in the inflammatory exudates that are present in the small-airway lumen. The hypothesis that mucous plugging of the peripheral airways is a reversible component of small-airway obstruction in COPD was controversial before our report and will probably remain so. Postmortem studies on which the hypothesis is based are confounded by the presence of terminal bronchopneumonia3; studies of surgically resected lung tissue have not supported the hypothesis, possibly because the patients in these studies had milder forms of the disease.4
Our study, which was based on surgically resected material from patients who represented the full range of COPD, supported the hypothesis by showing an association between a decline in FEV1 and progressive occlusion of the small-airway lumen in COPD. The experiments were not designed to investigate either the types of mucus present in the luminal exudates, as suggested by Chung and colleagues, or the circumstances of a reduction in the thickness of the periciliary fluid layer by excess sodium reabsorption, which results in defective mucociliary clearance from the peripheral airways and inflammatory lesions that are very similar to those we report.5 Clearly, the type of mucus in the exudates and the control of mucociliary clearance warrant further study, as do the control of the airway remodeling process and the innate and adaptive inflammatory immune cells that we describe in the small-airway lesions. Much remains to be learned about airway obstruction in COPD.
James C. Hogg, M.D., Ph.D.
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
jhogg@mrl.ubc.ca
References
Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000;55:12-18.
Turato G, Di Stefano A, Maestrelli P, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995;152:1262-1267.
Matsuba K, Thurlbeck WM. Disease of the small airways in chronic bronchitis. Am Rev Respir Dis 1973;107:552-558.
Cosio M, Ghezzo H, Hogg JC, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978;298:1277-1281.
Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004;10:487-493.
Dr. Barnes replies: Patients with severe COPD have an intense inflammatory response in their small airways, despite a mean interval since the cessation of smoking of more than nine years.1 This finding is consistent with other studies showing that patients with COPD who are former smokers have an inflammatory response in their airways that appears to be similar to the response in active smokers.2,3 However, it is not yet known whether smoking cessation in a person reduces the intensity or character of airway inflammation, since no longitudinal studies have been reported. Respiratory symptoms, particularly cough and sputum production, are certainly reduced by smoking cessation in patients with COPD,4 and as Lamela and colleagues note, several studies have demonstrated that it also reduces the decline in FEV1. However, the response to smoking cessation in patients with more severe disease is considerably less than that in patients with milder disease.5 This finding suggests that smoking cessation in patients with severe COPD may have little effect on the inflammatory process, which may be driven autonomously by the adaptive immune response in severe disease that Hogg et al. describe.
Peter J. Barnes, D.M., D.Sc.
Imperial College
London SW3 6LY, United Kingdom
References
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653.
Turato G, Di Stefano A, Maestrelli P, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995;152:1262-1267.
Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000;55:12-18.
Willemse BW, Postma DS, Timens W, ten Hacken NH. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J 2004;23:464-476.
Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: the Lung Health Study. Am J Respir Crit Care Med 2000;161:381-390.
Figure 1. Immunohistochemical Analysis Showing Respiratory Mucin 5AC–Positive Airway Mucus in Epithelial Goblet Cells from a Patient with COPD.
The scale bar represents 100 μm.
K. Fan Chung, M.D., D.Sc.
Imperial College
London SW3 6LY, United Kingdom
f.chung@imperial.ac.uk
Gaetano Caramori, M.D.
Universita di Ferrara
44100 Ferrara, Italy
David A. Groneberg, M.D.
Charité School of Medicine
D-13353 Berlin, Germany
References
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653.
Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004;350:2689-2697.
Singer M, Martin LD, Vargaftig BB, et al. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat Med 2004;10:193-196.
Groneberg DA, Eynott PR, Lim S, et al. Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 2002;40:367-373.
DiGregorio C, Caramori G, Carlstedt I, et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 2004;45:311-319.
To the Editor: In his Perspective article, Barnes (June 24 issue)1 discusses the findings by Hogg et al. and points out that the inflammatory response in the airways of patients with COPD does not resolve on cessation of smoking. However, this point is not addressed in the work of Hogg et al. We think that this statement does not correlate well with two clinical observations. First, it has been proved that cessation of smoking is the only measure that slows the rate of decline in the forced expiratory volume in one second (FEV1) in patients with COPD. In such patients, the annual decrease in FEV1 changes notably before and after the cessation of smoking.2 Second, patients with COPD who quit smoking have clinical improvement in terms of cough and sputum production.3 These observations suggest that even though both chronic inflammation and tissue remodeling and repair persist, a decrease in the acute inflammatory response might explain the clinical improvement in patients with COPD after they stop smoking.
Joaquín Lamela, M.D.
Complejo Hospitalario Universitario de Orense
32005 Orense, Spain
jlamela@separ.es
Francisco Vega, M.D., Ph.D.
Baylor College of Medicine
Houston, TX 77030
José Blanco, M.D.
Complejo Hospitalario Universitario de Orense
32005 Orense, Spain
References
Barnes PJ. Small airways in COPD. N Engl J Med 2004;350:2635-2637.
Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977;1:1645-1648.
Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med 1999;106:410-416.
Dr. Hogg replies: My colleagues and I agree with Lamela et al. that cessation of smoking is beneficial for patients with COPD, and we did not mean to imply that the patients in our study did not benefit from quitting. Our point is that the inflammatory reaction in the small airways persisted after a prolonged period of smoking cessation, and this point has been made by other authors.1,2
We also agree with Chung et al. that we did not study in detail the mucus contained in the inflammatory exudates that are present in the small-airway lumen. The hypothesis that mucous plugging of the peripheral airways is a reversible component of small-airway obstruction in COPD was controversial before our report and will probably remain so. Postmortem studies on which the hypothesis is based are confounded by the presence of terminal bronchopneumonia3; studies of surgically resected lung tissue have not supported the hypothesis, possibly because the patients in these studies had milder forms of the disease.4
Our study, which was based on surgically resected material from patients who represented the full range of COPD, supported the hypothesis by showing an association between a decline in FEV1 and progressive occlusion of the small-airway lumen in COPD. The experiments were not designed to investigate either the types of mucus present in the luminal exudates, as suggested by Chung and colleagues, or the circumstances of a reduction in the thickness of the periciliary fluid layer by excess sodium reabsorption, which results in defective mucociliary clearance from the peripheral airways and inflammatory lesions that are very similar to those we report.5 Clearly, the type of mucus in the exudates and the control of mucociliary clearance warrant further study, as do the control of the airway remodeling process and the innate and adaptive inflammatory immune cells that we describe in the small-airway lesions. Much remains to be learned about airway obstruction in COPD.
James C. Hogg, M.D., Ph.D.
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
jhogg@mrl.ubc.ca
References
Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000;55:12-18.
Turato G, Di Stefano A, Maestrelli P, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995;152:1262-1267.
Matsuba K, Thurlbeck WM. Disease of the small airways in chronic bronchitis. Am Rev Respir Dis 1973;107:552-558.
Cosio M, Ghezzo H, Hogg JC, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978;298:1277-1281.
Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004;10:487-493.
Dr. Barnes replies: Patients with severe COPD have an intense inflammatory response in their small airways, despite a mean interval since the cessation of smoking of more than nine years.1 This finding is consistent with other studies showing that patients with COPD who are former smokers have an inflammatory response in their airways that appears to be similar to the response in active smokers.2,3 However, it is not yet known whether smoking cessation in a person reduces the intensity or character of airway inflammation, since no longitudinal studies have been reported. Respiratory symptoms, particularly cough and sputum production, are certainly reduced by smoking cessation in patients with COPD,4 and as Lamela and colleagues note, several studies have demonstrated that it also reduces the decline in FEV1. However, the response to smoking cessation in patients with more severe disease is considerably less than that in patients with milder disease.5 This finding suggests that smoking cessation in patients with severe COPD may have little effect on the inflammatory process, which may be driven autonomously by the adaptive immune response in severe disease that Hogg et al. describe.
Peter J. Barnes, D.M., D.Sc.
Imperial College
London SW3 6LY, United Kingdom
References
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653.
Turato G, Di Stefano A, Maestrelli P, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995;152:1262-1267.
Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000;55:12-18.
Willemse BW, Postma DS, Timens W, ten Hacken NH. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J 2004;23:464-476.
Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: the Lung Health Study. Am J Respir Crit Care Med 2000;161:381-390.