pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2012-0-6-111-126pulmo-145Research ArticleОБЗОРЫREVIEWМалые дыхательные пути при хронической обструктивной болезни легких – важнейшая мишень эффективной терапииSmall airways in chronic obstructive pulmonary disease as a core target of effective therapyАвдеевС. Н.AvdeevS. N.

д. м. н., проф., руководитель клинического отдела

105077, Москва, ул. 11)я Парковая, 32, корп. 4. Тел. / факс: 8 (495) 465-52-64.

ФГБУ "НИИ пульмонологии" ФМБА РоссииRussian Federation20122812201206111126Copyright © Авдеев С.Н., 20122012Авдеев С.Н.Avdeev S.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/145

Малые дыхательные пути при хронической обструктивной болезни легких – важнейшая мишень эффективной терапии.

Small airways in chronic obstructive pulmonary disease as a core target of effective therapy.

малые дыхательные путихроническая обструктивная болезнь легкихтерапияsmall airwayschronic obstructive pulmonary diseasetreatmentReferencesGlobal Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO workshop report. Last updated 2011. www.goldcopd.orgGlobal Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO workshop report. Last updated 2011. www.goldcopd.orgCelli B.R., MacNee W. ATS / ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur. Respir. J. 2004; 23: 932–946.Celli B.R., MacNee W. ATS / ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur. Respir. J. 2004; 23: 932–946.Buist A.S., McBurnie M.A., Vollmer W.M. et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007; 370: 741–750.Buist A.S., McBurnie M.A., Vollmer W.M. et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007; 370: 741–750.Barnes P.J., Shapiro S.D., Pauwels R.A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur. Respir. J. 2003; 22: 672–688.Barnes P.J., Shapiro S.D., Pauwels R.A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur. Respir. J. 2003; 22: 672–688.Hogg J.C. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364: 709–721.Hogg J.C. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364: 709–721.Martin C., Frija J., Burgel P.4R. Dysfunctional lung anatomy and small airways degeneration in COPD. Int. J. COPD 2013; 8: 7–13.Martin C., Frija J., Burgel P.4R. Dysfunctional lung anatomy and small airways degeneration in COPD. Int. J. COPD 2013; 8: 7–13.Hogg J.C., Macklem P.T., Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease. N. Engl. J. Med. 1968; 278: 1355–1360.Hogg J.C., Macklem P.T., Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease. N. Engl. J. Med. 1968; 278: 1355–1360.Leach C., Colice G.L., Luskin A. Particle size of inhaled corticosteroids: does it matter? J. Allergy Clin. Immunol. 2009; 124 (Suppl. 6): S88–S93.Leach C., Colice G.L., Luskin A. Particle size of inhaled corticosteroids: does it matter? J. Allergy Clin. Immunol. 2009; 124 (Suppl. 6): S88–S93.Burgel P.4R., de Blic J., Chanez P. et al. Update on the roles of distal airways in asthma. Eur. Respir. Rev. 2009; 18: 80–95.Burgel P.4R., de Blic J., Chanez P. et al. Update on the roles of distal airways in asthma. Eur. Respir. Rev. 2009; 18: 80–95.Contoli M., Bousquet J., Fabbri L.M. et al. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy 2010; 65: 141–151.Contoli M., Bousquet J., Fabbri L.M. et al. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy 2010; 65: 141–151.Weibel E.R. Morphometry of the human lung. New York: Academic Press; 1963.Weibel E.R. Morphometry of the human lung. New York: Academic Press; 1963.Wright J.L. Small airway diseases: its role in chronic airway obstruction. Semin. Respir. Med. 1992; 13: 72–84.Wright J.L. Small airway diseases: its role in chronic airway obstruction. Semin. Respir. Med. 1992; 13: 72–84.Garg K., Lynch D.A., Newell J.D., King T.E. Proliferative and constrictive bronchiolitis: classification and radiological features. Am. J. Roentgenol. 1994; 162: 803–808.Garg K., Lynch D.A., Newell J.D., King T.E. Proliferative and constrictive bronchiolitis: classification and radiological features. Am. J. Roentgenol. 1994; 162: 803–808.McDonough J.E., Yuan R., Suzuki M. et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 2011; 365: 1567–1575.McDonough J.E., Yuan R., Suzuki M. et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 2011; 365: 1567–1575.Rohrer F. Der Stromungswiderstand in der menschlichen Atemwegen und der Einfluss der unregelmassigen Verzweigung es Bronchial-systems auf der Atmungsverlauf in vershiedenen Lungenbezinken. Arch. Ges. Physiol. 1915; 162: 225–229.Rohrer F. Der Stromungswiderstand in der menschlichen Atemwegen und der Einfluss der unregelmassigen Verzweigung es Bronchial-systems auf der Atmungsverlauf in vershiedenen Lungenbezinken. Arch. Ges. Physiol. 1915; 162: 225–229.Findeisen W. Uber das Absetzen kleiner, in dur Luft suspendierter Teilchen in der menschlichen Lunge bei der Atmung. Arch. Ges. Physiol. 1935; 236: 367–379.Findeisen W. Uber das Absetzen kleiner, in dur Luft suspendierter Teilchen in der menschlichen Lunge bei der Atmung. Arch. Ges. Physiol. 1935; 236: 367–379.Horsfield K., Cumming G. Morphology of the bronchial tree in man. J. Appl. Physiol. 1968; 24: 373–383.Horsfield K., Cumming G. Morphology of the bronchial tree in man. J. Appl. Physiol. 1968; 24: 373–383.Macklem P.T., Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J. Appl. Physiol. 1967, 22: 395–401.Macklem P.T., Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J. Appl. Physiol. 1967, 22: 395–401.Wagner E.M., Liu M.C., Weinmann G.G. et al. Peripheral lung resistance in normal and asthmatic subjects. Am. Rev. Respir. Dis. 1990; 148: 584–588.Wagner E.M., Liu M.C., Weinmann G.G. et al. Peripheral lung resistance in normal and asthmatic subjects. Am. Rev. Respir. Dis. 1990; 148: 584–588.Yanai M., Sekizawa K., Ohrui T. et al. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J. Appl. Physiol. 1992; 72: 1016–1023.Yanai M., Sekizawa K., Ohrui T. et al. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J. Appl. Physiol. 1992; 72: 1016–1023.Wagner E.M., Bleecker E.R., Permutt S. et al. Direct assessment of small airways reactivity in human subjects. Am. J. Respir. Crit. Care Med. 1998; 157: 447–452.Wagner E.M., Bleecker E.R., Permutt S. et al. Direct assessment of small airways reactivity in human subjects. Am. J. Respir. Crit. Care Med. 1998; 157: 447–452.Van Brabandt H., Cauberghs M., Verbeken E. et al. Partitioning of pulmonary impedance in excised human and canine lungs. J. Appl. Physiol. 1983, 55: 1733–1742.Van Brabandt H., Cauberghs M., Verbeken E. et al. Partitioning of pulmonary impedance in excised human and canine lungs. J. Appl. Physiol. 1983, 55: 1733–1742.Bethe A., von Bergmann G., Embden G. et al. Physiologie der Atembewegung. In: Bethe A., von Bergmann G., Embden G. et al., eds. Handbuch der normalen und pathologischen physiologie. Berlin: Springer; 1925. 70–127.Bethe A., von Bergmann G., Embden G. et al. Physiologie der Atembewegung. In: Bethe A., von Bergmann G., Embden G. et al., eds. Handbuch der normalen und pathologischen physiologie. Berlin: Springer; 1925. 70–127.Green M. How big are the bronchioles? St. Thomas Hosp. Gaz. 1965; 63:136–139.Green M. How big are the bronchioles? St. Thomas Hosp. Gaz. 1965; 63:136–139.Barnes P.J. Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343: 269–280Barnes P.J. Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343: 269–280Hogg J.C., 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.Hogg J.C., 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.Hogg J.C., Timens W. The pathology of chronic obstructive pulmonary disease. Ann. Rev. Pathol. 2009; 4: 435–459.Hogg J.C., Timens W. The pathology of chronic obstructive pulmonary disease. Ann. Rev. Pathol. 2009; 4: 435–459.Turato G., Zuin R., Miniati M. et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am. J. Respir. Crit. Care Med. 2002; 166: 105–110.Turato G., Zuin R., Miniati M. et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am. J. Respir. Crit. Care Med. 2002; 166: 105–110.Saetta M., Turato G., Maestrelli P. et al. Cellular and structural bases of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163: 1304–1309.Saetta M., Turato G., Maestrelli P. et al. Cellular and structural bases of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163: 1304–1309.O'Donnell R.A., Peebles C., Ward J.A. et al. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax 2004; 59: 837–842.O'Donnell R.A., Peebles C., Ward J.A. et al. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax 2004; 59: 837–842.Nadel J.A. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies. Chest 2000; 117 (Suppl. 2): 386S–389S.Nadel J.A. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies. Chest 2000; 117 (Suppl. 2): 386S–389S.Saetta M., Turato G., Baraldo S. et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am. J. Respir. Crit. Care Med. 2000; 161: 1016–1021.Saetta M., Turato G., Baraldo S. et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am. J. Respir. Crit. Care Med. 2000; 161: 1016–1021.Finkelstein R., Ma H.D., Ghezzo H. et al. Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1995; 152: 267–276.Finkelstein R., Ma H.D., Ghezzo H. et al. Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1995; 152: 267–276.Frankenberger M., Menzel M., Betz R. et al. Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers. Clin. Exp. Immunol. 2004; 138: 507–516.Frankenberger M., Menzel M., Betz R. et al. Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers. Clin. Exp. Immunol. 2004; 138: 507–516.Saetta M., Di Stefano A., Maestrelli P. et al. Activated T lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis. 1993; 147: 301–306.Saetta M., Di Stefano A., Maestrelli P. et al. Activated T lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis. 1993; 147: 301–306.Lams B.E., Sousa A.R., Rees P.J. et al. Immunopathology of the small-airway submucosa in smokers with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158: 1518–1523.Lams B.E., Sousa A.R., Rees P.J. et al. Immunopathology of the small-airway submucosa in smokers with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158: 1518–1523.Saetta M., Mariani M., Panina4Bordignon P. et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2002; 165: 1404–1409.Saetta M., Mariani M., Panina4Bordignon P. et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2002; 165: 1404–1409.Fairclough L., Urbanowicz R.A., Corne J. et al. Killer cells in chronic obstructive pulmonary disease. Clin. Sci. (Lond) 2008; 114: 533–541.Fairclough L., Urbanowicz R.A., Corne J. et al. Killer cells in chronic obstructive pulmonary disease. Clin. Sci. (Lond) 2008; 114: 533–541.Demedts I.K., Bracke K.R., Van Pottelberge G. et al. Accumulation of dendritic cells and increased CCL20 levels in the airways of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2007; 175: 998–1005.Demedts I.K., Bracke K.R., Van Pottelberge G. et al. Accumulation of dendritic cells and increased CCL20 levels in the airways of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2007; 175: 998–1005.Freeman C.M., Martinez F.J., Han M.K. et al. Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2009; 180: 1179–1188.Freeman C.M., Martinez F.J., Han M.K. et al. Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2009; 180: 1179–1188.Van Pottelberge G.R., Bracke K.R., Demedts I.K. et al. Selective accumulation of langerhans-type dendritic cells in small airways of patients with COPD. Respir. Res. 2010; 11: 35.Van Pottelberge G.R., Bracke K.R., Demedts I.K. et al. Selective accumulation of langerhans-type dendritic cells in small airways of patients with COPD. Respir. Res. 2010; 11: 35.Grashoff W.F., Sont J.K., Sterk P.J. et al. Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages. Am. J. Pathol. 1997; 151: 1785–1790.Grashoff W.F., Sont J.K., Sterk P.J. et al. Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages. Am. J. Pathol. 1997; 151: 1785–1790.Ballarin A., Bazzan E., Zenteno R.H. et al. Mast cell infiltration discriminates between histopathological phenotypes of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2012; 186: 233–239.Ballarin A., Bazzan E., Zenteno R.H. et al. Mast cell infiltration discriminates between histopathological phenotypes of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2012; 186: 233–239.Saetta M., Di Stefano A., Maestrelli P. et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150: 1646–1652.Saetta M., Di Stefano A., Maestrelli P. et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150: 1646–1652.Papi A., Bellettato C.M., Braccioni F. et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am. J. Respir. Crit. Care Med. 2006; 173: 1114–1121.Papi A., Bellettato C.M., Braccioni F. et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am. J. Respir. Crit. Care Med. 2006; 173: 1114–1121.Snoeck4Stroband J.B., Lapperre T.S., Gosman M.M. et al. Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies. Eur. Respir. J. 2008; 31: 70–77.Snoeck4Stroband J.B., Lapperre T.S., Gosman M.M. et al. Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies. Eur. Respir. J. 2008; 31: 70–77.Cosio M., Ghezzo H., Hogg J.C. et al. The relations between structural changes in small airways and pulmonary-function tests. N. Engl. J. Med. 1978; 298: 1277–1281.Cosio M., Ghezzo H., Hogg J.C. et al. The relations between structural changes in small airways and pulmonary-function tests. N. Engl. J. Med. 1978; 298: 1277–1281.Araya J., Cambier S., Markovics J.A. et al. Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J. Clin. Invest. 2007; 117: 3551–3562.Araya J., Cambier S., Markovics J.A. et al. Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J. Clin. Invest. 2007; 117: 3551–3562.Peters E.J., Morice R., Benner S.E. et al. Squamous metaplasia of the bronchial mucosa and its relationship to smoking. Chest 1993; 103: 1429–1432.Peters E.J., Morice R., Benner S.E. et al. Squamous metaplasia of the bronchial mucosa and its relationship to smoking. Chest 1993; 103: 1429–1432.Lapperre T.S., Sont J.K., van Schadewijk A. et al. Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir. Res. 2007; 8: 85.Lapperre T.S., Sont J.K., van Schadewijk A. et al. Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir. Res. 2007; 8: 85.Innes A.L., Woodruff P.G., Ferrando R.E. et al. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 2006; 130: 1102–1108.Innes A.L., Woodruff P.G., Ferrando R.E. et al. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 2006; 130: 1102–1108.Gaga M., Zervas E., Chanez P. Update on severe asthma: what we know and what we need. Eur. Respir. Rev. 2009; 18: 58–65.Gaga M., Zervas E., Chanez P. Update on severe asthma: what we know and what we need. Eur. Respir. Rev. 2009; 18: 58–65.Mitchell R.S., Stanford R.E., Johnson J.M. et al. The morphologic features of the bronchi, bronchioles, and alveoli in chronic airway obstruction: a clinicopathologic study. Am. Rev. Respir. Dis. 1976; 114: 137–145.Mitchell R.S., Stanford R.E., Johnson J.M. et al. The morphologic features of the bronchi, bronchioles, and alveoli in chronic airway obstruction: a clinicopathologic study. Am. Rev. Respir. Dis. 1976; 114: 137–145.Wright J.L., Postma D.S., Kerstjens H.A. et al. Airway remodeling in the smoke exposed guinea pig model. Inhal. Toxicol. 2007; 19: 915–923.Wright J.L., Postma D.S., Kerstjens H.A. et al. Airway remodeling in the smoke exposed guinea pig model. Inhal. Toxicol. 2007; 19: 915–923.Caramori G., Di Gregorio C., Carlstedt I. et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 2004; 45: 477–484.Caramori G., Di Gregorio C., Carlstedt I. et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology 2004; 45: 477–484.Cosio M.G., Saetta M., Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N. Engl. J. Med. 2009; 360: 2445–2454.Cosio M.G., Saetta M., Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N. Engl. J. Med. 2009; 360: 2445–2454.Bourdin A., Burgel P.R., Chanez P. et al. Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbidities. Eur. Respir. Rev. 2009; 18: 198–212.Bourdin A., Burgel P.R., Chanez P. et al. Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbidities. Eur. Respir. Rev. 2009; 18: 198–212.Marseglia G.L., Cirillo I., Vizzaccaro A. et al. Role of forced expiratory flow at 25–75 % as an early marker of small airways impairment in subjects with allergic rhinitis. Allergy Asthma Proc. 2007; 28: 74–78.Marseglia G.L., Cirillo I., Vizzaccaro A. et al. Role of forced expiratory flow at 25–75 % as an early marker of small airways impairment in subjects with allergic rhinitis. Allergy Asthma Proc. 2007; 28: 74–78.Hansen J.E., Sun X.G., Wasserman K. Discriminating measures and normal values for expiratory obstruction. Chest 2006; 129: 369–377.Hansen J.E., Sun X.G., Wasserman K. Discriminating measures and normal values for expiratory obstruction. Chest 2006; 129: 369–377.Wenzel S.E., Schwartz L.B., Langmack E.L. et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 1999; 160: 1001–1008.Wenzel S.E., Schwartz L.B., Langmack E.L. et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 1999; 160: 1001–1008.Gibson G.J. Pulmonary hyperinflation a clinical overview. Eur. Respir. J. 1996; 9: 2640–2649.Gibson G.J. Pulmonary hyperinflation a clinical overview. Eur. Respir. J. 1996; 9: 2640–2649.Sorkness R.L., Bleecker E.R., Busse W.W. et al. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J. Appl. Physiol. 2008; 104: 394–403.Sorkness R.L., Bleecker E.R., Busse W.W. et al. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J. Appl. Physiol. 2008; 104: 394–403.Bourdin A., Paganin F., Prefaut C. et al. Nitrogen washout slope in poorly controlled asthma. Allergy 2006; 61: 85–89.Bourdin A., Paganin F., Prefaut C. et al. Nitrogen washout slope in poorly controlled asthma. Allergy 2006; 61: 85–89.Make B., Lapp N.L. Factors influencing the measurement of closing volume. Am. Rev. Respir. Dis. 1975; 111: 749–754.Make B., Lapp N.L. Factors influencing the measurement of closing volume. Am. Rev. Respir. Dis. 1975; 111: 749–754.McFadden E.R., Holmes B., Kiser R. Variability of closing volume measurements in normal man. Am. Rev. Respir. Dis. 1975; 111: 135–140.McFadden E.R., Holmes B., Kiser R. Variability of closing volume measurements in normal man. Am. Rev. Respir. Dis. 1975; 111: 135–140.Verbanck S., Schuermans D., Meysman M. et al. Noninvasive assessment of airway alterations in smokers: the small airways revisited. Am. J. Respir. Crit. Care Med. 2004; 170: 414–419.Verbanck S., Schuermans D., Meysman M. et al. Noninvasive assessment of airway alterations in smokers: the small airways revisited. Am. J. Respir. Crit. Care Med. 2004; 170: 414–419.Verbanck S., Schuermans D., Van Muylem A. et al. Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD. Am. J. Respir. Crit. Care Med. 1998; 157: 1573–1577.Verbanck S., Schuermans D., Van Muylem A. et al. Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD. Am. J. Respir. Crit. Care Med. 1998; 157: 1573–1577.Verbanck S., Schuermans D., Vincken W. Small airways ventilation heterogeneity and hyperinflation in COPD: response to tiotropium bromide. Int. J. Chron. Obstruct. Pulm. Dis. 2007; 2: 625–634.Verbanck S., Schuermans D., Vincken W. Small airways ventilation heterogeneity and hyperinflation in COPD: response to tiotropium bromide. Int. J. Chron. Obstruct. Pulm. Dis. 2007; 2: 625–634.Verbanck S., Schuermans D., Paiva M. et al. Small airway function improvement after smoking cessation in smokers without airway obstruction. Am. J. Respir. Crit. Care Med. 2006; 174: 853–857.Verbanck S., Schuermans D., Paiva M. et al. Small airway function improvement after smoking cessation in smokers without airway obstruction. Am. J. Respir. Crit. Care Med. 2006; 174: 853–857.Saadeh C., Goldman M., Gaylor P. Forced oscillation using impulse oscillometry (IOS) detects false negative spirometry in symptomatic patients with reactive airways. J. Allergy Clin. Immunol. 2003; 111: 136.Saadeh C., Goldman M., Gaylor P. Forced oscillation using impulse oscillometry (IOS) detects false negative spirometry in symptomatic patients with reactive airways. J. Allergy Clin. Immunol. 2003; 111: 136.Landser F.J., Clement J., Van de Woestijne K.P. Normal values of total respiratory resistance and reactance determined by forced oscillations: influence of smoking. Chest 1982; 81: 586–591.Landser F.J., Clement J., Van de Woestijne K.P. Normal values of total respiratory resistance and reactance determined by forced oscillations: influence of smoking. Chest 1982; 81: 586–591.Кирюхина Л.Д., Кузнецова В.К., Аганезова Е.С. и др. Метод импульсной осциллометриии в диагностике нарушений механики дыхания. Пульмонология 2000; 2: 31–36.Кирюхина Л.Д., Кузнецова В.К., Аганезова Е.С. и др. Метод импульсной осциллометриии в диагностике нарушений механики дыхания. Пульмонология 2000; 2: 31–36.Goldman M.D, Saadeh C., Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir. Physiol. Neurobiol. 2005; 148: 179–194.Goldman M.D, Saadeh C., Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir. Physiol. Neurobiol. 2005; 148: 179–194.Oppenheimer B.W., Goldring R.M., Berger K.I. Distal airway function assessed by oscillometry at varying respiratory rate: comparison with dynamic compliance. COPD 2009; 6: 162–170.Oppenheimer B.W., Goldring R.M., Berger K.I. Distal airway function assessed by oscillometry at varying respiratory rate: comparison with dynamic compliance. COPD 2009; 6: 162–170.Borrill Z.L., Houghton C.M., Tal4Singer R. et al. The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD. Br. J. Clin. Pharmacol. 2008; 65: 244–252.Borrill Z.L., Houghton C.M., Tal4Singer R. et al. The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD. Br. J. Clin. Pharmacol. 2008; 65: 244–252.Coxson H.O., Mayo J., Lam S. et al. New and current clinical imaging techniques to study chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2009; 180: 588–597.Coxson H.O., Mayo J., Lam S. et al. New and current clinical imaging techniques to study chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2009; 180: 588–597.Berger P., Perot V., Desbarats P. et al. Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment. Radiology 2005; 235: 1055–1064.Berger P., Perot V., Desbarats P. et al. Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment. Radiology 2005; 235: 1055–1064.Fujimoto K., Kitaguchi Y., Kubo K. et al. Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography. Respirology 2006; 11: 731–740.Fujimoto K., Kitaguchi Y., Kubo K. et al. Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography. Respirology 2006; 11: 731–740.Desai S.R., Hansell D.M., Walker A. et al. Quantification of emphysema: a composite physiologic index derived from CT estimation of disease extent. Eur. Radiol. 2007; 17: 911–918.Desai S.R., Hansell D.M., Walker A. et al. Quantification of emphysema: a composite physiologic index derived from CT estimation of disease extent. Eur. Radiol. 2007; 17: 911–918.Madani A., Zanen J., de Maertelaer V. et al. Pulmonary emphysema: objective quantification at multi-detector row CT – comparison with macroscopic and microscopic morphometry. Radiology 2006; 238: 1036–1043.Madani A., Zanen J., de Maertelaer V. et al. Pulmonary emphysema: objective quantification at multi-detector row CT – comparison with macroscopic and microscopic morphometry. Radiology 2006; 238: 1036–1043.Akira M., Toyokawa K., Inoue Y. et al. Quantitative CT in chronic obstructive pulmonary disease: inspiratory and expiratory assessment. Am. J. Roentgenol. 2009; 192: 267–272.Akira M., Toyokawa K., Inoue Y. et al. Quantitative CT in chronic obstructive pulmonary disease: inspiratory and expiratory assessment. Am. J. Roentgenol. 2009; 192: 267–272.King G.G., Muller N.L., Par P.D. Evaluation of airways in obstructive pulmonary disease using high-resolution computed tomography. Am. J. Respir. Crit. Care Med. 1999; 159: 992–1004.King G.G., Muller N.L., Par P.D. Evaluation of airways in obstructive pulmonary disease using high-resolution computed tomography. Am. J. Respir. Crit. Care Med. 1999; 159: 992–1004.Lynch D.A., Newell J.D., Tschomper B.A. et al. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology 1993; 188: 829–833.Lynch D.A., Newell J.D., Tschomper B.A. et al. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology 1993; 188: 829–833.Park J.W., Hong Y.K., Kim C.W. et al. High-resolution computed tomography in patients with bronchial asthma: correlation with clinical features, pulmonary functions and bronchial hyperresponsiveness. J. Invest. Allergol. Clin. Immunol. 1997; 7: 186–192.Park J.W., Hong Y.K., Kim C.W. et al. High-resolution computed tomography in patients with bronchial asthma: correlation with clinical features, pulmonary functions and bronchial hyperresponsiveness. J. Invest. Allergol. Clin. Immunol. 1997; 7: 186–192.McNitt4Gray M.F., Goldin J.G., Johnson T.D. et al. Development and testing of image-processing methods for the quantitative assessment of airway hyperresponsiveness from high-resolution CT images. J. Comput. Assist. Tomography 1997; 21: 939–947.McNitt4Gray M.F., Goldin J.G., Johnson T.D. et al. Development and testing of image-processing methods for the quantitative assessment of airway hyperresponsiveness from high-resolution CT images. J. Comput. Assist. Tomography 1997; 21: 939–947.Goldin J.G., McNitt4Gray M.F., Sorenson S.M. et al. Airway hyperreactivity assessment with helical thin-section CT. Radiology 1998; 208: 321–329.Goldin J.G., McNitt4Gray M.F., Sorenson S.M. et al. Airway hyperreactivity assessment with helical thin-section CT. Radiology 1998; 208: 321–329.Goldin J.G., McNitt4Gray M.F., Johnson T. et al. Functional helical high-resolution CT: sensitive test for detecting air trapping due to reversible airway hyperreactivity. Radiology 1995; 197 (P): 437.Goldin J.G., McNitt4Gray M.F., Johnson T. et al. Functional helical high-resolution CT: sensitive test for detecting air trapping due to reversible airway hyperreactivity. Radiology 1995; 197 (P): 437.Jensen S.P., Lynch D.A., Brown K.K. et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin. Radiol. 2002; 57: 1078–1085.Jensen S.P., Lynch D.A., Brown K.K. et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin. Radiol. 2002; 57: 1078–1085.Matsuoka S., Kurihara Y., Yagihashi K. et al. Quantitative assessment of air trapping in chronic obstructive pulmonary disease using inspiratory and expiratory volumetric MDCT. Am. J. Roentgenol. 2008; 190: 762–769.Matsuoka S., Kurihara Y., Yagihashi K. et al. Quantitative assessment of air trapping in chronic obstructive pulmonary disease using inspiratory and expiratory volumetric MDCT. Am. J. Roentgenol. 2008; 190: 762–769.Yablonskiy D.A., Sukstanskii A.L., Leawoods J.C. et al. Quantitative in vivo assessment of lung microstructure at the alveolar level with hyperpolarized 3He diffusion MRI. Proc. Natl Acad. Sci. USA 2002; 99: 3111–3116.Yablonskiy D.A., Sukstanskii A.L., Leawoods J.C. et al. Quantitative in vivo assessment of lung microstructure at the alveolar level with hyperpolarized 3He diffusion MRI. Proc. Natl Acad. Sci. USA 2002; 99: 3111–3116.Samee S., Altes T., Powers P. et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J. Allergy Clin. Immunol. 2003; 111: 1205–1211.Samee S., Altes T., Powers P. et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J. Allergy Clin. Immunol. 2003; 111: 1205–1211.Kauczor H.U., Chen X.J., van Beek E.J., Schreiber W.G. Pulmonary ventilation imaged bymagnetic resonance: at the doorstep of clinical application. Eur. Respir. J. 2001; 17: 1008–1023.Kauczor H.U., Chen X.J., van Beek E.J., Schreiber W.G. Pulmonary ventilation imaged bymagnetic resonance: at the doorstep of clinical application. Eur. Respir. J. 2001; 17: 1008–1023.de Lange E.E., Altes T.A., Patrie J.T. et al. Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. Chest 2006; 130: 1055–1062.de Lange E.E., Altes T.A., Patrie J.T. et al. Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. Chest 2006; 130: 1055–1062.Roche N., Dalmay F., Perez T. et al. Impact of chronic airflow obstruction in a working population. Eur. Respir. J. 2008; 31: 1227–1233.Roche N., Dalmay F., Perez T. et al. Impact of chronic airflow obstruction in a working population. Eur. Respir. J. 2008; 31: 1227–1233.Ofir D., Laveneziana P., Webb K.A. et al. Understanding breathlessness in mild chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2008; 177: 564–565.Ofir D., Laveneziana P., Webb K.A. et al. Understanding breathlessness in mild chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2008; 177: 564–565.O'Donnell D.E., Laveneziana P., Ora J. et al. Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD. Thorax 2009; 64: 216–223.O'Donnell D.E., Laveneziana P., Ora J. et al. Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD. Thorax 2009; 64: 216–223.Vestbo J., Lange P. Can GOLD stage 0 provide information of prognostic value in chronic obstructive pulmonary disease? Am. J. Respir. Crit. Care Med. 2002; 166: 329–332.Vestbo J., Lange P. Can GOLD stage 0 provide information of prognostic value in chronic obstructive pulmonary disease? Am. J. Respir. Crit. Care Med. 2002; 166: 329–332.Hogg J.C., Chu F.S., Tan W.C. et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am. J. Respir. Crit. Care Med. 2007; 176: 454–459.Hogg J.C., Chu F.S., Tan W.C. et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am. J. Respir. Crit. Care Med. 2007; 176: 454–459.Mannino D.M., Doherty D.E., Buist S. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir. Med. 2006; 100: 115–122.Mannino D.M., Doherty D.E., Buist S. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir. Med. 2006; 100: 115–122.Grootendorst D.C., Gauw S.A., Verhoosel R.M. et al. The PDE4 inhibitor roflumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD. Thorax 2007; 62: 1081–1087.Grootendorst D.C., Gauw S.A., Verhoosel R.M. et al. The PDE4 inhibitor roflumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD. Thorax 2007; 62: 1081–1087.Calverley P.M., Rabe K.F., Goehring U.M. et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374: 685–694.Calverley P.M., Rabe K.F., Goehring U.M. et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374: 685–694.Fabbri L.M., Calverley P.M., Izquierdo4Alonso J.L. et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet 2009; 374: 695–703.Fabbri L.M., Calverley P.M., Izquierdo4Alonso J.L. et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet 2009; 374: 695–703.Tse H.N., Raiteri L., Wong K.Y. et al. High-dose n-acetylcysteine in stable chronic obstructive pulmonary disease: the 1-year, double-blind, randomized, placebo-controlled hiace study. Chest 2013; 143: online first. doi: 10.1378/chest. 12–2357.Tse H.N., Raiteri L., Wong K.Y. et al. High-dose n-acetylcysteine in stable chronic obstructive pulmonary disease: the 1-year, double-blind, randomized, placebo-controlled hiace study. Chest 2013; 143: online first. doi: 10.1378/chest. 12–2357.Task Group on Lung Dynamics. Deposition and retention models for internal dosimetry of the human respiratory flow tract. Hlth Physics 1966; 12: 173–208.Task Group on Lung Dynamics. Deposition and retention models for internal dosimetry of the human respiratory flow tract. Hlth Physics 1966; 12: 173–208.Lipworth B.J. Targets for inhaled drugs. Respir. Med. 2000; 94 (Suppl. D): S13–S16.Lipworth B.J. Targets for inhaled drugs. Respir. Med. 2000; 94 (Suppl. D): S13–S16.Newman S., Salmon A., Nave R. et al. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir. Med. 2006; 100: 375–384.Newman S., Salmon A., Nave R. et al. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir. Med. 2006; 100: 375–384.Leach C.L. The CFC to HFA transition and its impact on pulmonary drug development. Respir. Care 2005; 50: 1201–1206.Leach C.L. The CFC to HFA transition and its impact on pulmonary drug development. Respir. Care 2005; 50: 1201–1206.Leach C.L., Davidson P.J., Boudreau R.J. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur. Respir. J. 1998; 12: 1346–1353.Leach C.L., Davidson P.J., Boudreau R.J. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur. Respir. J. 1998; 12: 1346–1353.Haussermann S., Acerbi D., Brand P. et al. Lung deposition of formoterol HFA (Atimos / Forair) in healthy volunteers, asthmatic and COPD patients. J. Aerosol Med. 2007; 20: 331–341.Haussermann S., Acerbi D., Brand P. et al. Lung deposition of formoterol HFA (Atimos / Forair) in healthy volunteers, asthmatic and COPD patients. J. Aerosol Med. 2007; 20: 331–341.Acerbi D., Poli G., Haussermann S. et al. Lung deposition of formoterol HFA in healthy volunteers, asthmatic and COPD patients [abstract plus poster]. In: The European Respiratory Society annual congress (ERS), Copenhagen, Denmark, Sept. 17–21, 2005.Acerbi D., Poli G., Haussermann S. et al. Lung deposition of formoterol HFA in healthy volunteers, asthmatic and COPD patients [abstract plus poster]. In: The European Respiratory Society annual congress (ERS), Copenhagen, Denmark, Sept. 17–21, 2005.Meyer T., Brand P., Ehlich H. et al. Deposition of Foradil P in human lungs: comparison of in vitro and in vivo data. J. Aerosol. Med. 2004; 17: 43–49.Meyer T., Brand P., Ehlich H. et al. Deposition of Foradil P in human lungs: comparison of in vitro and in vivo data. J. Aerosol. Med. 2004; 17: 43–49.Dusser D., Vicaut E., Lefrancois G. Double-blind, doubledummy, multinational, multicenter, parallel-group design clinical trial of clinical non-inferiority of formoterol 12 μg / unit dose in a b.i.d. regimen administered via an HFA-propellant-pMDI or a dry powder inhaler in a 12-week treatment period of moderate to severe stable persistent asthma in adult patients. Respiration 2005; 72 (Suppl. 1): 20–27.Dusser D., Vicaut E., Lefrancois G. Double-blind, doubledummy, multinational, multicenter, parallel-group design clinical trial of clinical non-inferiority of formoterol 12 μg / unit dose in a b.i.d. regimen administered via an HFA-propellant-pMDI or a dry powder inhaler in a 12-week treatment period of moderate to severe stable persistent asthma in adult patients. Respiration 2005; 72 (Suppl. 1): 20–27.Bousquet J., Guenole E., Duvauchelle T. et al. A randomized, double-blind, double-dummy, single-dose, crossover trial evaluating the efficacy and safety profiles of two dose levels (12 and 24 μg) of formoterol-HFA (pMDI) vs. those of a dose level (24 μg) of formoterol-DPI (Foradil® / Aerolizer™) and of placebo (pMDI or Aerolizer) in moderate to severe asthmatic patients. Respiration 2005; 72 (Suppl. 1): 13–19.Bousquet J., Guenole E., Duvauchelle T. et al. A randomized, double-blind, double-dummy, single-dose, crossover trial evaluating the efficacy and safety profiles of two dose levels (12 and 24 μg) of formoterol-HFA (pMDI) vs. those of a dose level (24 μg) of formoterol-DPI (Foradil® / Aerolizer™) and of placebo (pMDI or Aerolizer) in moderate to severe asthmatic patients. Respiration 2005; 72 (Suppl. 1): 13–19.Houghton C.M., Langley S.J., Singh S.D. et al. Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study. Br. J. Clin. Pharmacol. 2004; 58: 359–366.Houghton C.M., Langley S.J., Singh S.D. et al. Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study. Br. J. Clin. Pharmacol. 2004; 58: 359–366.Bousquet J., Huchon G., Leclerc V. et al. A randomized, double-blind, double-dummy, single-dose, efficacy crossover trial comparing formoterol-HFA (pMDI) versus formoterol-DPI (Aerolizer) and placebo (pMDI or Aerolizer) in asthmatic patients. Respiration 2005; 72 (Suppl. 1): 6–12.Bousquet J., Huchon G., Leclerc V. et al. A randomized, double-blind, double-dummy, single-dose, efficacy crossover trial comparing formoterol-HFA (pMDI) versus formoterol-DPI (Aerolizer) and placebo (pMDI or Aerolizer) in asthmatic patients. Respiration 2005; 72 (Suppl. 1): 6–12.Molimard M., Guenole E., Duvauchelle T. et al. A randomized, double-blind, double-dummy, safety crossover trial comparing cumulative doses up to 96 μg of formoterol delivered via an HFA-134a-propelled pMDI vs same cumulative doses of formoterol DPI and placebo in asthmatic patients. Respiration 2005; 72 (Suppl. 1): 28–34.Molimard M., Guenole E., Duvauchelle T. et al. A randomized, double-blind, double-dummy, safety crossover trial comparing cumulative doses up to 96 μg of formoterol delivered via an HFA-134a-propelled pMDI vs same cumulative doses of formoterol DPI and placebo in asthmatic patients. Respiration 2005; 72 (Suppl. 1): 28–34.Di Marco F., Verga M., Santus P. et al. Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease. A pilot study. Respir. Med. 2006; 100: 1925–1932.Di Marco F., Verga M., Santus P. et al. Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease. A pilot study. Respir. Med. 2006; 100: 1925–1932.Dhillon S., Keating G.M. Beclometasone dipropionate / formotherol in an HFA-propelled pressurized metereddose inhaler. Drugs 2006; 66: 1475–1483.Dhillon S., Keating G.M. Beclometasone dipropionate / formotherol in an HFA-propelled pressurized metereddose inhaler. Drugs 2006; 66: 1475–1483.Bousquet J., Poli G., Acerbi D. et al. Systemic exposure and implications for lung deposition with extra-fine HFA beclometasone dipropionat / formoterol fixed combination. Clin. Pharmacokinet. 2009; 48: 347–358.Bousquet J., Poli G., Acerbi D. et al. Systemic exposure and implications for lung deposition with extra-fine HFA beclometasone dipropionat / formoterol fixed combination. Clin. Pharmacokinet. 2009; 48: 347–358.De Backer W., Devolder A., Poli G. et al. Lung deposition of BDP / formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J. Aerosol Med. Pulm. Drug Deliv. 2010; 23: 137–148.De Backer W., Devolder A., Poli G. et al. Lung deposition of BDP / formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J. Aerosol Med. Pulm. Drug Deliv. 2010; 23: 137–148.Tzani P., Crisafulli E., Nicolini G. et al. Effects of beclomethasone / formoterol fixed combination on lung hyperinflation and dyspnea in COPD patients. Intern. J. COPD 2011; 6: 503–509.Tzani P., Crisafulli E., Nicolini G. et al. Effects of beclomethasone / formoterol fixed combination on lung hyperinflation and dyspnea in COPD patients. Intern. J. COPD 2011; 6: 503–509.Calverley P.M., Kuna P., Monsó E. et al. Beclomethasone / formoterol in the management of COPD: A randomized controlled trial. Respir. Med. 2010; 104: 1858–1868.Calverley P.M., Kuna P., Monsó E. et al. Beclomethasone / formoterol in the management of COPD: A randomized controlled trial. Respir. Med. 2010; 104: 1858–1868.

The authors declare that there are no conflicts of interest present.