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Semin Respir Crit Care Med 2002; 23(4): 347-360
DOI: 10.1055/s-2002-34330
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Role of the Distal Lung in Asthma

Meri K. Tulic, Qutayba Hamid
  • Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada
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Publication History

Publication Date:
26 September 2002 (online)

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ABSTRACT

Accumulating patholological and physiological evidence in the last few years suggests that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T-helper (Th)2 cytokines as well as chemokines, and more recently, they have been recognized as a predominant site of airflow obstruction in asthmatics. A similar TH2-type cytokine profile and infiltration of inflammatory cells has also been reported in the lung parenchyma. The inflammation at this distal site has been described as more severe when compared with the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need also to consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.

KEYWORDS

Distal airways - parenchyma - asthma - allergic inflammation

REFERENCES

  • 1 Dunnill M S. The pathology of asthma, with special reference to changes in the bronchial mucosa.  J Clin Pathol . 1960;  13 27-33
    PubMedGoogle Scholar
  • 2 Curschmann H. Ueber bronchiolitis exsudative und ihr Verhaltniss zum asthma nervosum.  Dtsch Arch Klin Med . 1882;  32 1-34
    PubMedGoogle Scholar
  • 3 Levine G, Housley E, MacLeod P, Macklem P T. Gas exchange abnormalities in mild bronchitis and asymptomatic asthma.  N Eng J Med . 1970;  282 1277-1282
    PubMedGoogle Scholar
  • 4 Despas P J, Leroux M, Macklem P T. Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing: air and helium oxygen mixture.  J Clin Invest . 1972;  51 3235-3243
    PubMedGoogle Scholar
  • 5 Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure.  J Appl Physiol . 1992;  72 1016-1023
    PubMedGoogle Scholar
  • 6 Ohrui T, Sekizawa K, Yanai M. Partitioning of pulmonary responses to inhaled methacholine in subjects with asymptomatic asthma.  Am Rev Respir Dis . 1992;  146 1501-1505
    PubMedGoogle Scholar
  • 7 Kuwano K, Bosken C H, Pare P D, Bai T R, Wiggs B R, Hogg J C. Small airways dimensions in asthma and in chronic obstructive pulmonary disease.  Am Rev Respir Dis . 1993;  148 1220-1225
    PubMedGoogle Scholar
  • 8 Wagner E M, Bleecker E R, Permutt S, Liu M C. Direct assessment of small airways reactivity in human subjects.  Am J Respir Crit Care Med . 1998;  157 447-452
    PubMedGoogle Scholar
  • 9 Djukanovic R, Wilson J W, Lai C K, Holgate S T, Howarth P H. The safety aspects of fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy in asthma.  Am Rev Respir Dis . 1991;  143 772-777
    PubMedGoogle Scholar
  • 10 Bentley A M, Meng Q, Robinson D S, Hamid Q, Kay A B, Durham S R. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics.  Am J Resp Cell Mol Biol . 1993;  8 35-42
    PubMedGoogle Scholar
  • 11 Hamid Q, Song Y, Kotsimbos T C. Inflammation of small airways in asthma.  J Allergy Clin Immunol . 1997;  100 44-51
    CrossrefPubMedGoogle Scholar
  • 12 Minshall E M, Hogg J C, Hamid Q A. Cytokine mRNA expression in asthma is not restricted to the large airways.  J Allergy Clin Immunol . 1998;  101 386-390
    CrossrefPubMedGoogle Scholar
  • 13 Taha R A, Minshall E M, Miotto D. Eotaxin and monocyte chemotactic protein-4 mRNA expression in small airways of asthmatic and nonasthmatic individuals.  J Allergy Clin Immunol . 1999;  103 476-483
    PubMedGoogle Scholar
  • 14 Carroll N, Cooke C, James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics.  Eur Respir J . 1997;  10 292-300
    CrossrefPubMedGoogle Scholar
  • 15 Faul J L, Tormey V J, Leonard C. Lung immunopathology in cases of sudden asthma death.  Eur Respir J . 1997;  10 301-307
    CrossrefPubMedGoogle Scholar
  • 16 Christodoulopoulos P, Leung D Y, Elliott M W. Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.  J Allergy Clin Immunol . 2000;  106 479-484
    CrossrefPubMedGoogle Scholar
  • 17 Kraft M, Djukanovic R, Wilson S, Holgate S T, Martin R J. Alveolar tissue inflammation in asthma.  Am J Resp Crit Care Med . 1996;  154 1505-1510
    PubMedGoogle Scholar
  • 18 Kraft M, Martin R J, Wilson S, Djukanovic R, Holgate S T. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma.  Am J Respir Crit Care Med . 1999;  159 228-234
    PubMedGoogle Scholar
  • 19 Carroll N, Carello S, Cooke C, James A. Airway structure and inflammatory cells in fatal attacks of asthma.  Eur Respir J . 1996;  9 709-715
    CrossrefPubMedGoogle Scholar
  • 20 Synek M, Anto J M, Beasley R. Immunopathology of fatal soybean dust-induced asthma.  Eur Respir J . 1996;  9 54-57
    CrossrefPubMedGoogle Scholar
  • 21 Weibel E R. Morphometry of the human lung.  New York: Academic Press 1963
    Google Scholar
  • 22 Woolcock A J. Effects of drugs on small airways.  Am J Respir Crit Care Med . 1998;  157 S203-S207
    PubMedGoogle Scholar
  • 23 James A L, Pare P D, Hogg J C. The mechanics of airway narrowing in asthma.  Am Rev Respir Dis . 1989;  139 242-246
    PubMedGoogle Scholar
  • 24 Huber H L, Koessler K K. The pathology of bronchial asthma.  Arch Intern Med . 1922;  30 689-760
    PubMedGoogle Scholar
  • 25 Haley K J, Sunday M E, Wiggs B R. Inflammatory cell distribution within and along asthmatic airways.  Am J Respir Crit Care Med . 1998;  158 565-572
    PubMedGoogle Scholar
  • 26 Hamid Q A. Peripheral inflammation is more important than central inflammation.  Respir Med . 1997;  91 11-12
    PubMedGoogle Scholar
  • 27 Saetta M, Di Stefano A, Rosina C, Thiene G, Fabbri L M. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma.  Am Rev Respir Dis . 1991;  143 138-143
    PubMedGoogle Scholar
  • 28 Kraft M. The distal airways: are they important in asthma?.  Eur Respir J . 1999;  14 1403-1417
    CrossrefPubMedGoogle Scholar
  • 29 Kraft M, Vianna E, Martin R J, Leung D YM. Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night.  J Allergy Clin Immunol . 1999;  103 66-71
    PubMedGoogle Scholar
  • 30 Wenzel S E, Szefler S J, Leung D Y, Sloan S I, Rex M D, Martin R J. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids.  Am J Respir Crit Care Med . 1997;  156 737-743
    PubMedGoogle Scholar
  • 31 Macklem P T, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.  J Appl Physiol . 1967;  22 395-401
    PubMedGoogle Scholar
  • 32 Brown R, Woolcock A J, Vincent N J, Macklem P T. Physiological effects of experimental airway obstruction with beads.  J Appl Physiol . 1969;  27 328-335
    PubMedGoogle Scholar
  • 33 Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity.  J Appl Physiol . 1970;  28 596-608
    PubMedGoogle Scholar
  • 34 Sly P D, Willet K E, Kano S, Lanteri C J, Wale J. Pirenzepine blunts the pulmonary parenchymal response to inhaled methacholine.  Pulm Pharmacol . 1995;  8 123-129
    PubMedGoogle Scholar
  • 35 Petak F, Hantos Z, Adamicza Á, Asztalos T, Sly P D. Methacholine-induced bronchoconstriction in rats: effects of intravenous vs.  aerosol delivery. J Appl Physiol . 1997;  82 1479-1487
    PubMedGoogle Scholar
  • 36 Ludwig M S, Romero P V, Bates J H. A comparison of the dose-response behavior of canine airways and parenchyma.  J Appl Physiol . 1989;  67 1220-1225
    PubMedGoogle Scholar
  • 37 Suki B, Petak F, Adamicza Á, Hantos Z, Lutchen K R. Partitioning of airway and lung tissue properties: comparison of in situ and open-chest conditions.  J Appl Physiol . 1995;  79 861-869
    PubMedGoogle Scholar
  • 38 Sato J, Suki B, Davey B LK, Bates J HT. Effect of methacholine on low-frequency mechanics of canine airways and lung tissue.  J Appl Physiol . 1993;  75 55-62
    PubMedGoogle Scholar
  • 39 Romero P V, Robatto F M, Simard S, Ludwig M S. Lung tissue behavior during methacholine challenge in rabbits in vivo.  J Appl Physiol . 1992;  73 207-212
    PubMedGoogle Scholar
  • 40 Tepper R, Sato J, Suki B, Martin J G, Bates J HT. Low-frequency pulmonary impedance in rabbits and its response to inhaled methacholine.  J Appl Physiol . 1992;  73 290-295
    PubMedGoogle Scholar
  • 41 Ingenito E P, Davision B, Fredberg J J. Tissue resistance in the guinea pig at baseline and during methacholine constriction.  J Appl Physiol . 1993;  75 2541-2548
    PubMedGoogle Scholar
  • 42 Salerno F G, Moretto A, Dallaire M, Ludwig M S. How mode of stimulus affects the relative contribution of elastance and hysteresivity to changes in lung tissue resistance.  J Appl Physiol . 1995;  78 282-287
    PubMedGoogle Scholar
  • 43 Tulic M K, Wale J L, Petak F, Sly P D. Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats.  Thorax . 1999;  54 531-537
    PubMedGoogle Scholar
  • 44 Minshall E, Leung D, Song Y L, Cameron L, Hamid Q A. Eosinophil-associated TGF-mRNA expression and airway fibrosis in bronchial asthma.  Am J Respir Cell Mol Biol . 1997;  17 326-333
    PubMedGoogle Scholar
  • 45 Huang J, Olivenstien R, Taha R, Hamid Q, Ludwig M. Enhanced proteoglycan deposition in the airway wall of atopic asthmatics.  Am J Respir Crit Care Med . 1999;  160 725-729
    PubMedGoogle Scholar
  • 46 Boulet L P, Laviolette M, Turcotte H. Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine.  Chest . 1997;  112 45-52
    PubMedGoogle Scholar
  • 47 Wiggs B R, Bosken C, Pare P D, James A L, Hogg J C. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease.  Am Rev Respir Dis . 1992;  145 1251-1258
    PubMedGoogle Scholar
  • 48 Van Brabandt H, Cauberghs M, Verbeken E, Moerman P, Lauweryns J M, Van de Woestijne P K. Partitioning of pulmonary impedance in excised human and canine lungs.  J Appl Physiol . 1983;  55 1733-1742
    PubMedGoogle Scholar
  • 49 Ingram R HJ. Physiological assessment of inflammation in the peripheral lung of asthmatic patients.  Lung . 1990;  168 237-247
    PubMedGoogle Scholar
  • 50 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
    CrossrefPubMedGoogle Scholar
  • 51 Wagner E M, Liu M C, Weinmann G G, Permutt S, Bleecker E R. Peripheral lung resistance in normal and asthmatic subjects.  Am Rev Respir Dis . 1990;  141 584-588
    PubMedGoogle Scholar
  • 52 Petak F, Hall G L, Sly P D. Repeated measurements of airway and parenchymal mechanics in rats by using low-frequency oscillations.  J Appl Physiol . 1998;  84 1680-1686
    PubMedGoogle Scholar
  • 53 Sly P D, Hayden M J, Petak F, Hantos Z. Measurements of low-frequency respiratory impedance in infants.  Am J Respir Crit Care Med . 1996;  154 161-166
    PubMedGoogle Scholar
  • 54 Hall G L, Hantos Z, Wildhaber J H, Petak F, Sly P D. Methacholine responsiveness in infants assessed with low frequency forced oscillation and forced expiration techniques.  Thorax . 2001;  56 42-47
    CrossrefPubMedGoogle Scholar
  • 55 Hall G L, Hantos Z, Petak F. Airway and respiratory tissue mechanics in normal infants.  Am J Respir Crit Care Med . 2000;  162 1397-1402
    PubMedGoogle Scholar
  • 56 Djukanovic R, Wilson J W, Britten K M. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.  Am Rev Respir Dis . 1992;  145 669-674
    PubMedGoogle Scholar
  • 57 Booth H, Richmond I, Ward C, Gardiner P V, Harkawat R, Walters E H. Effect of high dose inhaled fluticasone propionate on airway inflammation in asthma.  Am J Respir Crit Care Med . 1995;  152 45-52
    CrossrefPubMedGoogle Scholar
  • 58 Jeffery P K, Godfrey R W, Adelroth E, Nelson F, Rogers A, Johansson S A. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma: a quantitative light and electron microscopic study.  Am Rev Respir Dis . 1992;  145 890-899
    PubMedGoogle Scholar
  • 59 Esmailpour N, Hogger P, Rabe K F, Heitmann U, Nakashima M, Rohdewald P. Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo.  Eur Respir J . 1997;  10 1496-1499
    CrossrefPubMedGoogle Scholar
  • 60 Dolovich M B, Rhem R, Gerrard L, Coates G. Lung deposition of coarse CFC vs fine HFA pMDI earosols of beclomethasone dipropionate (BDP) in asthma.  Am J Respir Crit Care Med . 2000;  161 A33
    PubMedGoogle Scholar
  • 61 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
    CrossrefPubMedGoogle Scholar
  • 62 Busse W W, Brazinsky S, Jacobson K. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant.  J Allergy Clin Immunol . 1999;  104 1215-1222
    CrossrefPubMedGoogle Scholar
  • 63 Vanden Burgt A J, Busse W W, Martin R J, Szefler S J, Donnell D. Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma [review].  J Allergy Clin Immunol . 2000;  106 1209-1226
    CrossrefPubMedGoogle Scholar
  • 64 Goldin J G, Tashkin D P, Kleerup E C. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography.  J Allergy Clin Immunol . 1999;  104 S258-S267
    PubMedGoogle Scholar
  • 65 Lipworth B J. The comparative safety/efficacy ratio of HFA-BDP [review].  Resp Med . 2000;  S21-S26
    PubMedGoogle Scholar
  • 66 Cohen R, Fireman P, Windom H. Long-term safety of beclomethasone dipropionate extrafine aerosol (HFA-BDP) [abstract].  Am J Respir Crit Care Med . 1999;  159 A631
    PubMedGoogle Scholar
  • 67 Thompson P J, Davies R J, Young W F, Grossman A B, Donnell D. Safety of hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol.  Resp Med . 1998;  33-39
    PubMedGoogle Scholar
  • 68 Muller N L, Miller R R. Diseases of the bronchioles: CT and pathological findings.  Radiology . 1995;  196 3-12
    PubMedGoogle Scholar
  • 69 Fend F, Kremer M, Quintanilla-Martinez L. Laser capture microdissection: methodical aspects and applications with emphasis on immuno-laser capture microdissection [review].  Pathobiology . 2000;  68 209-214
    PubMedGoogle Scholar