Airway Hyperresponsiveness: Inflammatory Mechanisms and Clinical Aspects

  • Salman Siddiqui
  • Fay Hollins
  • Christopher Brightling
Part of the Allergy Frontiers book series (ALLERGY, volume 3)


Airway hyperresponsiveness is the exaggerated response of the airway to direct and indirect stimuli and is a cardinal feature of asthma. The cause of airway hyperresponsiveness is uncertain and its relationship to airway inflammation is complex as eosinophilic inflammation can occur without airway hyperresponsivenes which in turn can be present in the absence of eosinophilic airway inflammation. Emerging evidence suggests that airway hyperresponsiveness is likely to be a consequence of intrinsic abnormalities in airway smooth muscle function together with changes in the airway wall geometry and interactions between the airway smooth muscle and mast cells localised within the airway smooth muscle bundle. Airway hyperresponsiveness improves with current treatment but often remains abnormal. The abolition of airway hyperresponsivenss therefore remains a goal for asthma therapy.


Mast Cell Airway Smooth Muscle Airway Hyperresponsiveness Airway Wall Methacholine Challenge 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Global Initiative for Asthma Guidelines (2007) Available from:
  2. 2.
    O'Byrne PM, Ryan G, Morris M, McCormack D, Jones NL, Morse JL, et al. (1982) Asthma induced by cold air and its relation to nonspecific bronchial responsiveness to methacholine. Am. Rev. Respir. Dis. 125:281–285.PubMedGoogle Scholar
  3. 3.
    Holgate ST, Mann JS, Cushley MJ (1984) Adenosine as a bronchoconstrictor mediator in asthma and its antagonism by methylxanthines. J. Allergy Clin. Immunol. 74:302–306.PubMedGoogle Scholar
  4. 4.
    Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, et al. (1997) A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am. J. Respir. Crit. Care Med. 156:758–765.PubMedGoogle Scholar
  5. 5.
    McFadden ER, Jr, Gilbert IA (1994) Exercise-induced asthma. N. Engl. J. Med. 330:1362–1367.PubMedGoogle Scholar
  6. 6.
    Curry JJ (1946) The action of histamine on the respiratory tract in normal and asthmatic subjects. J. Clin. Invest. 25:785–791.PubMedGoogle Scholar
  7. 7.
    Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE (1978) Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 33:705–710.PubMedGoogle Scholar
  8. 8.
    Allen ND, Davis BE, Hurst TS, Cockcroft DW (2005) Difference between dosimeter and tidal breathing methacholine challenge: contributions of dose and deep inspiration bronchoprotection. Chest 128:4018–4023.PubMedGoogle Scholar
  9. 9.
    Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ (2005) Methacholine challenge: comparison of two methods. Chest 127:839–844.PubMedGoogle Scholar
  10. 10.
    Cockcroft DW, Davis BE (2006) The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result. J. Allergy Clin. Immunol. 117:1244–1248.PubMedGoogle Scholar
  11. 11.
    Parker CD, Bilbo RE, Reed CE (1965) Methacholine aerosol as a test for bronchial asthma. Arch. Intern. Med. 115:452–458.PubMedGoogle Scholar
  12. 12.
    Kremer AM, Pal TM, Oldenziel M, Kerkhof M, de Monchy JG, Rijcken B (1995) Use and safety of a shortened histamine challenge test in an occupational study. Eur. Respir. J. 8:737–741.PubMedGoogle Scholar
  13. 13.
    Standardization of spirometry (2007) Am. J. Respir. Crit. Care Med. 152:1107–1136.Google Scholar
  14. 14.
    Cockcroft DW, Berscheid BA (1983) Measurement of responsiveness to inhaled histamine: comparison of FEV1 and Sgaw. Ann. Allergy 51:374–377.PubMedGoogle Scholar
  15. 15.
    van Broekhoven P, Hop WC, Rasser E, de Jongste JC, Kerrebijn KF (1991) Comparison of FEV1 and transcutaneous oxygen tension in the measurement of airway responsiveness to methacholine. Pediatr. Pulmonol. 11:254–258.PubMedGoogle Scholar
  16. 16.
    Wilson NM, Bridge P, Phagoo SB, Silverman M (1995) The measurement of methacholine responsiveness in 5 year old children: three methods compared. Eur. Respir. J. 8:364–370.PubMedGoogle Scholar
  17. 17.
    Christopher KL, Wood RP, Eckert RC, Blager FB, Raney RA, Souhrada JF (1983) Vocal-cord dysfunction presenting as asthma. N. Engl. J. Med. 308:1566–7150.PubMedGoogle Scholar
  18. 18.
    Eiser NM, Kerrebjjn KF, Quanjer PJ (1983) Guidelines for standardization of bronchial challenges with (nonspecific) bronchoconstrictor agents. Bull. Eur. Physiopathol. Respir. 19:495–514.Google Scholar
  19. 19.
    Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW, O'Byrne PM, Anderson SD, et al. (1993) Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur. Respir. J. (Suppl 16):53–83.Google Scholar
  20. 20.
    Verlato G, Cerveri I, Villani A, Pasquetto M, Ferrari M, Fanfulla F, et al. (1996) Evaluation of methacholine dose-response curves by linear and exponential mathematical models: goodness-of-fit and validity of extrapolation. Eur. Respir. J. 9:506–511.PubMedGoogle Scholar
  21. 21.
    Cockcroft DW, Murdock KY, Mink JT (1983) Determination of histamine PC20. Comparison of linear and logarithmic interpolation. Chest 84:505–506.Google Scholar
  22. 22.
    Cockcroft DW, Murdock KY, Berscheid BA, Gore BP (1992) Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J. Allergy Clin. Immunol. 89:23–30.PubMedGoogle Scholar
  23. 23.
    Gilbert R, Auchincloss JH, Jr (1990) Post-test probability of asthma following methacholine challenge. Chest 97:562–565.PubMedGoogle Scholar
  24. 24.
    Juniper EF, Cockcroft DW, Hargreave FE (1994) Histamine and methacholine inhalaltion tests: tidal breathing method-laboratory procedure and standardisation. Lund, Astra Draco.Google Scholar
  25. 25.
    Boulet LP, Cartier A, Thomson NC, Roberts RS, Dolovich J, Hargreave FE (1983) Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J. Allergy Clin. Immunol. 71:399–406.PubMedGoogle Scholar
  26. 26.
    Hargreave FE, Ramsdale EH, Pugsley SO (1984) Occupational asthma without bronchial hyperresponsiveness. Am. Rev. Respir. Dis. 130:513–515.PubMedGoogle Scholar
  27. 27.
    Ramsdell JW, Nachtwey FJ, Moser KM (1982) Bronchial hyperreactivity in chronic obstructive bronchitis. Am. Rev. Respir. Dis. 126:829–832.PubMedGoogle Scholar
  28. 28.
    Ramsdale EH, Roberts RS, Morris MM, Hargreave FE (1985) Differences in responsiveness to hyperventilation and methacholine in asthma and chronic bronchitis. Thorax 40:422–426.PubMedGoogle Scholar
  29. 29.
    Ramsdale EH, Morris MM, Roberts RS, Hargreave FE (1984) Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 39:912–918.PubMedGoogle Scholar
  30. 30.
    Verma VK, Cockcroft DW, Dosman JA (1988) Airway responsiveness to inhaled histamine in chronic obstructive airways disease: chronic bronchitis vs emphysema. Chest 94:457–461.PubMedGoogle Scholar
  31. 31.
    Ryan G, Dolovich MB, Roberts RS, Frith PA, Juniper EF, Hargreave FE, et al. (1981) Standardization of inhalation provocation tests: two techniques of aerosol generation and inhalation compared. Am. Rev. Respir. Dis. 123:195–199.PubMedGoogle Scholar
  32. 32.
    Yan K, Salome C, Woolcock AJ (1983) Rapid method for measurement of bronchial responsiveness. Thorax 38:760–765.PubMedGoogle Scholar
  33. 33.
    Knox AJ, Wisniewski A, Cooper S, Tattersfield AE (1991) A comparison of the Yan and a dosimeter method for methacholine challenge in experienced and inexperienced subjects. Eur. Respir. J. 4:497–502.PubMedGoogle Scholar
  34. 34.
    Peat JK, Salome CM, Bauman A, Toelle BG, Wachinger SL, Woolcock AJ (1991) Repeatability of histamine bronchial challenge and comparability with methacholine bronchial challenge in a population of Australian school children. Am. Rev. Respir. Dis. 144:338–343.PubMedGoogle Scholar
  35. 35.
    Dehaut P, Rachiele A, Martin RR, Malo JL (1983) Histamine dose-response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 38:516–522.PubMedGoogle Scholar
  36. 36.
    Chinn S, Britton JR, Burney PG, Tattersfield AE, Papacosta AO (1987) Estimation and repeatability of the response to inhaled histamine in a community survey. Thorax 42:45–52.PubMedGoogle Scholar
  37. 37.
    Weiss ME, Wheeler B, Eggleston P, Adkinson NF, Jr (1989) A protocol for performing reproducible methacholine inhalation tests in children with moderate to severe asthma. Am. Rev. Respir. Dis. 139:67–72.PubMedGoogle Scholar
  38. 38.
    Boulet LP, Morin D, Turcotte H (1990) Variations of airway responsiveness to methacholine and exercise in asthmatic and normal subjects over a 12-month period. Clin. Invest. Med. 13:60–66.PubMedGoogle Scholar
  39. 39.
    Balzano G, Delli CI, Gallo C, Cocco G, Melillo G (1989) Intrasubject between-day variability of PD20 methacholine assessed by the dosimeter inhalation test. Chest 95:1239–1243.PubMedGoogle Scholar
  40. 40.
    Josephs LK, Gregg I, Mullee MA, Campbell MJ, Holgate ST (1992) A longitudinal study of baseline FEV1 and bronchial responsiveness in patients with asthma. Eur. Respir. J. 5:32–39.PubMedGoogle Scholar
  41. 41.
    Cockcroft DW, Davis BE (2005) Lack of tachyphylaxis to methacholine at 24 h. Chest 128:1248–1251.PubMedGoogle Scholar
  42. 42.
    Van Schoor J, Joos GF, Pauwels RA (2000) Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur. Respir. J. 16:514–533.PubMedGoogle Scholar
  43. 43.
    Guidelines for Methacholine and Exercise Challenge Testing (1999) Am. J. Respir. Crit. Care Med. 161:309–329.Google Scholar
  44. 44.
    Cushley MJ, Tattersfield AE, Holgate ST (2004) Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects (Reprinted from Br. J. Clin. Pharmacol. 15:161–165, 1983). Br. J. Clin. Pharmacol. 58:S751–S755.PubMedGoogle Scholar
  45. 45.
    Phillips GD, Ng WH, Church MK, Holgate ST (1989) The response of plasma histamine to bronchoprovocation with methacholine, adenosine 5′-monophosphate, and allergen in atopic nonasthmatic subjects. Am. Rev. Respir. Dis. 141:9–13.Google Scholar
  46. 46.
    Polosa R, Ng WH, Crimi N, Vancheri C, Holgate ST, Church MK, et al. (1995) Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am. J. Respir. Crit. Care Med. 151:624–629.PubMedGoogle Scholar
  47. 47.
    Phillips GD, Holgate ST (1989) The effect of oral terfenadine alone and in combination with flurbiprofen on the bronchoconstrictor response to inhaled adenosine 5-monophosphate in nonatopic asthma. Am. Rev. Respir. Dis. 139:463–469.PubMedGoogle Scholar
  48. 48.
    Meijer RJ, Kerstjens HA, Arends LR, Kauffman HF, Koeter GH, Postma DS (1999) Effects of inhaled fluticasone and oral prednisolone on clinical and inflammatory parameters in patients with asthma. Thorax 54:894–899.PubMedGoogle Scholar
  49. 49.
    van den BM, Meijer RJ, Kerstjens HA, de Reus DM, Koeter GH, Kauffman HF, et al. (2001) PC(20) adenosine 5′-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine. Am. J. Respir. Crit. Care Med. 163:1546–1550.Google Scholar
  50. 50.
    Prieto L, Uixera S, Gutierrez V, Bruno L (2002) Modifications of airway responsiveness to adenosine 5′-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjects with pollen-induced rhinitis. Chest 122:940–947.PubMedGoogle Scholar
  51. 51.
    Rodwell LT, Anderson SD, Seale JP (1992) Inhaled steroids modify bronchial responses to hyperosmolar saline. Eur. Respir. J. 5:953–962.PubMedGoogle Scholar
  52. 52.
    Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, et al. (2001) Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am. J. Respir. Crit. Care Med. 163:406–412.PubMedGoogle Scholar
  53. 53.
    In't Veen JC, Smits HH, Hiemstra PS, Zwinderman AE, Sterk PJ, Bel EH (1999) Lung function and sputum characteristics of patients with severe asthma during an induced exacerbation by double-blind steroid withdrawal. Am. J. Respir. Crit. Care Med. 160:93–99.Google Scholar
  54. 54.
    Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B (2005) The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyper-responsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir. Res. 6:144.PubMedGoogle Scholar
  55. 55.
    Seow CY, Schellenberg RR, Pare PD (1998) Structural and functional changes in the airway smooth muscle of asthmatic subjects. Am. J. Respir. Crit. Care Med. 158(5 Pt 3): S179–S186PubMedGoogle Scholar
  56. 56.
    Whicker SD, Armour CL, Black JL (1988) Responsiveness of bronchial smooth muscle from asthmatic patients to relaxant and contractile agonists. Pulm. Pharmacol. 1:25–31.PubMedGoogle Scholar
  57. 57.
    Bai TR (1991) Abnormalities in airway smooth muscle in fatal asthma: a comparison between trachea and bronchus. Am. Rev. Respir. Dis. 143:441–443.PubMedGoogle Scholar
  58. 58.
    Bai TR (1990) Abnormalities in airway smooth muscle in fatal asthma. Am. Rev. Respir. Dis. 141:552–557.PubMedGoogle Scholar
  59. 59.
    Goldie RG, Spina D, Henry PJ, Lulich KM, Paterson JW (1986) In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline. Br. J. Clin. Pharmacol. 22:669–676.PubMedGoogle Scholar
  60. 60.
    Ma X, Cheng Z, Kong H, Wang Y, Unruh H, Stephens NL, et al. (2002) Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects. Am. J. Physiol. Lung Cell Mol. Physiol. 283:L1181–L1189.PubMedGoogle Scholar
  61. 61.
    Jackson AC, Murphy MM, Rassulo J, Celli BR, Ingram RH, Jr (2004) Deep breath reversal and exponential return of methacholine-induced obstruction in asthmatic and nonasthmatic subjects. J. Appl. Physiol. 96:137–142.PubMedGoogle Scholar
  62. 62.
    Skloot G, Permutt S, Togias A (1995) Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J. Clin. Invest. 96:2393–2403.PubMedGoogle Scholar
  63. 63.
    O'Byrne PM, Inman MD (2003) Airway hyperresponsiveness. Chest 123:411S–416S.PubMedGoogle Scholar
  64. 64.
    Gil FR, Lauzon AM (2007) Smooth muscle molecular mechanics in airway hyperresponsiveness and asthma. Can. J. Physiol. Pharmacol. 85:133–140.PubMedGoogle Scholar
  65. 65.
    Stephens NL, Li W, Jiang H, Unruh H, Ma X (2003) The biophysics of asthmatic airway smooth muscle. Respir. Physiol. Neurobiol. 137:125–140.PubMedGoogle Scholar
  66. 66.
    Seow CY (2005) Myosin filament assembly in an ever-changing myofilament lattice of smooth muscle. Am. J. Physiol. Cell Physiol. 289:C1363–C1368.PubMedGoogle Scholar
  67. 67.
    Gunst SJ, Wu MF (2001) Selected contribution: plasticity of airway smooth muscle stiffness and extensibility: role of length-adaptive mechanisms. J. Appl. Physiol. 90:741–749.PubMedGoogle Scholar
  68. 68.
    Gunst SJ, Meiss RA, Wu MF, Rowe M (1995) Mechanisms for the mechanical plasticity of tracheal smooth muscle. Am. J. Physiol. 268:C1267–C1276.PubMedGoogle Scholar
  69. 69.
    Gunst SJ, Wu MF, Smith DD (1993) Contraction history modulates isotonic shortening velocity in smooth muscle. Am. J. Physiol. 265:C467–C476.PubMedGoogle Scholar
  70. 70.
    Bursac P, Lenormand G, Fabry B, Oliver M, Weitz DA, Viasnoff V, et al. (2005) Cytoskeletal remodelling and slow dynamics in the living. Cell Nat. Mater. 4:557–561.Google Scholar
  71. 71.
    Wang L, Pare PD, Seow CY (2001) Selected contribution: effect of chronic passive length change on airway smooth muscle length-tension relationship. J. Appl. Physiol. 90:734–740.PubMedGoogle Scholar
  72. 72.
    Silberstein J, Hai CM (2002) Dynamics of length-force relations in airway smooth muscle. Respir. Physiol. Neurobiol. 132:205–221.PubMedGoogle Scholar
  73. 73.
    Bai TR, Bates JH, Brusasco V, Camoretti-Mercado B, Chitano P, Deng LH, et al. (2004) On the terminology for describing the length-force relationship and its changes in airway smooth muscle. J. Appl. Physiol. 97:2029–2034.PubMedGoogle Scholar
  74. 74.
    Naghshin J, Wang L, Pare PD, Seow CY (2003) Adaptation to chronic length change in explanted airway smooth muscle. J. Appl. Physiol. 95:448–453.PubMedGoogle Scholar
  75. 75.
    An SS, Fabry B, Trepat X, Wang N, Fredberg JJ (2006) Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness? Am. J. Respir. Cell Mol. Biol. 35:55–64.Google Scholar
  76. 76.
    An SS, Bai TR, Bates JH, Black JL, Brown RH, Brusasco V, et al. (2007) Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur. Respir. J. 29:834–860.PubMedGoogle Scholar
  77. 77.
    Hollins F, Saunders D, Kaur D, Sutcliffe A, Challiss RAJ, Bradding P, Brightling CE (2007) Human airway smooth muscle activation. Clin. Exp. Allergy 37:1881(abstract).Google Scholar
  78. 78.
    Mahn K, Hirst SJ, McVicker CG, Snelkov VA, Kanabar V, Simcock DE, O'Connor BJ, Lee TH (2006) Calcium signaling in asthmatic airway smooth muscle is abnormal. Proc. Am. Thorac. Soc. A772.Google Scholar
  79. 79.
    Tao FC, Tolloczko B, Eidelman DH, Martin JG (1999) Enhanced Ca(2+) mobilization in airway smooth muscle contributes to airway hyperresponsiveness in an inbred strain of rat. Am. J. Respir. Crit. Care Med. 160:446–453.PubMedGoogle Scholar
  80. 80.
    Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M (2003) Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med. 167:1360–1368.PubMedGoogle Scholar
  81. 81.
    Oliver BG, Black JL (2006) Airway smooth muscle and asthma. Allergol. Int. 55:215–223.PubMedGoogle Scholar
  82. 82.
    Roth M, Johnson PR, Borger P, Bihl MP, Rudiger JJ, King GG, et al. (2004) Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N. Engl. J. Med. 351:560–574.PubMedGoogle Scholar
  83. 83.
    Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST (2003) Airway remodeling in asthma: new insights. J. Allergy Clin. Immunol. 111:215–225.PubMedGoogle Scholar
  84. 84.
    Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Panizzolo C, et al. (2006) Epithelial damage and angiogenesis in the airways of children with asthma. Am. J. Respir. Crit. Care Med. 174:975–981.PubMedGoogle Scholar
  85. 85.
    Siddiqui S, Sutcliffe A, Shikotra A, Woodman L, Doe C, McKenna S, Wardlaw AJ, Bradding P, Pavord I, and Brightling CE (2007) Vascular remodelling is a feature of asthma and non-asthmatic eosinophilic bronchitis. J. Allergy Clin. Immunol. 120(4): 813–819.PubMedGoogle Scholar
  86. 86.
    Carroll N, Elliot J, Morton A, James A (1993) The structure of large and small airways in nonfatal and fatal asthma. Am. Rev. Respir. Dis. 147:405–410.PubMedGoogle Scholar
  87. 87.
    Ebina M, Takahashi T, Chiba T, Motomiya M (1993) Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am. Rev. Respir. Dis. 148:720–726.Google Scholar
  88. 88.
    Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC (1993) Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 148:1220–1225.PubMedGoogle Scholar
  89. 89.
    Woodruff PG, Dolganov GM, Ferrando RE, Donnelly S, Hays SR, Solberg OD, et al. (2004) Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am. J. Respir. Crit. Care Med. 169:1001–1006.PubMedGoogle Scholar
  90. 90.
    Lambert RK, Wiggs BR, Kuwano K, Hogg JC, Pare PD (1993) Functional significance of increased airway smooth muscle in asthma and COPD. J. Appl. Physiol. 74:2771–2781.PubMedGoogle Scholar
  91. 91.
    McParland BE, Macklem PT, Pare PD (2003) Airway wall remodeling: friend or foe? J. Appl. Physiol. 95:426–434.Google Scholar
  92. 92.
    Moreno RH, Hogg JC, Pare PD (1986) Mechanics of airway narrowing. Am. Rev. Respir. Dis. 133:1171–1180.PubMedGoogle Scholar
  93. 93.
    Wiggs BR, Bosken C, Pare PD, James A, Hogg JC (1992) A model of airway narrowing in asthma and in chronic obstructive pulmonary-disease. Am. Rev. Respir. Dis. 145:1251–1258.PubMedGoogle Scholar
  94. 94.
    Wiggs BR, Hrousis CA, Drazen JM, Kamm RD (1997) On the mechanism of mucosal folding in normal and asthmatic airways. J. Appl. Physiol. 83:1814–1821.PubMedGoogle Scholar
  95. 95.
    James AL, Pare PD, Hogg JC (1989) The mechanics of airway narrowing in asthma. Am. Rev. Respir. Dis. 139:242–246.PubMedGoogle Scholar
  96. 96.
    Macklem PT (1995) Theoretical basis of airway instability: Roger S. Mitchell lecture. Chest 107:87S–88S.Google Scholar
  97. 97.
    Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M (2003) Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am. J. Respir. Crit. Care Med. 168:983–988.PubMedGoogle Scholar
  98. 98.
    Beigelman-Aubry C, Capderou A, Grenier PA, Straus C, Becquemin MH, Similowski T, et al. (2002) Mild intermittent asthma: CT assessment of bronchial cross-sectional area and lung attenuation at controlled lung volume. Radiology 223:181–187.PubMedGoogle Scholar
  99. 99.
    Goldin JG, McNitt-Gray MF, Sorenson SM, Johnson TD, Dauphinee B, Kleerup EC, et al. (1998) Airway hyperreactivity: assessment with helical thin-section CT. Radiology 208:321–329.PubMedGoogle Scholar
  100. 100.
    Siddiqui S, Cruse G, Haldar P, McKenna S, Monteiro W, Bradding P, Wardlaw AJ, Pavord ID, Entwisle J, Brightling CE. Differences in airway wall geometry of the apical bronchus in asthma and non asthmatic eosinophilic bronchitis. Proc. Am. Thorac. Soc. A332.Google Scholar
  101. 101.
    Altounyan RE (1964) Variation of drug action on airway obstruction in man. Thorax 19:406–415.PubMedGoogle Scholar
  102. 102.
    Cartier A, Thomson NC, Frith PA, Roberts R, Hargreave FE (1982) Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway calibre. J. Allergy Clin. Immunol. 170:170–177.Google Scholar
  103. 103.
    De Monchy JG, Kauffman HF, Venge P, Koeter GH, Jansen HM, Sluiter HJ, et al. (1985) Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am. Rev. Respir. Dis. 131:373–376.PubMedGoogle Scholar
  104. 104.
    Metzger WJ, Richerson HB, Worden K, Monick M, Hunninghake GW (1986) Bronchoalveolar lavage of allergic asthmatic patients following allergen bronchoprovocation. Chest 89:477–483.PubMedGoogle Scholar
  105. 105.
    Fabbri LM, Boschetto P, Zocca E, Milani G, Pivirotto F, Plebani M, et al. (1987) Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate. Am. Rev. Respir. Dis. 136:36–42.PubMedGoogle Scholar
  106. 106.
    Flint KC, Leung KB, Hudspith BN, Brostoff J, Pearce FL, Johnson NM (1985) Bronchoalveolar mast cells in extrinsic asthma: a mechanism for the initiation of antigen specific Bronchoconstriction. Br. Med. J. 291:923–926.Google Scholar
  107. 107.
    Pin I, Freitag AP, O'Byrne PM, Girgis-Gabardo A, Watson RM, Dolovich J, et al. (1992) Changes in the cellular profile of induced sputum after allergen-induced asthmatic responses. Am. Rev. Respir. Dis. 145:1265–1269.PubMedGoogle Scholar
  108. 108.
    Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB (1988) Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am. Rev. Respir. Dis. 137:62–69.PubMedGoogle Scholar
  109. 109.
    Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ (1998) Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 53:91–95.PubMedGoogle Scholar
  110. 110.
    Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID (2002) Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57:875–879.PubMedGoogle Scholar
  111. 111.
    Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB (1988) Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am. Rev. Respir. Dis. 137:62–69.PubMedGoogle Scholar
  112. 112.
    Polosa R, Renaud L, Cacciola R, Prosperini G, Crimi N, Djukanovic R (1998) Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma. Eur. Respir. J. 12:551–556.PubMedGoogle Scholar
  113. 113.
    Rosi E, Ronchi MC, Grazzini M, Duranti R, Scano G (1999) Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis. J. Allergy Clin. Immunol. 103:232–237.PubMedGoogle Scholar
  114. 114.
    van Velzen E, van den Bos JW, Benckhuijsen JA, van Essel T, de Bruijn R, Aalbers R (1996) Effect of allergen avoidance at high altitude on direct and indirect bronchial hyper-responsiveness and markers of inflammation in children with allergic asthma. Thorax 51:582–584.PubMedGoogle Scholar
  115. 115.
    Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE (1989) Chronic cough: eosinophilic bronchitis without asthma. Lancet 1:1346–1348.PubMedGoogle Scholar
  116. 116.
    Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID (1999) Eosinophilic bronchitis is an important cause of chronic cough. Am. J. Respir. Crit. Care Med. 160:406–410.PubMedGoogle Scholar
  117. 117.
    Berry MA, Hargadon B, McKenna S, Shaw D, Green RH, Brightling CE, et al. (2005) Observational study of the natural history of eosinophilic bronchitis. Clin. Exp. Allergy 35:598–601.PubMedGoogle Scholar
  118. 118.
    Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID (1999) Development of irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma. Eur. Respir. J. 314:1228–1230.Google Scholar
  119. 119.
    Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID (2002) Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346:1699–7105.PubMedGoogle Scholar
  120. 120.
    Brightling CE, Symon FA, Birring SS, Bradding P, Wardlaw AJ, Pavord ID (2003) Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 58:528–532.PubMedGoogle Scholar
  121. 121.
    Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ (2002) T(H)2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J. Allergy Clin. Immunol. 110:899–905.PubMedGoogle Scholar
  122. 122.
    Berry MA, Parker D, Neale N, Woodman L, Morgan A, Monk P, et al. (2004) Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis. J. Allergy Clin. Immunol. 114:1106–1109.PubMedGoogle Scholar
  123. 123.
    Brightling CE, Ward R, Woltmann G, Bradding P, Sheller JR, Dworski R, et al. (2000) Induced sputum inflammatory mediator concentrations in eosinophilic bronchitis and asthma. Am. J. Respir. Crit. Care Med. 162:878–882.PubMedGoogle Scholar
  124. 124.
    Park SW, Park JS, Lee YM, Lee JH, Jang AS, Kim DJ, et al. (2005) Differences in radiological/HRCT findings in eosinophilic bronchitis compared to asthma: implication for bronchial responsiveness. Thorax 61:41–47.PubMedGoogle Scholar
  125. 125.
    O'Donnell RA, Frew AJ (2002) Is there more than one inflammatory phenotype in asthma. Thorax 57:566–568.PubMedGoogle Scholar
  126. 126.
    Douwes J, Gibson P, Pekkanen J, Pearce N (2002) Non-eosinophilic asthma: importance and possible mechanisms. Thorax 57:643–648.PubMedGoogle Scholar
  127. 127.
    Gibson PG, Simpson JL, Saltos N (2001) Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 119:1329–1336.PubMedGoogle Scholar
  128. 128.
    Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, et al. (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 160:1001–1008.PubMedGoogle Scholar
  129. 129.
    Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ (1999) Non-eosinophilic corticosteroid unresponsive asthma. Lancet 353:2213–2214.PubMedGoogle Scholar
  130. 130.
    Godon P, Boulet LP, Malo JL, Cartier A, Lemiere C (2002) Assessment and evaluation of symptomatic steroid-naive asthmatics without sputum eosinophilia and their response to inhaled corticosteroids. Eur. Respir. J. 20:1364–1369.PubMedGoogle Scholar
  131. 131.
    Berry MA, Morgan A, Shaw DE, Parker D, Green RH, Brightling CE, et al. (2007) Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 62:1043–1049.PubMedGoogle Scholar
  132. 132.
    Koshino T, Teshima S, Fukushima N, Takaishi T, Hirai K, Miyamoto Y, et al. (1993) Identification of basophils by immunohistochemistry in the airways of post-mortem cases of fatal asthma. Clin. Exp. Allergy 23:919–925.PubMedGoogle Scholar
  133. 133.
    Amin K, Janson C, Boman G, Venge P (2005) The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma. Allergy 60:1241–1247.PubMedGoogle Scholar
  134. 134.
    Ammit AJ, Bekir SS, Johnson PR, Hughes JM, Armour CL, Black JL (1997) Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi. Am. J. Respir. Crit. Care Med. 155:1123–1129.PubMedGoogle Scholar
  135. 135.
    El Shazly A, Berger P, Girodet PO, Ousova O, Fayon M, Vernejoux JM, et al. (2006) Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. J. Immunol. 176:1860–1868.PubMedGoogle Scholar
  136. 136.
    Berger P, Girodet PO, Begueret H, Ousova O, Perng DW, Marthan R, et al. (2003) Tryptasestimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. FASEB J. 17:2139–2141.PubMedGoogle Scholar
  137. 137.
    Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, Tunon-de-Lara JM (2007) Inflammation of bronchial smooth muscle in allergic asthma. Thorax 62:8–15.PubMedGoogle Scholar
  138. 138.
    Yang W, Kaur D, Okayama Y, Ito A, Wardlaw AJ, Brightling CE, et al. (2006) Human lung mast cells adhere to human airway smooth muscle, in part, via tumor suppressor in lung cancer-1. J. Immunol. 176:1238–1243.PubMedGoogle Scholar
  139. 139.
    Slats AM, Janssen K, van Schadewijk A, van der Plas DT, Schot R, van den Aardweg JG, et al. (2007) Bronchial inflammation and airway responses to deep inspiration in asthma and COPD. Am. J. Respir. Crit. Care Med. (in press).Google Scholar
  140. 140.
    Carroll NG, Mutavdzic S, James AL (2002) Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur. Respir. J. 19:879–885.PubMedGoogle Scholar
  141. 141.
    Chen FH, Samson KT, Miura K, Ueno K, Odajima Y, Shougo T, et al. (2004) Airway remodeling: a comparison between fatal and nonfatal asthma. J. Asthma 41:631–638.PubMedGoogle Scholar
  142. 142.
    Brightling CE, Bradding P, Pavord ID, Wardlaw AJ (2003) New insights into the role of the mast cell in asthma. Clin. Exp. Allergy 33:550–556.PubMedGoogle Scholar
  143. 143.
    Saha S, Neale N, Berry M, May R, Monk R, Bradding P, Wardlaw AJ, Pavord ID, Brightling CE (2006) Interleukin-13 + cells are increased in the airway smooth muscle bundle of asthmatics but not COPD. Proc. Am. Thorac. Soc. A29.Google Scholar
  144. 144.
    Laporte JC, Moore PE, Baraldo S, Jouvin MH, Church TL, Schwartzman IN, et al. (2001) Direct effects of interleukin-13 on signalling pathways for physiological responses in cultured human airway smooth muscle cells. Am. J. Respir. Crit. Care Med. 164:141–148.PubMedGoogle Scholar
  145. 145.
    Grunstein MM, Hakonarson H, Leiter J, Chen M, Whelan R, Grunstein JS, et al. (2002) IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 282:L520–L528.PubMedGoogle Scholar
  146. 146.
    Johnson PR, Ammit AJ, Carlin SM, Armour CL, Caughey GH, Black JL (1997) Mast cell tryptase potentiates histamine-induced contraction in human sensitized bronchus. Eur. Respir. J. 10:38–43.PubMedGoogle Scholar
  147. 147.
    Berger P, Walls AF, Marthan R, Tunon-de-Lara JM (1998) Immunoglobulin E-induced passive sensitization of human airways: an immunohistochemical Study. Am. J. Respir. Crit. Care Med. 157:610–616.PubMedGoogle Scholar
  148. 148.
    Woodman L, Kaur D, Sutcliffe A, Bradding P, Brightling CE (2005) α-smooth muscle actin expression by human airway smooth muscle cells is upregulated in co-culture with mast cells. Thorax 60:ii118.Google Scholar
  149. 149.
    Panettieri RA, Yadvish PA, Kelly AM, Rubinstein NA, Kotlikoff MI (1990) Histamine stimulates proliferation of airway smooth muscle and induces c-fos expression. Am. J. Physiol. 259:L365–L371.PubMedGoogle Scholar
  150. 150.
    Berger P, Perng DW, Thabrew H, Compton SJ, Cairns JA, McEuen AR, et al. (2001) Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. J. Appl. Physiol. 9:1372–1379.Google Scholar
  151. 151.
    Espinosa K, Bosse Y, Stankova J, Rola-Pleszczynski M (2003) CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J. Allergy Clin. Immunol. 111:1032–10440.PubMedGoogle Scholar
  152. 152.
    Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J. Immunol. 171:380–389.PubMedGoogle Scholar
  153. 153.
    Kaur D, Saunders R, Berger P, Siddiqui S, Woodman L, Wardlaw A, et al. (2006) Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma. Am. J. Respir. Crit. Care Med. 174:1179–1188.PubMedGoogle Scholar
  154. 154.
    Wardlaw AJ, Brightling C, Green R, Woltmann G, Pavord I (2000) Eosinophils in asthma and other allergic diseases. Br. Med. Bull. 56:985–1003.PubMedGoogle Scholar
  155. 155.
    Claman DM, Boushey HA, Liu J, Wong H, Fahy JV (1994) Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects. J. Allergy Clin. Immunol. 94:861–869.PubMedGoogle Scholar
  156. 156.
    Pizzichini MM, Pizzichini E, Clelland L, Efthimiadis A, Mahony J, Dolovich J, et al. (1997) Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am. J. Respir. Crit. Care Med. 155:1501–1508.PubMedGoogle Scholar
  157. 157.
    Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, et al. (1992) Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am. Rev. Respir. Dis. 145:669–674.PubMedGoogle Scholar
  158. 158.
    Lim S, Jatakanon A, John M, Gilbey T, O'Connor BJ, Chung KF, et al. (1999) Effect of inhaled budesonide on lung function and airway inflammation assessment by various inflammatory markers in mild asthma. Am. J. Respir. Crit. Care Med. 159:22–30.PubMedGoogle Scholar
  159. 159.
    Bentley AM, Hamid Q, Robinson DS, Schotman E, Meng Q, Assoufi B, et al. (1996) Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptaseonly positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am. J. Respir. Crit. Care Med. 153:551–556.PubMedGoogle Scholar
  160. 160.
    Aubier M, Neukirch C, Peiffer C, Melac M (2001) Effect of cetirizine on bronchial hyper-responsiveness in patients with seasonal allergic rhinitis and asthma. Allergy 56:35–42.PubMedGoogle Scholar
  161. 161.
    Hamilton A, Faiferman I, Stober P, Watson RM, O'Byrne PM (1998) Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J. Allergy Clin. Immunol. 102:177–183.PubMedGoogle Scholar
  162. 162.
    Boulet LP, Chapman KR, Cote J, Kalra S, Bhagat R, Swystun VA, et al. (1997) Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am. J. Respir. Crit. Care Med. 155:1835–1840.PubMedGoogle Scholar
  163. 163.
    Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 35:2144–2148.Google Scholar
  164. 164.
    Kips JC, O'Connor BJ, Langley SJ, Woodcock A, Kerstjens HA, Postma DS, et al. (2003) Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am. J. Respir. Crit. Care Med. 167:1655–1659.PubMedGoogle Scholar
  165. 165.
    Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. (2001) Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 107:963–970.PubMedGoogle Scholar
  166. 166.
    Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, et al. (1999) Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160:1816–1823.PubMedGoogle Scholar
  167. 167.
    Boguniewicz M, Schneider LC, Milgrom H, Newell D, Kelly N, Tam P, et al. (1993) Treatment of steroid-dependent asthma with recombinant interferon-gamma. Clin. Exp. Allergy 23:785–790.PubMedGoogle Scholar
  168. 168.
    Bryan SA, O'Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, et al. (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2149–2153.PubMedGoogle Scholar
  169. 169.
    Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354:697–708.PubMedGoogle Scholar
  170. 170.
    Cox G, Miller JD, McWilliams A, FitzGerald JM, Lam S (2006) Bronchial thermoplasty for asthma. Am. J. Respir. Crit. Care Med. 173:965–969.PubMedGoogle Scholar
  171. 171.
    Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, et al. (2007) Asthma control during the year after bronchial thermoplasty. N. Engl. J. Med. 356:1327–1337.PubMedGoogle Scholar
  172. 172.
    Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. (2002) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360:1715–1721.PubMedGoogle Scholar
  173. 173.
    Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. (2006) Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J. 27:483–494.PubMedGoogle Scholar
  174. 174.
    Chlumsky J, Striz I, Terl M, Vondracek J (2006) Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. J. Int. Med. Res. 34:129–139.PubMedGoogle Scholar
  175. 175.
    Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ (1999) Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am. J. Respir. Crit. Care Med. 159:1043–1051.Google Scholar
  176. 176.
    Nuijsink M, Hop WC, Sterk PJ, Duiverman EJ, de Jongste JC (2007) Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomized controlled trial. Eur. Respir. J 30:457–466.PubMedGoogle Scholar
  177. 177.
    Wardlaw AJ, Silverman M, Siva R, Pavord ID, Green R (2005) Multi-dimensional phenotyping: towards a new taxonomy for airway disease. Clin. Exp. Allergy 35:1254–1262.PubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Salman Siddiqui
    • 1
  • Fay Hollins
    • 1
  • Christopher Brightling
    • 1
    • 2
  1. 1.Institute for Lung Health, Department of Infection, Inflammation and ImmunityUniversity of LeicesterLeicesterUK
  2. 2.Department of Respiratory MedicineUniversity Hospitals of LeicesterLeicesterUK

Personalised recommendations