A new look at the pathogenesis of asthma

Clinical Science

Volumn 118, Issue 7, 2010, Pages 439-450

  Holgate, Stephen T ^a   Arshad, Hasan S ^a   Roberts, Graham C ^a   Howarth, Peter H ^a   Thurner, Philipp ^a   Davies, Donna E ^a  

^a UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

Author keywords

Allergen; Asthma; Inflammation; Remodelling; T cell; Virus infection

Indexed keywords

ADAM PROTEIN; ALLERGEN; AZATHIOPRINE; BASILIXIMAB; BRONCHODILATING AGENT; CORTICOSTEROID DERIVATIVE; CYCLINE; CYCLOSPORIN A; CYTOKINE; EPIDERMAL GROWTH FACTOR RECEPTOR; IMMUNOGLOBULIN G1 ANTIBODY; INTERLEUKIN 5 RECEPTOR ALPHA; KI 67 ANTIGEN; MEDI 563; MEPOLIZUMAB; METHOTREXATE; MONTELUKAST; OKT 4; OMALIZUMAB; PRANLUKAST; SMOOTH MUSCLE ACTIN; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; ZAFIRLUKAST;

AIR POLLUTION; ALLERGIC ASTHMA; ASTHMA; BRONCHUS BIOPSY; CELL POLARITY; CLINICAL TRIAL; DISEASE PREDISPOSITION; DRUG RECEPTOR BINDING; ENVIRONMENTAL EXPOSURE; GENETIC RISK; HUMAN; IMMUNOPATHOGENESIS; INNATE IMMUNITY; LUNG ALVEOLUS EPITHELIUM; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REMISSION; RESPIRATORY EPITHELIUM; RESPIRATORY VIRUS; REVIEW; TH2 CELL; TREATMENT RESPONSE; VIRUS INFECTION;

ADOLESCENT; ADULT; AGE OF ONSET; ALLERGENS; ASTHMA; CHILD; CHRONIC DISEASE; DISEASE PROGRESSION; HUMANS; IMMUNITY, INNATE; RESPIRATORY TRACT INFECTIONS; YOUNG ADULT;

EID: 74749084658     PISSN: 01435221     EISSN: None     Source Type: Journal    
DOI: 10.1042/CS20090474     Document Type: Review

References (110)

1. Holgate, S., Bisgaard, H., Bjermer, L., Haahtela, T., Haughney, J., Horne, R., McIvor, A., Palkonen, S., Price, D. B., Thomas, M. et al. (2008) The Brussels Declaration: the need for change in asthma management. Eur. Respir. J. 32, 1433-1442
2. Editorial (2008) Still more questions than answers. Lancet 372, 1009
3. Sly, P. D., Boner,A. L., Björksten, B., Bush, A., Custovic, A., Eigenmann, P. A., Gern, J. E., Gerritsen, J., Hamelmann, E., Helms, P. J. et al. (2008) Early identification of atopy in the prediction of persistent asthma in children. Lancet 372, 1100-1106
4. Sears, M. R., Greene, J. M., Willan, A. R., Wiecek, E. M., Taylor, D. R., Flannery, E. M., Cowan, J. O., Herbison, G. P., Silva, P. A. and Poulton, R. (2003) A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N. Engl. J. Med. 349, 1414-1422
5. Horne, R., Price, D., Cleland, J., Costa, R., Covey, D., Gruffydd-Jones, K., Haughney, J., Henrichsen, S. H., Kaplan, A., Langhammer, A. et al. (2007) Can asthma control be improved by understanding the patient's perspective? BMC Pulm. Med. 7, 8
6. Haughney, J., Price, D., Kaplan, A., Chrystyn, H., Horne, R., May, N., Moffat, M., Versnel, J., Shanahan, E. R., Hillyer, E. V. et al. (2008) Achieving asthma control in practice: understanding the reasons for poor control. Respir. Med. 102, 1681-1693
7. Boushey, H. A., Sorkness, C. A., King, T. S., Sullivan, S. D., Fahy, J. V., Lazarus, S. C., Chinchilli, V. M., Craig, T. J., Dimango, E. A., Deykin, A. et al. (2005) Daily versus as-needed corticosteroids for mild persistent asthma. N. Engl. J. Med. 352, 1519-1528
8. Pedersen, S. E., Bateman, E. D., Bousquet, J., Busse, W.W., Yoxall, S. and Clark, T. J. (2007) Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the Gaining Optimal Asthma controL study. J. Allergy Clin. Immunol. 120, 1036-1042
9. Mendis, S., Fukino, K., Cameron, A., Laing, R., Filipe, Jr, A., Khatib, O., Leowski, J. and Ewen, M. (2007) The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries. Bull. World Health Organ. 85, 279-288
10. Anderson, G. P. (2008) Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107-1119
11. Turato, G., Barbato, A., Baraldo, S., Zanin, M. E., Bazzan, E., Lokar-Oliani, K., Calabrese, F., Panizzolo, C., Snijders, D., Maestrelli, P. et al. (2008) Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. Am. J. Respir. Crit. Care Med. 178, 476-482
12. Pearce, N., Pekkanen, J. and Beasley, R. (1999) How much asthma is really attributable to atopy? Thorax 54, 268-272
13. Woodcock, A., Forster, L., Matthews, E., Martin, J., Letley, L., Vickers, M., Britton, J., Strachan, D., Howarth, P., Altmann, D. et al. (2003) Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N. Engl. J. Med. 17; 349, 225-236
14. Barnes, P. J.. (1996) Is there a role for immunotherapy in the treatment of asthma? No. Am. J. Respir. Crit. Care Med. 154, 1227-1228
15. Scadding, G. K., Durham, S. R., Mirakian, R., Jones, N. S., Leech, S. C., Farooque, S., Ryan, D., Walker, S. M., Clark, A. T., Dixon, T. A. et al. (2008) British Society for Allergy and Clinical Immunology guidelines for the management of allergic and non-allergic rhinitis. Clin. Exp. Allergy 38, 19-42
16. Holgate, S. T. (2009) Novel targets of therapy in asthma. Curr. Opin. Pulm. Med. 15, 63-71
17. Flood-Page, P., Swenson, C., Faiferman, I., Matthews, J., Williams, M., Brannick, L., Robinson, D., Wenzel, S., Busse, W., Hansel, T. T. et al. (2007) A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062-1071
18. Rothenberg, M. E., Klion, A. D., Roufosse, F. E., Kahn, J. E., Weller, P. F., Simon, H. U., Schwartz, L. B., Rosenwasser, L. J., Ring, J., Griffin, E. F. et al. (2008) Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N. Engl. J. Med. 358, 1215-1228
19. Mehr, S., Rego, S., Kakakios, A., Kilham, H. and Kemp, A. (2009) Treatment of a case of pediatric hypereosinophilic syndrome with anti-interleukin-5. J. Pediatr. 155, 289-291
20. Nair, P., Pizzichini, M. M., Kjarsgaard, M., Inman, M. D., Efthimiadis, A., Pizzichini, E., Hargreave, F. E. and O'Byrne, P. M. (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985-993
21. Haldar, P., Brightling, C. E., Hargadon, B., Gupta, S., Monteiro, W., Sousa, A., Marshall, R. P., Bradding, P., Green, R. H., Wardlaw, A. J. and Pavord, I. D. (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973-984
22. Yamane-Ohnuki, N., Kinoshita, S., Inoue-Urakubo, M., Kusunoki, M., Iida, S., Nakano, R., Wakitani, M., Niwa, R., Sakurada, M., Uchida, K. et al. (2004) Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol. Bioeng. 87, 614-622
23. Austen, K. F. (1979) Biologic implications of the structural and functional characteristics of the chemical mediators of immediate-type hypersensitivity. Harvey Lect. 73, 93-161
24. Holgate, S. T., Davies, D. E., Lackie, P. M., Wilson, S. J., Puddicombe, S. M. and Lordan, J. L. (2000) Epithelial-mesenchymal interactions in the pathogenesis of asthma. J. Allergy Clin. Immunol. 105, 193-204
25. Holgate, S. T. (2002) Asthma: more than an inflammatory disease. Curr. Opin. Allergy Clin. Immunol. 2, 27-29
26. Holgate, S. T. (2007) Epithelium dysfunction in asthma. J. Allergy Clin. Immunol. 120, 1233-1244
27. Bucchieri, F., Puddicombe, S. M., Lordan, J. L., Richter, A., Buchanan, D., Wilson, S. J., Ward, J., Zummo, G., Howarth, P. H., Djukanovic, R. et al. (2002) Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis. Am. J. Respir. Cell. Mol. Biol. 27, 179-185
28. Wark, P. A., Johnston, S. L., Bucchieri, F., Powell, R., Puddicombe, S., Laza-Stanca, V., Holgate, S. T. and Davies, D. E. (2005) Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937-947
29. Swindle, E. J., Collins, J. E. and Davies, D. E. (2009) Breakdown in epithelial barrier function in patients with asthma: identification of novel therapeutic approaches. J. Allergy Clin. Immunol. 124, 23-34
30. O'Regan, G. M., Sandilands, A., McLean, W. H. and Irvine, A. D. (2008) Filaggrin in atopic dermatitis. J. Allergy Clin. Immunol. 122, 689-693
31. Groschwitz, K. R. and Hogan, S. P. (2009) Intestinal barrier function: molecular regulation and disease pathogenesis J. Allergy Clin. Immunol. 124, 3-20
32. Tieu, D. D., Kern, R. C. and Schleimer, R. P. (2009) Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J. Allergy Clin. Immunol. 124, 37-42
33. Cookson, W. (2004) The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat. Rev. Immunol. 4, 978-988
34. Holgate, S. T., Davies, D. E., Powell, R. M., Howarth, P. H., Haitchi, H. M. and Holloway, J.W. (2007) Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur. Respir. J. 29, 793-803
35. Eder,W., Ege, M. J. and von Mutius, E. (2006) The asthma epidemic. N. Engl. J. Med. 355, 2226-2235
36. Nadeem, A., Masood, A. and Siddiqui, N. (2008) Oxidant-antioxidant imbalance in asthma: scientific evidence, epidemiological data and possible therapeutic options. Ther. Adv. Respir. Dis. 2, 215-235
37. Sears, M. R. (2008) Epidemiology of asthma exacerbations. J. Allergy Clin. Immunol. 122, 662-668
38. Martinez, F. D. (2002) Development of wheezing disorders and asthma in preschool children. Pediatrics 109 (Suppl. 2), 362-367
39. Simpson, A., Maniatis, N., Jury, F., Cakebread, J. A., Lowe, L. A., Holgate, S. T.,Woodcock, A., Ollier, W. E., Collins, A., Custovic, A. et al. (2005) Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am. J. Respir. Crit. Care Med. 172, 55-60
40. Turner, S. W. and Devereux, G. (2007) Early life influences on the development of allergy and asthma - how early is early? Clin. Exp. Allergy 37, 163-165
41. Lucas, J. S., Inskip, H. M., Godfrey, K. M., Foreman, C. T., Warner, J. O., Gregson, R. K. and Clough, J. B. (2004) Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function. Am. J. Respir. Crit. Care Med. 170, 534-540
42. Håland, G., Carlsen, K. C., Sandvik, L., Devulapalli, C. S., Munthe-Kaas, M. C., Pettersen, M. and Carlsen, K. H. (2006) Reduced lung function at birth and the risk of asthma at 10 years of age. N. Engl. J. Med. 355, 1682-1689
43. Illi, S., von Mutius, E., Lau, S., Niggemann, B., Grüber, C. and Wahn, U. (2006) Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 368, 763-770
44. Kurukulaaratchy, R. J., Matthews, S., Waterhouse, L. and Arshad, S. H. (2003) Factors influencing symptom expression in children with bronchial hyperresponsiveness at 10 years of age. J. Allergy Clin. Immunol. 112, 311-316
45. Matricardi, P. M., Illi, S., Grüber, C., Keil, T., Nickel, R., Wahn, U. and Lau, S. (2008) Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur. Respir. J. 32, 585-592
46. Wennergren, G. (2009) What if it is the other way around? Early introduction of peanut and fish seems to be better than avoidance. Acta Paediatr. 98, 1085-1087
47. Sporik, R., Holgate, S. T., Platts-Mills, T. A. and Cogswell, J. J. (1990) Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N. Engl. J. Med. 323, 502-507
48. H2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid. J. Allergy Clin. Immunol. 108, 394-401
49. Guilbert, T.W., Morgan, W. J., Zeiger, R. S., Mauger, D. T., Boehmer, S. J., Szefler, S. J., Bacharier, L. B., Lemanske, Jr, R. F., Strunk, R. C. et al. (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med. 354, 1985-1997
50. Murray, C. S.,Woodcock, A., Langley, S. J., Morris, J. and Custovic, A. (2006) Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 368, 754-762
51. Jackson, D. J., Gangnon, R. E., Evans, M. D., Roberg, K. A., Anderson, E. L., Pappas, T. E., Printz, M. C., Lee, W. M., Shult, P. A., Reisdorf, E. et al. (2008) Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am. J. Respir. Crit. Care Med. 178, 667-672
52. Raza, A., Kurukulaaratchy, R. J. and Arshad, S. H. (2008) Predicting risk of asthma in wheezing infants. Thorax 63, 842
53. Arshad, S. H., Kurukulaaratchy, R. J., Fenn, M. and Matthews, S. (2005) Early life risk factors for current wheeze, asthma, and bronchial hyperresponsiveness at 10 years of age. Chest 127, 502-508
54. Dharmage, S. C., Erbas, B., Jarvis, D., Wjst, M., Raherison, C., Norbäck, D., Heinrich, J., Sunyer, J. and Svanes, C. (2009) Do childhood respiratory infections continue to influence adult respiratory morbidity? Eur. Respir. J. 33, 237-244
55. Wu, P., Dupont, W. D., Griffin, M. R., Carroll, K. N., Mitchel, E. F., Gebretsadik, T. and Hartert, T. V. (2008) Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am. J. Respir. Crit. Care Med. 178, 1123-1129
56. Turato, G., Barbato, A., Baraldo, S., Zanin, M. E., Bazzan, E., Lokar-Oliani, K., Calabrese, F., Panizzolo, C., Snijders, D., Maestrelli, P. et al. (2008) Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. Am. J. Respir. Crit. Care Med. 178, 476-482
57. Tschernig, T., Debertin, A. S., Paulsen, F., Kleemann, W. J. and Pabst, R. (2001) Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life. Thorax 56, 427-431
58. Wan, H., Winton, H. L., Soeller, C., Tovey, E. R., Gruenert, D. C., Thompson, P. J., Stewart, G. A., Taylor, G. W., Garrod, D. R., Cannell, M. B. and Robinson, C. (1999) Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Invest. 104, 123-133
59. Matzinger, P. (2007) Friendly and dangerous signals: is the tissue in control? Nat. Immunol. 8, 11-13
60. Contoli, M., Message, S. D., Laza-Stanca, V., Edwards, M. R., Wark, P. A., Bartlett, N.W., Kebadze, T., Mallia, P., Stanciu, L. A., Parker, H. L. et al. (2006) Role of deficient type III interferon-λ production in asthma exacerbations. Nat. Med. 12, 1023-1026
61. Bossios, A., Gourgiotis, D., Skevaki, C. L., Saxoni-Papageorgiou, P., Lötvall, J., Psarras, S., Karpathios, T., Constandopoulos, A. G., Johnston, S. L. and Papadopoulos, N. G. (2008) Rhinovirus infection and house dust mite exposure synergize in inducing bronchial epithelial cell interleukin-8 release. Clin. Exp. Allergy 38, 1615-1626
62. de Boer, W. I., Sharma, H. S., Baelemans, S. M., Hoogsteden, H. C., Lambrecht, B. N. and Braunstahl, G. J. (2008) Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. Can. J. Physiol. Pharmacol. 86, 105-112
63. Rusznak, C., Sapsford, R. J., Devalia, J. L., Shah, S. S., Hewitt, E. L., Lamont, A. G.,Davies, R. J. and Lozewicz, S. (2001) Interaction of cigarette smoke and house dust mite allergens on inflammatory mediator release from primary cultures of human bronchial epithelial cells. Clin. Exp. Allergy 31, 226-238
64. Rothen-Rutishauser, B. M., Kiama, S. G. and Gehr, P. (2005) A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am. J. Respir. Cell. Mol. Biol. 32, 281-289
65. Sajjan, U., Wang, Q., Zhao, Y., Gruenert, D. C. and Hershenson, M. B. (2008) Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 178, 1271-1281
66. Holgate, S. T. (2007) Epithelium dysfunction in asthma. J. Allergy Clin. Immunol. 120, 1233-1244
67. Rochman, Y. and Leonard, W. J. (2008) Thymic stromal lymphopoietin: a new cytokine in asthma. Curr. Opin. Pharmacol. 8, 249-254
68. Liu, Y. J. (2007) Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J. Allergy Clin. Immunol. 120, 238-244
69. Reference deleted
70. Saglani, S., Malmstrom, K., Pelkonen, A. S., Malmberg, L. P., Lindahl, H., Kajosaari, M., Turpeinen, M., Rogers, A. V., Payne, D. N., Bush, A. et al. (2005) Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction. Am. J. Respir. Crit. Care Med. 171, 722-727
71. Barbato, A., Turato, G., Baraldo, S., Bazzan, E., Calabrese, F., Panizzolo, C., Zanin, M. E., Zuin, R., Maestrelli, P., Fabbri, L. M. and Saetta, M. (2006) Epithelial damage and angiogenesis in the airways of children with asthma. Am. J. Respir. Crit. Care Med. 174, 975-981
72. Saglani, S., Payne, D. N., Zhu, J., Wang, Z., Nicholson, A. G., Bush, A. and Jeffery, P. K. (2007) Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir. Crit. Care Med. 176, 858-864
73. Kim, E. S., Kim, S. H.,Kim,K.W., Park, J.W., Kim, Y. S., Sohn, M. H. and Kim, K. E. (2007) Basement membrane thickening and clinical features of children with asthma. Allergy 62, 635-640
74. Bourdin, A., Neveu, D., Vachier, I., Paganin, F., Godard, P. and Chanez, P. (2007) Specificity of basement membrane thickening in severe asthma. J. Allergy Clin. Immunol. 119, 1367-1374
75. Law, L., Zheng, L., Orsida, B., Levvey, B., Oto, T., Kotsimbos, A. T., Snell, G. I. and Williams, T. J. (2005) Early changes in basement membrane thickness in airway walls post-lung transplantation, J. Heart Lung Transplant. 24, 1571-1576
76. waf cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium. Am. J. Respir. Cell. Mol. Biol. 28, 61-68
77. Fedorov, I. A., Wilson, S. J., Davies, D. E. and Holgate, S. T. (2005) Epithelial stress and structural remodelling in childhood asthma. Thorax 60, 389-394
78. Stevens, P. T., Kicic, A., Sutanto, E. N., Knight, D. A. and Stick, S. M. (2008) Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1. Clin. Exp. Allergy 38, 1901-1910
79. To, T., Gershon, A., Wang, C., Dell, S. and Cicutto, L. (2007) Persistence and remission in childhood asthma: a population-based asthma birth cohort study. Arch. Pediatr. Adolesc. Med. 161, 1197-1204
80. Bjerg-Bäcklund, A., Perzanowski, M. S., Platts-Mills, T., Sandström, T., Lundbäck, B. and Rönmark, E. (2006) Asthma during the primary school ages: prevalence, remission and the impact of allergic sensitization. Allergy 61, 549-555
81. Stern, D. A., Morgan, W. J., Halonen, M., Wright, A. L. and Martinez, F. D. (2008) Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 372, 1058-1064
82. Postma, D. S. (2007) Gender differences in asthma development and progression. Gend. Med. 4 (Suppl. B), S133-S146
83. van den Toorn, L. M., Overbeek, S. E., de Jongste, J. C., Leman, K., Hoogsteden, H. C. and Prins, J. B. (2001) Airway inflammation is present during clinical remission of atopic asthma. Am. J. Respir. Crit. Care Med. 164, 2107-2113
84. Obase, Y., Shimoda, T., Kawano, T., Saeki, S., Tomari, S., Izaki, K., Fukushima, C., Matsuse, H. and Kohno, S. (2003) Bronchial hyperresponsiveness and airway inflammation in adolescents with asymptomatic childhood asthma. Allergy 58, 213-220
85. Hara, J., Fujimura, M., Myou, S., Kita, T., Abo, M., Katayama, N., Furusho, S., Nobata, K., Oribe, Y., Kimura, H. et al. (2008) Sputum eosinophilia, airway hyperresponsiveness and airway narrowing in young adults with former asthma. Allergol. Int. 57, 211-217
86. Morgan, W. J., Stern, D. A., Sherrill, D. L., Guerra, S., Holberg, C. J., Guilbert, T.W., Taussig, L. M., Wright, A. L. and Martinez, F. D. (2005) Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am. J. Respir. Crit. Care Med. 172, 1253-1258
87. Panettieri, Jr, R. A., Covar, R., Grant, E., Hillyer, E. V. and Bacharier, L. (2008) Natural history of asthma: persistence versus progression: does the beginning predict the end? J. Allergy Clin. Immunol. 121, 607-613
88. Haldar, P., Pavord, I. D., Shaw, D. E., Berry, M. A., Thomas, M., Brightling, C. E., Wardlaw, A. J. and Green, R. H. (2008) Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 178, 218-224
89. James, A. L., Bai, T. R., Mauad, T., Abramson, M. J., Dolhnikoff, M., McKay, K. O., Maxwell, P. S., Elliot, J. G. and Green, F. H. (2009) Airway smooth muscle thickness in asthma is related to severity but not duration of asthma. Eur. Respir. J. 34, 1040-1045
90. An, S. S. and Fredberg, J. J. (2007) Biophysical basis for airway hyperresponsiveness. Can. J. Physiol. Pharmacol. 85, 700-714
91. Brightling, C. E., Bradding, P., Symon, F. A., Holgate, S. T, Wardlaw, A. J. and Pavord, I. D. (2002) Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346, 1699-1705
92. Begueret, H., Berger, P., Vernejoux, J. M., Dubuisson, L., Marthan, R. and Tunon-de-Lara, J. M. (2007) Inflammation of bronchial smooth muscle in allergic asthma. Thorax 62, 8-15
93. Siddiqui, S., Mistry, V., Doe, C., Roach, K., Morgan, A., Wardlaw, A., Pavord, I., Bradding, P. and Brightling, C. (2008) Airway hyperresponsiveness is dissociated from airway wall structural remodeling. J. Allergy Clin. Immunol. b122, 335-341
94. ten Brinke, A. (2008) Risk factors associated with irreversible airflow limitation in asthma. Curr. Opin. Allergy Clin. Immunol. 8, 63-69
95. Lange, P., Parner, J., Vestbo, J., Schnohr, P. and Jensen, G. (1998) A 15-year follow-up study of ventilatory function in adults with asthma. N. Engl. J. Med. 339, 1194-1200
96. An, S. S., Kim, J., Ahn, K., Trepat, X., Drake, K. J., Kumar, S., Ling, G., Purington, C., Rangasamy, T., Kensler, T.W. et al. (2009) Cell stiffness, contractile stress and the role of extracellular matrix. Biochem. Biophys. Res. Commun. 382, 697-703
97. Dijkstra, A., Vonk, J. M., Jongepier, H., Koppelman, G. H., Schouten, J. P., ten Hacken, N. H., Timens, W. and Postma, D. S. (2006) Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax 61, 105-110
98. Tschumperlin, D. J., Shively, J. D., Kikuchi, T. and Drazen, J. M. (2003) Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am. J. Respir. Cell. Mol. Biol. 28, 142-149
99. Choe, M. M., Sporn, P. H. and Swartz, M. A. (2006) Extracellular matrix remodeling by dynamic strain in a three-dimensional tissue-engineered human airway wall model. Am. J. Respir. Cell. Mol. Biol. 35, 306-313
100. Shaw, T. J.,Wakely, S. L., Peebles, C. R., Mehta, R. L., Turner, J. M., Wilson, S. J. and Howarth, P. H. (2004) Endobronchial ultrasound to assess airway wall thickening: validation in vitro and in vivo. Eur. Respir. J. 23, 813-817
101. Wenzel, S. E. and Busse, W.W (2007) Severe asthma: lessons from the Severe Asthma Research Program. J. Allergy Clin. Immunol. 119, 14-21
102. Ueda, T., Niimi, A., Matsumoto, H., Takemura, M., Hirai, T., Yamaguchi, M., Matsuoka, H., Jinnai, M., Muro, S., Chin, K. and Mishima, M. (2006) Role of small airways in asthma: investigation using high-resolution computed tomography. J. Allergy Clin. Immunol. 118, 1019-1025
103. de Blic, J., Tillie-Leblond, I., Emond, S., Mahut, B., Dang Duy, T. L. and Scheinmann, P. (2005) High-resolution computed tomography scan and airway remodeling in children with severe asthma. J. Allergy Clin. Immunol. 116, 750-754
104. James, A. L., Paré, P. D. and Hogg, J. C. (1989) The mechanics of airway narrowing in asthma. Am. Rev. Respir. Dis. 139, 242-246
105. Saunders, R., Siddiqui, S., Kaur, D., Doe, C., Sutcliffe, A., Hollins, F., Bradding, P., Wardlaw, A. and Brightling, C. E. (2009) Fibrocyte localization to the airway smooth muscle is a feature of asthma. J. Allergy Clin. Immunol. 123, 376-384
106. Wicks, J., Haitchi, H. M., Holgate, S. T., Davies, D. E. and Powell, R. M. (2006) Enhanced upregulation of smooth muscle related transcripts by TGFβ2 in asthmatic (myo)fibroblasts. Thorax 61, 313-319
107. Hackett, T. L., Warner, S. M., Stefanowicz, D., Shaheen, F., Pechkovsky, D. V., Murray, L. A., Argentieri, R., Kicic, A., Stick, S. M., Bai, T. R. and Knight, D. A. (2009) Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β1. Am. J. Respir. Crit. Care Med. 180, 122-133
108. Tschumperlin, D. J., Shively, J. D., Kikuchi, T. and Drazen, J. M. (2003) Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am. J. Respir. Cell. Mol. Biol. 28, 142-149
109. Malavia, N. K., Raub, C. B., Mahon, S. B., Brenner, M., Panettieri, Jr, R. A. and George, S. C. (2009) Airway epithelium stimulates smooth muscle proliferation, Am. J. Respir. Cell. Mol. Biol. 41, 297-304
110. Wang, J., Fan, J., Laschinger, C., Arora, P. D., Kapus, A., Seth, A. and McCulloch, C. A. (2005) Smooth muscle actin determines mechanical force-induced p38 activation. J. Biol. Chem. 280, 7273-7284