1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pathology: Mechanisms of Disease
  4. Volume 10, 2015
  5. Article

Annual Review of Pathology: Mechanisms of Disease

Volume 10, 2015

Pathobiology of Severe Asthma

Abstract

Severe asthma (SA) afflicts a heterogeneous group of asthma patients who exhibit poor responses to traditional asthma medications. SA patients likely represent 5–10% of all asthma patients; however, they have a higher economic burden when compared with milder asthmatics. Considerable research has been performed on pathological pathways and structural changes associated with SA. Although limitations of the pathological approaches, ranging from sampling, to quantitative assessments, to heterogeneity of disease, have prevented a more definitive understanding of the underlying pathobiology, studies linking pathology to molecular markers to targeted therapies are beginning to solidify the identification of select molecular phenotypes. This review addresses the pathobiology of SA and discusses the current limitations of studies, the inflammatory cells and pathways linked to emerging phenotypes, and the structural and remodeling changes associated with severe disease. In all cases, an effort is made to link pathological findings to specific clinical/molecular phenotypes.

Keyword(s): airway, epithelium, histology, inflammation, interleukins, pathology
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-012414-040343
2015-01-24
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/pathol/10/1/annurev-pathol-012414-040343.html?itemId=/content/journals/10.1146/annurev-pathol-012414-040343&mimeType=html&fmt=ahah

Literature Cited

  1. Serra-Batlles J, Plaza V, Morejón E, Comella A, Brugués J. 1.  1998. Costs of asthma according to the degree of severity. Eur. Respir. J. 12:1322–26 [Google Scholar]
  2. Chakir J, Shannon J, Molet S, Fukakusa M, Elias J. 2.  et al. 2003. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression. J. Allergy Clin. Immunol. 111:1293–98 [Google Scholar]
  3. Szefler SJ, Leung DY. 3.  1997. Glucocorticoid-resistant asthma: pathogenesis and clinical implications for management. Eur. Respir. J. 10:1640–47 [Google Scholar]
  4. Adcock IM, Lane SJ. 4.  2003. Corticosteroid-insensitive asthma: molecular mechanisms. J. Endocrinol. 178:347–55 [Google Scholar]
  5. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M. 5.  et al. 2014. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 43:343–73 [Google Scholar]
  6. 6. American Thoracic Society 2000. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am. J. Respir. Crit. Care Med. 1622341–51
  7. Brown HM. 7.  1958. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet 2:1245–47 [Google Scholar]
  8. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB. 8.  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. 160:1001–8 [Google Scholar]
  9. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. 9.  2004. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J. Allergy Clin. Immunol. 113:101–8 [Google Scholar]
  10. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H. 10.  et al. 2010. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181:315–23 [Google Scholar]
  11. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR. 11.  et al. 2011. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet. 43:887–92 [Google Scholar]
  12. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M. 12.  et al. 2008. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 178:218–24 [Google Scholar]
  13. Siroux V, Basagaña X, Boudier A, Pin I, Garcia-Aymerich J. 13.  et al. 2011. Identifying adult asthma phenotypes using a clustering approach. Eur. Respir. J. 38:310–17 [Google Scholar]
  14. Wu W, Bleecker E, Moore W, Busse WW, Castro M. 14.  et al. 2014. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J. Allergy Clin. Immunol. 133:1280–88 [Google Scholar]
  15. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E. 15.  et al. 2010. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363:1211–21 [Google Scholar]
  16. Siroux V, Gonzalez JR, Bouzigon E, Curjuric I, Boudier A. 16.  et al. 2014. Genetic heterogeneity of asthma phenotypes identified by a clustering approach. Eur. Respir. J. 43:439–52 [Google Scholar]
  17. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR. 17.  et al. 2009. T-helper type 2–driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180:388–95 [Google Scholar]
  18. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV. 18.  et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365:1088–98 [Google Scholar]
  19. Corren J, Busse W, Meltzer EO, Mansfield L, Bensch G. 19.  et al. 2010. A randomized, controlled, phase 2 study of AMG 317, an IL-4Rα antagonist, in patients with asthma. Am. J. Respir. Crit. Care Med. 181:788–96 [Google Scholar]
  20. Piper E, Brightling C, Niven R, Oh C, Faggioni R. 20.  et al. 2013. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur. Respir. J. 41:330–38 [Google Scholar]
  21. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R. 21.  et al. 2012. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380:651–59 [Google Scholar]
  22. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W. 22.  et al. 2009. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360:973–84 [Google Scholar]
  23. Mauad T, Silva LF, Santos MA, Grinberg L, Bernardi FD. 23.  et al. 2004. Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma. Am. J. Respir. Crit. Care Med. 170:857–62 [Google Scholar]
  24. Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR. 24.  et al. 1997. Inflammation of small airways in asthma. J. Allergy Clin. Immunol. 100:44–51 [Google Scholar]
  25. Kuyper LM, Paré PD, Hogg JC, Lambert RK, Ionescu D. 25.  et al. 2003. Characterization of airway plugging in fatal asthma. Am. J. Med. 115:6–11 [Google Scholar]
  26. Wenzel SE, Vitari CA, Shende M, Strollo DC, Larkin A, Yousem SA. 26.  2012. Asthmatic granulomatosis: a novel disease with asthmatic and granulomatous features. Am. J. Respir. Crit. Care Med. 186:501–7 [Google Scholar]
  27. Balzar S, Wenzel SE, Chu HW. 27.  2002. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur. Respir. J. 20:254–59 [Google Scholar]
  28. Balzar S, Chu HW, Strand M, Wenzel S. 28.  2005. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am. J. Respir. Crit. Care Med. 171:431–39 [Google Scholar]
  29. Moore WC, Evans MD, Bleecker ER, Busse WW, Calhoun WJ. 29.  et al. 2011. Safety of investigative bronchoscopy in the Severe Asthma Research Program. J. Allergy Clin. Immunol. 128:328–36.e3 [Google Scholar]
  30. Wenzel SE. 30.  2012. Tissue-based and bronchoalveolar lavage–based biomarkers in asthma. Immunol. Allergy Clin. North Am. 32:401–11 [Google Scholar]
  31. Wenzel S, Holgate ST. 31.  2006. The mouse trap: It still yields few answers in asthma. Am. J. Respir. Crit. Care Med. 174:1173–76 [Google Scholar]
  32. Manni ML, Trudeau JB, Scheller EV, Mandalapu S, Elloso MM. 32.  et al. 2014. The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol. 7:1186–98 [Google Scholar]
  33. Lewkowich IP, Lajoie S, Stoffers SL, Suzuki Y, Richgels PK. 33.  et al. 2013. PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol. 6:728–39 [Google Scholar]
  34. Ochs M, Mühlfeld C. 34.  2013. Quantitative microscopy of the lung: a problem-based approach. Part 1: basic principles of lung stereology. Am. J. Physiol. Lung Cell. Mol. Physiol. 305:L15–22 [Google Scholar]
  35. Mühlfeld C, Ochs M. 35.  2013. Quantitative microscopy of the lung: a problem-based approach. Part 2: stereological parameters and study designs in various diseases of the respiratory tract. Am. J. Physiol. Lung Cell. Mol. Physiol. 305:L205–21 [Google Scholar]
  36. Avdalovic MV, Putney LF, Schelegle ES, Miller L, Usachenko JL. 36.  et al. 2006. Vascular remodeling is airway generation-specific in a primate model of chronic asthma. Am. J. Respir. Crit. Care Med. 174:1069–76 [Google Scholar]
  37. Lai Y, Altemeier WA, Vandree J, Piliponsky AM, Johnson B. 37.  et al. 2014. Increased density of intraepithelial mast cells in patients with exercise-induced bronchoconstriction regulated through epithelially derived thymic stromal lymphopoietin and IL-33. J. Allergy Clin. Immunol. 133:1448–55 [Google Scholar]
  38. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD. 38.  et al. 2010. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma. J. Allergy Clin. Immunol. 125:1046–53.e8 [Google Scholar]
  39. Barlow JL, Peel S, Fox J, Panova V, Hardman CS. 39.  et al. 2013. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J. Allergy Clin. Immunol. 132:933–41 [Google Scholar]
  40. Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB. 40.  et al. 2013. Prostaglandin D2 pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J. Allergy Clin. Immunol. 131:1504–12 [Google Scholar]
  41. Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D. 41.  et al. 2010. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am. J. Respir. Crit. Care Med. 181:1033–41 [Google Scholar]
  42. Voraphani N, Gladwin MT, Contreras AU, Kaminski N, Tedrow JR. 42.  et al. 2014. An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma. Mucosal Immunol. 7:1175–85 [Google Scholar]
  43. Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ. 43.  2002. TH2 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 [Google Scholar]
  44. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H. 44.  et al. 2006. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J. Allergy Clin. Immunol. 118:98–104 [Google Scholar]
  45. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH. 45.  et al. 2007. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. PNAS 104:15858–63 [Google Scholar]
  46. Jia L, Wang R, Tang DD. 46.  2012. Abl regulates smooth muscle cell proliferation by modulating actin dynamics and ERK1/2 activation. Am. J. Physiol. Cell Physiol. 302:C1026–34 [Google Scholar]
  47. Agrawal S, Townley RG. 47.  2014. Role of periostin, FENO, IL-13, lebrikizumab, other IL-13 antagonist and dual IL-4/IL-13 antagonist in asthma. Expert Opin. Biol. Ther. 14:165–81 [Google Scholar]
  48. Wenzel S, Ford L, Pearlman D, Spector S, Sher L. 48.  et al. 2013. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368:2455–66 [Google Scholar]
  49. Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP. 49.  et al. 2012. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti–IL-4 receptor α antagonist. J. Allergy Clin. Immunol. 130:516–22.e4 [Google Scholar]
  50. Al-Samri MT, Benedetti A, Préfontaine D, Olivenstein R, Lemière C. 50.  et al. 2010. Variability of sputum inflammatory cells in asthmatic patients receiving corticosteroid therapy: a prospective study using multiple samples. J. Allergy Clin. Immunol. 125:1161–63.e4 [Google Scholar]
  51. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. 51.  2002. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57:875–79 [Google Scholar]
  52. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A. 52.  et al. 2003. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Investig. 112:1029–36 [Google Scholar]
  53. Chu HW, Balzar S, Westcott JY, Trudeau JB, Sun Y. 53.  et al. 2002. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition. Clin. Exp. Allergy 32:1558–65 [Google Scholar]
  54. Zhao J, O'Donnell VB, Balzar S, St Croix CM, Trudeau JB, Wenzel SE. 54.  2011. 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells. PNAS 108:14246–51 [Google Scholar]
  55. Zhao J, Maskrey B, Balzar S, Chibana K, Mustovich A. 55.  et al. 2009. Interleukin-13–induced MUC5AC is regulated by 15-lipoxygenase 1 pathway in human bronchial epithelial cells. Am. J. Respir. Crit. Care Med. 179:782–90 [Google Scholar]
  56. Coleman JM, Naik C, Holguin F, Ray A, Ray P. 56.  et al. 2012. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset. Thorax 67:1061–66 [Google Scholar]
  57. Moore PE, Church TL, Chism DD, Panettieri RA Jr., Shore SA. 57.  2002. IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. Am. J. Physiol. Lung Cell. Mol. Physiol. 282:L847–53 [Google Scholar]
  58. van Wetering S, Zuyderduyn S, Ninaber DK, van Sterkenburg MA, Rabe KF, Hiemstra PS. 58.  2007. Epithelial differentiation is a determinant in the production of eotaxin-2 and -3 by bronchial epithelial cells in response to IL-4 and IL-13. Mol. Immunol. 44:803–11 [Google Scholar]
  59. Wenzel SE, Trudeau JB, Barnes S, Zhou X, Cundall M. 59.  et al. 2002. TGF-β and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts. J. Immunol. 169:4613–19 [Google Scholar]
  60. Dent G, Hadjicharalambous C, Yoshikawa T, Handy RL, Powell J. 60.  et al. 2004. Contribution of eotaxin-1 to eosinophil chemotactic activity of moderate and severe asthmatic sputum. Am. J. Respir. Crit. Care Med. 169:1110–17 [Google Scholar]
  61. Castro M, Mathur S, Hargreave F, Boulet LP, Xie F. 61.  et al. 2011. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184:1125–32 [Google Scholar]
  62. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R. 62.  et al. 2013. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J. Allergy Clin. Immunol. 132:1086–96.e5 [Google Scholar]
  63. Gupta S, Siddiqui S, Haldar P, Raj JV, Entwisle JJ. 63.  et al. 2009. Qualitative analysis of high-resolution CT scans in severe asthma. Chest 136:1521–28 [Google Scholar]
  64. Wenzel SE, Balzar S, Ampleford E, Hawkins GA, Busse WW. 64.  et al. 2007. IL4Rα mutations are associated with asthma exacerbations and mast cell/IgE expression. Am. J. Respir. Crit. Care Med. 175:570–76 [Google Scholar]
  65. Irani AA, Schechter NM, Craig SS, DeBlois G, Schwartz LB. 65.  1986. Two types of human mast cells that have distinct neutral protease compositions. PNAS 83:4464–68 [Google Scholar]
  66. Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E. 66.  et al. 2011. Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 183:299–309 [Google Scholar]
  67. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. 67.  2002. Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346:1699–705 [Google Scholar]
  68. Brightling CE, Ammit AJ, Kaur D, Black JL, Wardlaw AJ. 68.  et al. 2005. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am. J. Respir. Crit. Care Med. 171:1103–8 [Google Scholar]
  69. Yu M, Eckart MR, Morgan AA, Mukai K, Butte AJ. 69.  et al. 2011. Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J. Clin. Investig. 121:3133–43 [Google Scholar]
  70. Kaur D, Saunders R, Berger P, Siddiqui S, Woodman L. 70.  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. 174:1179–88 [Google Scholar]
  71. Wakahara K, Van VQ, Baba N, Bégin P, Rubio M. 71.  et al. 2013. Basophils are recruited to inflamed lungs and exacerbate memory Th2 responses in mice and humans. Allergy 68:180–89 [Google Scholar]
  72. Kepley CL, McFeeley PJ, Oliver JM, Lipscomb MF. 72.  2001. Immunohistochemical detection of human basophils in postmortem cases of fatal asthma. Am. J. Respir. Crit. Care Med. 164:1053–58 [Google Scholar]
  73. Just J, Gouvis-Echraghi R, Rouve S, Wanin S, Moreau D, Annesi-Maesano I. 73.  2012. Two novel, severe asthma phenotypes identified during childhood using a clustering approach. Eur. Respir. J. 40:55–60 [Google Scholar]
  74. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I. 74.  et al. 2011. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med. 154:573–82 [Google Scholar]
  75. Hill DA, Siracusa MC, Ruymann KR, Tait Wojno ED, Artis D, Spergel JM. 75.  2014. Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children. Allergy 69:674–77 [Google Scholar]
  76. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S. 76.  et al. 2013. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am. J. Respir. Crit. Care Med. 187:804–11 [Google Scholar]
  77. Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M. 77.  et al. 2012. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur. J. Immunol. 42:1106–16 [Google Scholar]
  78. Hazenberg MD, Spits H. 78.  2014. Human innate lymphoid cells. Blood 124:700–9 [Google Scholar]
  79. Mjösberg J, Bernink J, Golebski K, Karrich JJ, Peters CP. 79.  et al. 2012. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37:649–59 [Google Scholar]
  80. Barnig C, Cernadas M, Dutile S, Liu X, Perrella MA. 80.  et al. 2013. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5:174ra26 [Google Scholar]
  81. Dakhama A, Collins ML, Ohnishi H, Goleva E, Leung DY. 81.  et al. 2013. IL-13-producing BLT1-positive CD8 cells are increased in asthma and are associated with airway obstruction. Allergy 68:666–73 [Google Scholar]
  82. Magnan AO, Mély LG, Camilla CA, Badier MM, Montero-Julian FA. 82.  et al. 2000. Assessment of the Th1/Th2 paradigm in whole blood in atopy and asthma. Increased IFN-γ-producing CD8+ T cells in asthma. Am. J. Respir. Crit. Care Med. 161:1790–96 [Google Scholar]
  83. Oda H, Kawayama T, Imaoka H, Sakazaki Y, Kaku Y. 83.  et al. 2014. Interleukin-18 expression, CD8+ T cells, and eosinophils in lungs of nonsmokers with fatal asthma. Ann. Allergy Asthma Immunol. 112:23–28.e1 [Google Scholar]
  84. Moore WC, Hastie AT, Li X, Li H, Busse WW. 84.  et al. 2014. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 133:1557–63 [Google Scholar]
  85. Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. 85.  2011. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J. Allergy Clin. Immunol. 127:153–60.e1–9 [Google Scholar]
  86. McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER. 86.  et al. 2012. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am. J. Respir. Crit. Care Med. 185:612–19 [Google Scholar]
  87. Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemière C. 87.  et al. 2008. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 133:420–26 [Google Scholar]
  88. Wysocki K, Park SY, Bleecker E, Busse W, Castro M. 88.  et al. 2014. Characterization of factors associated with systemic corticosteroid use in severe asthma: data from the Severe Asthma Research Program. J. Allergy Clin. Immunol. 133:915–18 [Google Scholar]
  89. Li X, Hawkins GA, Ampleford EJ, Moore WC, Li H. 89.  et al. 2013. Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. J. Allergy Clin. Immunol. 132:313–20.e15 [Google Scholar]
  90. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. 90.  1997. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med. 156:737–43 [Google Scholar]
  91. Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV. 91.  et al. 1993. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa?. Am. Rev. Respir. Dis. 148:713–19 [Google Scholar]
  92. Wenzel SE, Balzar S, Cundall M, Chu HW. 92.  2003. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J. Allergy Clin. Immunol. 111:1345–52 [Google Scholar]
  93. Kato T, Takeda Y, Nakada T, Sendo F. 93.  1995. Inhibition by dexamethasone of human neutrophil apoptosis in vitro. Nat. Immun. 14:198–208 [Google Scholar]
  94. Roussel L, Houle F, Chan C, Yao Y, Berube J. 94.  et al. 2010. IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J. Immunol. 184:4531–37 [Google Scholar]
  95. Chang Y, Al-Alwan L, Risse P-A, Halayko AJ, Martin JG. 95.  et al. 2012. Th17-associated cytokines promote human airway smooth muscle cell proliferation. FASEB J. 26:5152–60 [Google Scholar]
  96. Kudo M, Melton AC, Chen C, Engler MB, Huang KE. 96.  et al. 2012. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med. 18:547–54 [Google Scholar]
  97. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S. 97.  et al. 2008. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181:4089–97 [Google Scholar]
  98. Lajoie S, Lewkowich IP, Suzuki Y, Clark JR, Sproles AA. 98.  et al. 2010. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. 11:928–35 [Google Scholar]
  99. Truyen E, Coteur L, Dilissen E, Hellings PW. 99.  Bullens DMA, et al. 2006. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?. Respir. Res. 7:135 [Google Scholar]
  100. Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V. 100.  et al. 2010. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 138:1140–47 [Google Scholar]
  101. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J. 101.  et al. 2013. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am. J. Respir. Crit. Care Med. 188:1294–302 [Google Scholar]
  102. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T. 102.  et al. 2002. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169:443–53 [Google Scholar]
  103. Lai HY, Rogers DF. 103.  2010. Mucus hypersecretion in asthma: intracellular signalling pathways as targets for pharmacotherapy. Curr. Opin. Allergy Clin. Immunol. 10:67–76 [Google Scholar]
  104. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE. 104.  et al. 2006. Evidence of a role of tumor necrosis factor α in refractory asthma. N. Engl. J. Med. 354:697–708 [Google Scholar]
  105. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W. 105.  et al. 2009. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179:549–58 [Google Scholar]
  106. Thomson NC, Chaudhuri R, Livingston E. 106.  2004. Asthma and cigarette smoking. Eur. Respir. J. 24:822–33 [Google Scholar]
  107. Telenga ED, Kerstjens HA, ten Hacken NH, Postma DS, van den Berge M. 107.  2013. Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics. BMC Pulm. Med. 13:58 [Google Scholar]
  108. Broekema M, ten Hacken NH, Volbeda F, Lodewijk ME, Hylkema MN. 108.  et al. 2009. Airway epithelial changes in smokers but not in ex-smokers with asthma. Am. J. Respir. Crit. Care Med. 180:1170–78 [Google Scholar]
  109. Taylor B, Mannino D, Brown C, Crocker D, Twum-Baah N, Holguin F. 109.  2008. Body mass index and asthma severity in the National Asthma Survey. Thorax 63:14–20 [Google Scholar]
  110. Gibeon D, Batuwita K, Osmond M, Heaney LG, Brightling CE. 110.  et al. 2013. Obesity-associated severe asthma represents a distinct clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest 143:406–14 [Google Scholar]
  111. Holguin F, Bleecker ER, Busse WW, Calhoun WJ, Castro M. 111.  et al. 2011. Obesity and asthma: an association modified by age of asthma onset. J. Allergy Clin. Immunol. 127:1486–93.e2 [Google Scholar]
  112. Desai D, Newby C, Symon FA, Haldar P, Shah S. 112.  et al. 2013. Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am. J. Respir. Crit. Care Med. 188:657–63 [Google Scholar]
  113. Holguin F, Comhair SA, Hazen SL, Powers RW, Khatri SS. 113.  et al. 2013. An association between l-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype. Am. J. Respir. Crit. Care Med. 187:153–59 [Google Scholar]
  114. Al-Alwan A, Bates JH, Chapman DG, Kaminsky DA, DeSarno MJ. 114.  et al. 2014. The nonallergic asthma of obesity. A matter of distal lung compliance. Am. J. Respir. Crit. Care Med. 189:1494–502 [Google Scholar]
  115. Ferreira DS, Annoni R, Silva LF, Buttignol M, Santos AB. 115.  et al. 2012. Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma. Clin. Exp. Allergy 42:1459–71 [Google Scholar]
  116. Shikotra A, Choy DF, Ohri CM, Doran E, Butler C. 116.  et al. 2012. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J. Allergy Clin. Immunol. 129:104–11.e1–9 [Google Scholar]
  117. Meyer EH, Goya S, Akbari O, Berry GJ, Savage PB. 117.  et al. 2006. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. PNAS 103:2782–87 [Google Scholar]
  118. Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S. 118.  et al. 2003. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9:582–88 [Google Scholar]
  119. Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G. 119.  et al. 2007. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356:1410–22 [Google Scholar]
  120. Thomas SY, Chyung YH, Luster AD. 120.  2010. Natural killer T cells are not the predominant T cell in asthma and likely modulate, not cause, asthma. J. Allergy Clin. Immunol. 125:980–84 [Google Scholar]
  121. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S. 121.  et al. 2005. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201:937–47 [Google Scholar]
  122. McErlean P, Berdnikovs S, Favoreto S Jr, Shen J, Biyasheva A. 122.  et al. 2014. Asthmatics with exacerbation during acute respiratory illness exhibit unique transcriptional signatures within the nasal mucosa. Genome Med. 6:1 [Google Scholar]
  123. Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G. 123.  et al. 2011. Effect of bronchoconstriction on airway remodeling in asthma. N. Engl. J. Med. 364:2006–15 [Google Scholar]
  124. Chetta A, Foresi A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. 124.  1997. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest 111:852–57 [Google Scholar]
  125. Bousquet J, Vignola AM, Chanez P, Campbell AM, Bonsignore G, Michel FB. 125.  1995. Airways remodelling in asthma: no doubt, no more?. Int. Arch. Allergy Immunol. 107:211–14 [Google Scholar]
  126. Elias JA, Zhu Z, Chupp G, Homer RJ. 126.  1999. Airway remodeling in asthma. J. Clin. Investig. 104:1001–6 [Google Scholar]
  127. Cohen L, Xueping E, Tarsi J, Ramkumar T, Horiuchi TK. 127.  et al. 2007. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am. J. Respir. Crit. Care Med. 176:138–45 [Google Scholar]
  128. Carroll N, Elliot J, Morton A, James A. 128.  1993. The structure of large and small airways in nonfatal and fatal asthma. Am. Rev. Respir. Dis. 147:405–10 [Google Scholar]
  129. Jenkins HA, Cool C, Szefler SJ, Covar R, Brugman S. 129.  et al. 2003. Histopathology of severe childhood asthma: a case series. Chest 124:32–41 [Google Scholar]
  130. Ordoñez CL, Khashayar R, Wong HH, Ferrando R, Wu R. 130.  et al. 2001. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am. J. Respir. Crit. Care Med. 163:517–23 [Google Scholar]
  131. Gordon IO, Husain AN, Charbeneau J, Krishnan JA, Hogarth DK. 131.  2013. Endobronchial biopsy: a guide for asthma therapy selection in the era of bronchial thermoplasty. J. Asthma 50:634–41 [Google Scholar]
  132. Kanoh S, Tanabe T, Rubin BK. 132.  2011. IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells. Clin. Exp. Allergy 41:1747–56 [Google Scholar]
  133. Atherton HC, Jones G, Danahay H. 133.  2003. IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am. J. Physiol. Lung Cell. Mol. Physiol. 285:L730–39 [Google Scholar]
  134. Chu HW, Balzar S, Seedorf GJ, Westcott JY, Trudeau JB. 134.  et al. 2004. Transforming growth factor-β2 induces bronchial epithelial mucin expression in asthma. Am. J. Pathol. 165:1097–106 [Google Scholar]
  135. Agusti C, Takeyama K, Cardell LO, Ueki I, Lausier J. 135.  et al. 1998. Goblet cell degranulation after antigen challenge in sensitized guinea pigs. Role of neutrophils. Am. J. Respir. Crit. Care Med. 158:1253–58 [Google Scholar]
  136. Roy MG, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE. 136.  et al. 2014. Muc5b is required for airway defence. Nature 505:412–16 [Google Scholar]
  137. Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T. 137.  1992. Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest 101:916–21 [Google Scholar]
  138. de Medeiros Matsushita M, da Silva LF, dos Santos MA, Fernezlian S, Schrumpf JA. 138.  et al. 2005. Airway proteoglycans are differentially altered in fatal asthma. J. Pathol. 207:102–10 [Google Scholar]
  139. Carroll NG, Mutavdzic S, James AL. 139.  2002. Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax 57:677–82 [Google Scholar]
  140. Chen FH, Samson KT, Miura K, Ueno K, Odajima Y. 140.  et al. 2004. Airway remodeling: a comparison between fatal and nonfatal asthma. J. Asthma 41:631–38 [Google Scholar]
  141. Green FH, Williams DJ, James A, McPhee LJ, Mitchell I, Mauad T. 141.  2010. Increased myoepithelial cells of bronchial submucosal glands in fatal asthma. Thorax 65:32–38 [Google Scholar]
  142. Thomas B, Rutman A, Hirst RA, Haldar P, Wardlaw AJ. 142.  et al. 2010. Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma. J. Allergy Clin. Immunol. 126:722–29.e2 [Google Scholar]
  143. Talbot TR, Hartert TV, Mitchel E, Halasa NB, Arbogast PG. 143.  et al. 2005. Asthma as a risk factor for invasive pneumococcal disease. N. Engl. J. Med. 352:2082–90 [Google Scholar]
  144. Ordoñez C, Ferrando R, Hyde DM, Wong HH, Fahy JV. 144.  2000. Epithelial desquamation in asthma: artifact or pathology?. Am. J. Respir. Crit. Care Med. 162:2324–29 [Google Scholar]
  145. Benayoun L, Druilhe A, Dombret M-C, Aubier M, Pretolani M. 145.  2003. Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med. 167:1360–68 [Google Scholar]
  146. Aoshiba K, Rennard SI, Spurzem JR. 146.  1997. Cell-matrix and cell-cell interactions modulate apoptosis of bronchial epithelial cells. Am. J. Physiol. 272:L28–37 [Google Scholar]
  147. Poon A, Eidelman D, Laprise C, Hamid Q. 147.  2012. ATG5, autophagy and lung function in asthma. Autophagy 8:694–95 [Google Scholar]
  148. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V. 148.  et al. 2011. Defective epithelial barrier function in asthma. J. Allergy Clin. Immunol. 128:549–56.e1–12 [Google Scholar]
  149. Hardyman MA, Wilkinson E, Martin E, Jayasekera NP, Blume C. 149.  et al. 2013. TNF-α-mediated bronchial barrier disruption and regulation by src-family kinase activation. J. Allergy Clin. Immunol. 132:665–75.e8 [Google Scholar]
  150. Hackett TL, Singhera GK, Shaheen F, Hayden P, Jackson GR. 150.  et al. 2011. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution. Am. J. Respir. Cell Mol. Biol. 45:1090–100 [Google Scholar]
  151. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH. 151.  et al. 2000. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 14:1362–74 [Google Scholar]
  152. Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I. 152.  et al. 2003. The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma. Clin. Exp. Allergy 33:233–40 [Google Scholar]
  153. Burgel PR, Nadel JA. 153.  2004. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59:992–96 [Google Scholar]
  154. Roche WR, Beasley R, Williams JH, Holgate ST. 154.  1989. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1:520–24 [Google Scholar]
  155. Sullivan P, Stephens D, Ansari T, Costello J, Jeffery P. 155.  1998. Variation in the measurements of basement membrane thickness and inflammatory cell number in bronchial biopsies. Eur. Respir. J. 12:811–15 [Google Scholar]
  156. Ferrando RE, Nyengaard JR, Hays SR, Fahy JV, Woodruff PG. 156.  2003. Applying stereology to measure thickness of the basement membrane zone in bronchial biopsy specimens. J. Allergy Clin. Immunol. 112:1243–45 [Google Scholar]
  157. Chu HW, Halliday JL, Martin RJ, Leung DY, Szefler SJ, Wenzel SE. 157.  1998. Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease. Am. J. Respir. Crit. Care Med. 158:1936–44 [Google Scholar]
  158. Jeffery PK, Laitinen A, Venge P. 158.  2000. Biopsy markers of airway inflammation and remodelling. Respir. Med. 94:Suppl. FS9–15 [Google Scholar]
  159. Jeffery PK. 159.  2001. Remodeling in asthma and chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 164:S28–38 [Google Scholar]
  160. Bourdin A, Neveu D, Vachier I, Paganin F, Godard P, Chanez P. 160.  2007. Specificity of basement membrane thickening in severe asthma. J. Allergy Clin. Immunol. 119:1367–74 [Google Scholar]
  161. Ward C, Pais M, Bish R, Reid D, Feltis B. 161.  et al. 2002. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 57:309–16 [Google Scholar]
  162. Redington AE, Madden J, Frew AJ, Djukanovic R, Roche WR. 162.  et al. 1997. Transforming growth factor-β 1 in asthma. Measurement in bronchoalveolar lavage fluid. Am. J. Respir. Crit. Care Med. 156:642–47 [Google Scholar]
  163. Michalik M, Pierzchalska M, Legutko A, Ura M, Ostaszewska A. 163.  et al. 2009. Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture. Med. Sci. Monit. 15:BR194–201 [Google Scholar]
  164. Bergeron C, Pagé N, Joubert P, Barbeau B, Hamid Q, Chakir J. 164.  2003. Regulation of procollagen I (α1) by interleukin-4 in human bronchial fibroblasts: a possible role in airway remodelling in asthma. Clin. Exp. Allergy 33:1389–97 [Google Scholar]
  165. Cundall M, Sun Y, Miranda C, Trudeau JB, Barnes S, Wenzel SE. 165.  2003. Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J. Allergy Clin. Immunol. 112:1064–71 [Google Scholar]
  166. Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L. 166.  et al. 1997. Eosinophil-associated TGF-β1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 17:326–33 [Google Scholar]
  167. Shi HZ, Deng JM, Xu H, Nong ZX, Xiao CQ. 167.  et al. 1998. Effect of inhaled interleukin-4 on airway hyperreactivity in asthmatics. Am. J. Respir. Crit. Care Med. 157:1818–21 [Google Scholar]
  168. Bellini A, Marini MA, Bianchetti L, Barczyk M, Schmidt M, Mattoli S. 168.  2012. Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal Immunol. 5:140–49 [Google Scholar]
  169. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG. 169.  et al. 2010. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. PNAS 107:14170–75 [Google Scholar]
  170. Zhou X, Trudeau JB, Schoonover KJ, Lundin JI, Barnes SM. 170.  et al. 2005. Interleukin-13 augments transforming growth factor-β1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts. Am. J. Physiol. Cell Physiol. 288:C435–42 [Google Scholar]
  171. Tschumperlin DJ, Shively JD, Kikuchi T, Drazen JM. 171.  2003. Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am. J. Respir. Cell Mol. Biol. 28:142–49 [Google Scholar]
  172. Bentley JK, Hershenson MB. 172.  2008. Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration. Proc. Am. Thorac. Soc. 5:89–96 [Google Scholar]
  173. Kaminska M, Foley S, Maghni K, Storness-Bliss C, Coxson H. 173.  et al. 2009. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J. Allergy Clin. Immunol. 124:45–51e1–4 [Google Scholar]
  174. Hassan M, Jo T, Risse P-A, Tolloczko B, Lemière C. 174.  et al. 2010. Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma. J. Allergy Clin. Immunol. 125:1037–45.e3 [Google Scholar]
  175. Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret M-C. 175.  et al. 2001. Regulation of peroxisome proliferator-activated receptor γ expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am. J. Respir. Crit. Care Med. 164:1487–94 [Google Scholar]
  176. Siddiqui S, Hollins F, Brightling CE. 176.  2008. What can we learn about airway smooth muscle from the company it keeps?. Eur. Respir. J. 32:9–11 [Google Scholar]
  177. Bossé Y, Rola-Pleszczynski M. 177.  2008. FGF2 in asthmatic airway-smooth-muscle-cell hyperplasia. Trends Mol. Med. 14:3–11 [Google Scholar]
  178. Bissonnette EY, Madore AM, Chakir J, Laviolette M, Boulet LP. 178.  et al. 2014. Fibroblast growth factor-2 is a sputum remodeling biomarker of severe asthma. J. Asthma 51:119–26 [Google Scholar]
  179. Li X, Wilson JW. 179.  1997. Increased vascularity of the bronchial mucosa in mild asthma. Am. J. Respir. Crit. Care Med. 156:229–33 [Google Scholar]
  180. Vrugt B, Wilson S, Bron A, Holgate ST, Djukanovic R, Aalbers R. 180.  2000. Bronchial angiogenesis in severe glucocorticoid-dependent asthma. Eur. Respir. J. 15:1014–21 [Google Scholar]
  181. Sidebotham HJ, Roche WR. 181.  2003. Asthma deaths; persistent and preventable mortality. Histopathology 43:2105–17 [Google Scholar]
  182. Orsida BE, Li X, Hickey B, Thien F, Wilson JW, Walters EH. 182.  1999. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 54:289–95 [Google Scholar]
  183. Chu HW, Kraft M, Rex MD, Martin RJ. 183.  2001. Evaluation of blood vessels and edema in the airways of asthma patients: regulation with clarithromycin treatment. Chest 120:416–22 [Google Scholar]
  184. Makinde T, Murphy RF, Agrawal DK. 184.  2006. Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodeling. Curr. Mol. Med. 6:831–41 [Google Scholar]
  185. Hoshino M, Takahashi M, Aoike N. 185.  2001. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J. Allergy Clin. Immunol. 107:295–301 [Google Scholar]
  186. Tseliou E, Bakakos P, Kostikas K, Hillas G, Mantzouranis K. 186.  et al. 2012. Increased levels of angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma. Allergy 67:396–402 [Google Scholar]
  187. Papadaki G, Bakakos P, Kostikas K, Hillas G, Tsilogianni Z. 187.  et al. 2013. Vascular endothelial growth factor and cysteinyl leukotrienes in sputum supernatant of patients with asthma. Respir. Med. 107:1339–45 [Google Scholar]
  188. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S. 188.  et al. 2004. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat. Med. 10:1095–103 [Google Scholar]
  189. Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C. 189.  et al. 2006. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. PNAS 103:11021–26 [Google Scholar]
  190. Szczeklik W, Sokolowska BM, Zuk J, Mastalerz L, Szczeklik A, Musial J. 190.  2011. The course of asthma in Churg-Strauss syndrome. J. Asthma 48:183–87 [Google Scholar]
  191. Dolhnikoff M, da Silva LFF, de Araujo BB, Gomes HAP, Fernezlian S. 191.  et al. 2009. The outer wall of small airways is a major site of remodeling in fatal asthma. J. Allergy Clin. Immunol. 123:1090–97.e1 [Google Scholar]
  192. Wenzel SE, Busse WW. 192.  2007. Severe asthma: lessons from the Severe Asthma Research Program. J. Allergy Clin. Immunol. 119:14–21 [Google Scholar]
  193. Walker C, Gupta S, Hartley R, Brightling CE. 193.  2012. Computed tomography scans in severe asthma: utility and clinical implications. Curr. Opin. Pulm. Med. 18:42–47 [Google Scholar]
  194. Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ. 194.  2011. Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung 189:121–29 [Google Scholar]
  195. Gonem S, Natarajan S, Desai D, Corkill S, Singapuri A. 195.  et al. 2014. Clinical significance of small airway obstruction markers in patients with asthma. Clin. Exp. Allergy 44:499–507 [Google Scholar]
  196. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. 196.  1996. Alveolar tissue inflammation in asthma. Am. J. Respir. Crit. Care Med. 154:1505–10 [Google Scholar]
  197. Haley KJ, Sunday ME, Wiggs BR, Kozakewich HP, Reilly JJ. 197.  et al. 1998. Inflammatory cell distribution within and along asthmatic airways. Am. J. Respir. Crit. Care Med. 158:565–72 [Google Scholar]
  198. Booth H, Richmond I, Ward C, Gardiner PV, Harkawat R, Walters EH. 198.  1995. Effect of high dose inhaled fluticasone propionate on airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 152:45–52 [Google Scholar]
  199. Wilson JW, Li X. 199.  1997. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin. Exp. Allergy 27:363–71 [Google Scholar]
  200. Kotaru C, Schoonover KJ, Trudeau JB, Huynh ML, Zhou X. 200.  et al. 2006. Regional fibroblast heterogeneity in the lung: implications for remodeling. Am. J. Respir. Crit. Care Med. 173:1208–15 [Google Scholar]
  201. Pechkovsky DV, Hackett TL, An SS, Shaheen F, Murray LA, Knight DA. 201.  2010. Human lung parenchyma but not proximal bronchi produces fibroblasts with enhanced TGF-β signaling and α-SMA expression. Am. J. Respir. Cell Mol. Biol. 43:641–51 [Google Scholar]
  202. Zhou X, Wu W, Hu H, Milosevic J, Konishi K. 202.  et al. 2011. Genomic differences distinguish the myofibroblast phenotype of distal lung fibroblasts from airway fibroblasts. Am. J. Respir. Cell Mol. Biol. 45:1256–62 [Google Scholar]
  203. James AL, Elliot JG, Jones RL, Carroll ML, Mauad T. 20.  et al. 2012. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am. J. Respir. Crit. Care Med. 185:1058–64 [Google Scholar]
  204. Stephens NL, Jiang H. 204.  1995. Basic pathology of the airways smooth muscle. Asthma and Rhinitis WW Busse, ST Holgate 1087–115 Boston: Blackwell Sci [Google Scholar]
  205. in ‘t Veen JCCM, Beekman AJ, Bel EH, Sterk PJ. 205.  2000. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am. J. Respir. Crit. Care Med. 161:1902–6 [Google Scholar]
  206. Gelb AF, Licuanan J, Shinar CM, Zamel N. 206.  2002. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest 121:715–21 [Google Scholar]
  207. Bai TR, Cooper J, Koelmeyer T, Paré PD, Weir TD. 207.  2000. The effect of age and duration of disease on airway structure in fatal asthma. Am. J. Respir. Crit. Care Med. 162:663–69 [Google Scholar]
  208. Mochizuki T, Nakajima H, Kokubu F, Kushihashi T, Adachi M. 208.  1997. Evaluation of emphysema in patients with reversible airway obstruction using high-resolution CT. Chest 112:1522–26 [Google Scholar]
  209. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M. 209.  et al. 2004. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am. J. Respir. Crit. Care Med. 170:583–93 [Google Scholar]
/content/journals/10.1146/annurev-pathol-012414-040343
Loading
Pathobiology of Severe Asthma
Annual Review of Pathology: Mechanisms of Disease 10, 511 (2015); https://doi.org/10.1146/annurev-pathol-012414-040343
/content/journals/10.1146/annurev-pathol-012414-040343
/content/journals/10.1146/annurev-pathol-012414-040343
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error