Pathogenesis of Severe Asthma

  • So Ri Kim


Patients with severe asthma suffer tremendously in their quality of life, and the disease management is often ineffective and weary. Although considerable effort has been concentrated to understand the pathophysiology and variability of treatment response in severe asthma and to develop new therapies, to date, many unknowns of severe asthma are still remained. For the appropriate treatment and prevention of severe asthma, many questions concerning the pathogenesis of severe asthma must be answered. In addition, identification of various types of asthma and better understanding of the mechanisms underlying each type of severe asthma are crucial for the future personalized medicine of the patients. In this chapter, recent advances in pathogenesis of severe asthma will be highlighted, specifically about the type of severe asthma defined as failure to achieve control with maximum doses of corticosteroid therapies (i.e., refractory severe asthma).


Airway remodeling Steroid resistance Th2 inflammation Non-Th2 inflammation Subcellular organelles 


  1. 1.
    Chiappara G, Gagliardo R, Siena A, Bonsignore MR, Bousquet J, Bonsignore G, et al. Airway remodelling in the pathogenesis of asthma. Curr Opin Allergy Clin Immunol. 2001;1(1):85–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol. 2011;128(3):451–62.PubMedCrossRefGoogle Scholar
  3. 3.
    Cohen L, Xueping E, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, et al. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med. 2007;176(2):138–45.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Gras D, Bourdin A, Vachier I, de Senneville L, Bonnans C, Chanez P. An ex vivo model of severe asthma using reconstituted human bronchial epithelium. J Allergy Clin Immunol. 2012;129(5):1259–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol. 2011;128(3):549–56.PubMedCrossRefGoogle Scholar
  6. 6.
    Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis. 1985;131(4):599–606.PubMedGoogle Scholar
  7. 7.
    Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis. 1989;140(6):1745–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Panizzolo C, et al. Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med. 2006;174(9):975–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol. 2007;120(6):1233–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Swartz MA, Tschumperlin DJ, Kamm RD, Drazen JM. Mechanical stress is communicated between different cell types to elicit matrix remodeling. Proc Natl Acad Sci U S A. 2001;98(11):6180–5.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Park JA, Tschumperlin DJ. Chronic intermittent mechanical stress increases MUC5AC protein expression. Am J Respir Cell Mol Biol. 2009;41(4):459–66.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G, Wilson S, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Park JA, Kim JH, Bi D, Mitchell JA, Qazvini NT, Tantisira K, et al. Unjamming and cell shape in the asthmatic airway epithelium. Nat Mater. 2015;14(10):1040–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Thomas B, Rutman A, Hirst RA, Haldar P, Wardlaw AJ, Bankart J, et al. Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma. J Allergy Clin Immunol. 2010;126(4):722–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Locksley RM. Asthma and allergic inflammation. Cell. 2010;140(6):777–83.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Scanlon ST, AN MK. Type 2 innate lymphoid cells: new players in asthma and allergy. Curr Opin Immunol. 2012;24(6):707–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Bando JK, Nussbaum JC, Liang HE, Locksley RM. Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. J Leukoc Biol. 2013;94(5):877–84.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Barlow JL, Peel S, Fox J, Panova V, Hardman CS, Camelo A, et al. 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. 2013;132(4):933–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013;502(7470):245–8.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O’Byrne PM, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137(1):75–86.PubMedCrossRefGoogle Scholar
  21. 21.
    Siew LQ, Wu SY, Ying S, Corrigan CJ. Cigarette smoking increases bronchial mucosal IL-17A expression in asthmatics, which acts in concert with environmental aeroallergens to engender neutrophilic inflammation. Clin Exp Allergy. 2017;47(6):740–50.Google Scholar
  22. 22.
    Kim SR, Kim HJ, Kim DI, Lee KB, Park HJ, Jeong JS, et al. Blockade of interplay between IL-17A and endoplasmic reticulum stress attenuates LPS-induced lung injury. Theranostics. 2015;5(12):1343–62.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Gras D, Chanez P, Vachier I, Petit A, Bourdin A. Bronchial epithelium as a target for innovative treatments in asthma. Pharmacol Ther. 2013;140(3):290–305.PubMedCrossRefGoogle Scholar
  24. 24.
    Pothoven KL, Norton JE, Suh LA, Carter RG, Harris KE, Biyasheva A, et al. Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease. J Allergy Clin Immunol. 2017;139(6):1966–78.Google Scholar
  25. 25.
    Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E. Diminished lipoxin biosynthe824sis in severe asthma. Am J Respir Crit Care Med. 2005;172(7):–30.Google Scholar
  26. 26.
    Bonnans C, Vachier I, Chavis C, Godard P, Bousquet J, Chanez P. Lipoxins are potential endogenous antiinflammatory mediators in asthma. Am J Respir Crit Care Med. 2002;165(11):1531–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Ordoñez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde DM, et al. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med. 2001;163(2):517–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Kuyper LM, Paré PD, Hogg JC, Lambert RK, Ionescu D, Woods R, et al. Characterization of airway plugging in fatal asthma. Am J Med. 2003;115(1):6–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Yu H, Li Q, Kolosov VP, Perelman JM, Zhou X. Interleukin-13 induces mucin 5AC production involving STAT6/SPDEF in human airway epithelial cells. Cell Commun Adhes. 2010;17(4–6):83–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Yan F, Li W, Zhou H, Wu Y, Ying S, Chen Z, et al. Interleukin-13-induced MUC5AC expression is regulated by a PI3K-NFAT3 pathway in mouse tracheal epithelial cells. Biochem Biophys Res Commun. 2014;446(1):49–53.PubMedCrossRefGoogle Scholar
  31. 31.
    Nakano T, Inoue H, Fukuyama S, Matsumoto K, Matsumura M, Tsuda M, et al. Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am J Respir Crit Care Med. 2006;173(11):1216–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167(10):1360–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Johnson PR, Roth M, Tamm M, Hughes M, Ge Q, King G, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med. 2001;164(3):474–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Macedo P, Hew M, Torrego A, Jouneau S, Oates T, Durham A, et al. Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma. Clin Exp Allergy. 2009;39(11):1668–76.PubMedCrossRefGoogle Scholar
  35. 35.
    Kaminska M, Foley S, Maghni K, Storness-Bliss C, Coxson H, Ghezzo H, et al. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J Allergy Clin Immunol. 2009;124:45–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Tillie-Leblond I, de Blic J, Jaubert F, Wallaert B, Scheinmann P, Gosset P. Airway remodeling is correlated with obstruction in children with severe asthma. Allergy. 2008;63(5):533–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Woodruff PG, Dolganov GM, Ferrando RE, Donnelly S, Hays SR, Solberg OD, et al. Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am J Respir Crit Care Med. 2004;169:1001–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, et al. IL-17A produced by T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012;18(4):547–54.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Goto K, Chiba Y, Sakai H, Misawa M. Tumor necrosis factor-alpha (TNF-alpha) induces upregulation of RhoA via NF-kappaB activation in cultured human bronchial smooth muscle cells. J Pharmacol Sci. 2009;110(4):437–44.PubMedCrossRefGoogle Scholar
  40. 40.
    Chiba Y, Nakazawa S, Todoroki M, Shinozaki K, Sakai H, Misawa M. Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein. Am J Respir Cell Mol Biol. 2009;40(2):159–67.PubMedCrossRefGoogle Scholar
  41. 41.
    Ebina M, Takahashi T, Chiba T, Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am Rev Respir Dis. 1993;148(3):720–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Thomson RJ, Schellenberg RR. Increased amount of airway smooth muscle does not account for excessive bronchoconstriction in asthma. Can Respir J. 1998;5(1):61–2.PubMedGoogle Scholar
  43. 43.
    Jeffery PK. Remodeling in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(10 Pt 2):S28–38.PubMedCrossRefGoogle Scholar
  44. 44.
    Aubier M, Thabut G, Hamidi F, Guillou N, Brard J, Dombret MC, et al. Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma. J Allergy Clin Immunol. 2016;138(3):729–39.PubMedCrossRefGoogle Scholar
  45. 45.
    Roche WR, Williams JH, Beasley R, Holgate ST. Subepithelial fibrosis in bronchi of asthmatics. Lancet. 1989;1(8637):520–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111(6):1293–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Laitinen A, Altraja A, Kampe M, Linden M, Virtanen I, Laitinen LA. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med. 1997;156(3 Pt 1):951–8.PubMedCrossRefGoogle Scholar
  48. 48.
    de Medeiros MM, da Silva LF, dos Santos MA, Fernezlian S, Schrumpf JA, Roughley P, et al. Airway proteoglycans are differentially altered in fatal asthma. J Pathol. 2005;207(1):102–10.CrossRefGoogle Scholar
  49. 49.
    Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002;346(22):1699–705.PubMedCrossRefGoogle Scholar
  50. 50.
    Brightling CE, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID, Bradding P. Interleukin-4 and -13 expression is co-localised to mast cells within the airway smooth muscle in asthma. Clin Exp Allergy. 2003;33(12):1711–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Carroll NG, Mutavdzic S, James AL. Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax. 2002;57(8):677–82.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Carroll N, Carello S, Cooke C, James A. Airway structure and inflammatory cells in fatal attacks of asthma. Eur Respir J. 1996;9(4):709–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Brightling CE, Desai D, Siddiqui S. Severe asthma: a consequence of over exuberant repair? Clin Exp Allergy. 2009;39(11):1630–2.PubMedCrossRefGoogle Scholar
  54. 54.
    Bourdin A, Neveu D, Vachier I, Paganin F, Godard P, Chanez P. Specificity of basement membrane thickening in severe asthma. J Allergy Clin Immunol. 2007;119(6):1367–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Saunders R, Siddiqui S, Kaur D, Doe C, Sutcliffe A, Hollins F, et al. Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol. 2009;123(2):376–84.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang CH, Huang CD, Lin HC, Lee KY, Lin SM, Liu CY, et al. Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med. 2008;178(6):583–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000;161(5):1720–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Kips JC, Pauwels RA. Airway wall remodelling: does it occur and what does it mean? Clin Exp Allergy. 1999;29(11):1457–66.PubMedCrossRefGoogle Scholar
  59. 59.
    Payne DN, Rogers AV, Adelroth E, Bandi V, Guntupalli KK, Bush A, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167(1):78–82.PubMedCrossRefGoogle Scholar
  60. 60.
    Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160(3):1001–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Dolhnikoff M, da Silva LF, de Araujo BB, Gomes HA, Fernezlian S, Mulder A, et al. The outer wall of small airways is a major site of remodeling in fatal asthma. J Allergy Clin Immunol. 2009;123(5):1090–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Saglani S, Lui S, Ullmann N, Campbell GA, Sherburn RT, Mathie SA, et al. IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma. J Allergy Clin Immunol. 2013;132(3):676–85.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Castanhinha S, Sherburn R, Walker S, Gupta A, Bossley CJ, Buckley J, et al. Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33. J Allergy Clin Immunol. 2015;136(2):312–22.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Vrugt B, Wilson S, Bron A, Holgate ST, Djukanovic R, Aalbers R. Bronchial angiogenesis in severe glucocorticoid-dependent asthma. Eur Respir J. 2000;15(6):1014–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Charan NB, Baile EM, Pare PD. Bronchial vascular congestion and angiogenesis. Eur Respir J. 1997;10(5):1173–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Walters EH, Soltani A, Reid DW, Ward C. Vascular remodeling in asthma. Curr Opin Allergy Clin Immunol. 2008;8(1):39–43.PubMedCrossRefGoogle Scholar
  67. 67.
    Abdel-Rahman AM, El-Sahrigy SA, Bakr SI. A comparative study of two angiogenic factors: vascular endothelial growth factor and angiogenin in induced sputum from asthmatic children in acute attack. Chest. 2006;129(2):266–71.PubMedCrossRefGoogle Scholar
  68. 68.
    Bradding P, Holgate ST. Immunopathology and human mast cell cytokines. Crit Rev Oncol Hematol. 1999;31(2):119–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Long WM, Yerger LD, Martinez H, Codias E, Sprung CL, Abraham WM, et al. Modification of bronchial blood flow during allergic airway responses. J Appl Physiol. 1988;65(1):272–82.PubMedGoogle Scholar
  70. 70.
    Wanner A. Circulation of the airway mucosa. J Appl Physiol. 1989;67(3):917–25.PubMedGoogle Scholar
  71. 71.
    Webber SE, Salonen RO, Corfield DR, Widdicombe JG. Effects of non-neural mediators and allergen on tracheobronchial blood flow. Eur Respir J Suppl. 1990;12:638–43.Google Scholar
  72. 72.
    Barnes PJ. Pathophysiology of asthma. Br J Clin Pharmacol. 1996;42(1):3–10.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Gallagher SJ, Shank JA, Bochner BS, Wagner EM. Methods to track leukocyte and erythrocyte transit through the bronchial vasculature in sheep. J Immunol Methods. 2002;271(1–2):89–97.PubMedCrossRefGoogle Scholar
  74. 74.
    Redington AE, Roche WR, Madden J, Frew AJ, Djukanovic R, Holgate ST, et al. Basic fibroblast growth factor in asthma: measurement in bronchoalveolar lavage fluid basally and following allergen challenge. J Allergy Clin Immunol. 2001;107(2):384–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Chetta A, Zanini A, Foresi A, D’Ippolito R, Tipa A, Castagnaro A, et al. Vascular endothelial growth factor up-regulation and bronchial wall remodelling in asthma. Clin Exp Allergy. 2005;35(11):1437–42.PubMedCrossRefGoogle Scholar
  76. 76.
    Feltis BN, Wignarajah D, Zheng L, Ward C, Reid D, Harding R, et al. Increased vascular endothelial growth factor and receptors: relationship to angiogenesis in asthma. Am J Respir Crit Care Med. 2006;173(11):1201–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Lee KY, Lee KS, Park SJ, Kim SR, Min KH, Choe YH, et al. Clinical significance of plasma and serum vascular endothelial growth factor in asthma. J Asthma. 2008;45(9):735–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Lee HY, Min KH, Lee SM, Lee JE, Rhee CK. Clinical significance of serum vascular endothelial growth factor in young male asthma patients. Korean J Intern Med. 2017;32(2):295–301.PubMedCrossRefGoogle Scholar
  79. 79.
    Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Choe YH, et al. Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis. Am J Respir Crit Care Med. 2008;178(8):787–97.PubMedCrossRefGoogle Scholar
  80. 80.
    Lee KS, Park SJ, Kim SR, Min KH, Lee KY, Choe YH, et al. Inhibition of VEGF blocks TGF-beta1 production through a PI3K/Akt signalling pathway. Eur Respir J. 2008;31(3):523–31.PubMedCrossRefGoogle Scholar
  81. 81.
    Park SJ, Lee KS, Lee SJ, Kim SR, Park SY, Jeon MS, et al. L-2-Oxothiazolidine-4-carboxylic acid or α-lipoic acid attenuates airway remodeling: involvement of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF). Int J Mol Sci. 2012;13(7):7915–37.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Marwick JA, Caramori G, Casolari P, Mazzoni F, Kirkham PA, Adcock IM, et al. A role for phosphoinositol 3-kinase δ in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2010;125(5):1146–53.PubMedCrossRefGoogle Scholar
  83. 83.
    Kim SR, Lee KS, Park HS, Park SJ, Min KH, Moon H, et al. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40(10):2858–69.PubMedCrossRefGoogle Scholar
  84. 84.
    Lee KS, Park SJ, Kim SR, Min KH, Jin SM, Puri KD, et al. Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma. J Allergy Clin Immunol. 2006;118(2):403–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Carmichael J, Paterson IC, Diaz P, Crompton GK, Kay AB, Grant IW. Corticosteroid resistance in asthma. Br Med J. 1981;282(6274):1419–22.CrossRefGoogle Scholar
  86. 86.
    Hakonarson H, Bjornsdottir US, Halapi E, Bradfield J, Zink F, Mouy M, et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci U S A. 2005;102(41):14789–94.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Donn R, Berry A, Stevens A, Farrow S, Betts J, Stevens R, et al. Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII. FASEB J. 2007;21(2):402–14.PubMedCrossRefGoogle Scholar
  88. 88.
    Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365(13):1173–83.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, et al. Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J Clin Endocrinol Metab. 2006;91(7):2800–3.PubMedCrossRefGoogle Scholar
  90. 90.
    Weigel NL, Moore NL. Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol. 2007;21(10):2311–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, et al. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One. 2012;7(7):e41582.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor function via phosphorylation. Ann N Y Acad Sci. 2004;1024:86–101.PubMedCrossRefGoogle Scholar
  93. 93.
    Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med. 2006;203(8):1883–9.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Bhavsar P, Hew M, Khorasani N, Alfonso T, Barnes PJ, Adcock I, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared to non-severe asthma. Thorax. 2008;63(9):784–90.PubMedCrossRefGoogle Scholar
  95. 95.
    Kobayashi Y, Mercado N, Barnes PJ, Ito K. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS One. 2011;6(12):e27627.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Li LB, Goleva E, Hall CF, Ou LS, Leung DY. Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol. 2004;114(5):1059–69.PubMedCrossRefGoogle Scholar
  97. 97.
    Li JJ, Wang W, Baines KJ, Bowden NA, Hansbro PM, Gibson PG, et al. IL-27/IFN-gamma induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J Immunol. 2010;185(7):4401–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Galigniana MD, Piwien-Pilipuk G, Assreuy J. Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol. 1999;55(2):317–23.PubMedGoogle Scholar
  99. 99.
    Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905–17.PubMedCrossRefGoogle Scholar
  100. 100.
    Oakley RH, Cidlowski JA. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem. 2011;286(5):3177–84.PubMedCrossRefGoogle Scholar
  101. 101.
    Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. 1997;186(9):1567–74.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. 1999;274(39):27857–66.PubMedCrossRefGoogle Scholar
  103. 103.
    Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173(6):607–16.PubMedCrossRefGoogle Scholar
  104. 104.
    DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol. 2002;81(2):103–22.PubMedCrossRefGoogle Scholar
  105. 105.
    Vazquez-Tello A, Semlali A, Chakir J, Martin JG, Leung DY, Eidelman DH, et al. Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clin Exp Allergy. 2010;40(9):1312–22.PubMedCrossRefGoogle Scholar
  106. 106.
    Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci U S A. 2001;98(12):6865–70.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Salem S, Harris T, Mok JS, Li MY, Keenan CR, Schuliga MJ, Stewart AG. Transforming growth factor-b impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. Br J Pharmacol. 2012;166(7):2036–48.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Adcock IM, Lane SJ, Brown CA, Lee TH, Barnes PJ. Abnormal glucocorticoid receptor/AP-1 interaction in steroid resistant asthma. J Exp Med. 1995;182(6):1951–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Loke TK, Mallett KH, Ratoff J, O’Connor BJ, Ying S, Meng Q, et al. Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol. 2006;118(2):368–75.PubMedCrossRefGoogle Scholar
  110. 110.
    Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest. 1998;102(12):2156–64.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Goleva E, Kisich KO, Leung DY. A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance. J Immunol. 2002;169(10):5934–40.PubMedCrossRefGoogle Scholar
  112. 112.
    Bhandare R, Damera G, Banerjee A, Flammer JR, Keslacy S, Rogatsky I, et al. Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural cells. Am J Respir Cell Mol Biol. 2010;42(1):9–15.PubMedCrossRefGoogle Scholar
  113. 113.
    Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest. 2006;129(1):151–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174(2):134–41.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Murahidy A, Ito M, Adcock IM, Barnes PJ, Ito K. Reduction is histone deacetylase expression and activity in smoking asthmatics: a mechanism of steroid resistance. Proc Am Thorac Soc. 2005;2:A889.Google Scholar
  116. 116.
    To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, et al. Targeting phosphoinositide-3-kinase-d with theophylline reverses corticosteroid insensitivity in COPD. Am J Respir Crit Care Med. 2010;182(7):897–904.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008;181(6):4089–97.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Hawrylowicz CM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med. 2005;202(11):1459–63.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid resistant asthma patients. J Clin Invest. 2006;116(1):146–55.PubMedCrossRefGoogle Scholar
  120. 120.
    Wu W, Bleecker E, Moore W, Busse WW, Castro M, Chung KF, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol. 2014;133(5):1280–8.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB, Holguin F, et al. Prostaglandin D2 pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013;131(6):1504–12.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Modena BD, Tedrow JR, Milosevic J, Bleecker ER, Meyers DA, Wu W, et al. Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways. Am J Respir Crit Care Med. 2014;190(12):1363–72.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119(2):405–13.PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J. 2003;22(3):470–7.CrossRefGoogle Scholar
  126. 126.
    Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46(5):1308–21.PubMedCrossRefGoogle Scholar
  127. 127.
    Holgate ST. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches? J Allergy Clin Immunol. 2011;128(3):495–505.PubMedCrossRefGoogle Scholar
  128. 128.
    Ray A, Raundhal M, Oriss TB, Ray P, Wenzel SE. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394–403.PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997;272(34):21597–603.PubMedCrossRefGoogle Scholar
  130. 130.
    Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89(4):587–96.PubMedCrossRefGoogle Scholar
  131. 131.
    Zhang DH, Yang L, Cohn L, Parkyn L, Homer R, Ray P, et al. Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity. 1999;11(4):473–82.PubMedCrossRefGoogle Scholar
  132. 132.
    Nakamura Y, Ghaffar O, Olivenstein R, Taha RA, Soussi-Gounni A, Zhang DH, et al. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol. 1999;103(2 Pt 1):215–22.PubMedCrossRefGoogle Scholar
  133. 133.
    Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5(11):1157–65.PubMedCrossRefGoogle Scholar
  134. 134.
    Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J, Trudeau J, et al. High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015;125(8):3037–50.PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Chiba Y, Todoroki M, Nishida Y, Tanabe M, Misawa M. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am J Respir Cell Mol Biol. 2009;41(5):516–24.PubMedCrossRefGoogle Scholar
  136. 136.
    Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A. 2007;104(40):15858–63.PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–98.PubMedCrossRefGoogle Scholar
  138. 138.
    Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455–66.PubMedCrossRefGoogle Scholar
  139. 139.
    Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370(9596):1422–31.PubMedCrossRefGoogle Scholar
  140. 140.
    Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM, Kappeler D, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015;372(21):1987–95.PubMedCrossRefGoogle Scholar
  141. 141.
    Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804–11.PubMedCrossRefGoogle Scholar
  142. 142.
    Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71.PubMedCrossRefGoogle Scholar
  143. 143.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84.PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.PubMedCrossRefGoogle Scholar
  145. 145.
    Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207.PubMedCrossRefGoogle Scholar
  146. 146.
    Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2(11):879–90.PubMedCrossRefGoogle Scholar
  147. 147.
    Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.PubMedCrossRefGoogle Scholar
  148. 148.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93.PubMedCrossRefGoogle Scholar
  149. 149.
    Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184(10):1125–32.PubMedCrossRefGoogle Scholar
  150. 150.
    Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–8.PubMedCrossRefGoogle Scholar
  151. 151.
    Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy. 2012;42(1):38–48.PubMedCrossRefGoogle Scholar
  152. 152.
    Pettipher R, Hunter MG, Perkins CM, Collins LP, Lewis T, Baillet M, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223–32.PubMedCrossRefGoogle Scholar
  153. 153.
    Erpenbeck VJ, Popov TA, Miller SD, Weinstein SF, Spector S, Magnusson B, et al. QAW309 (fevipiprant) improves lung function and control of asthma symptoms in patients with more severe air flow limitation: a proof-of-concept study. Eur Respir J. 2015;46(suppl 59):PA2125.Google Scholar
  154. 154.
    Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370(22):2102–10.PubMedCrossRefGoogle Scholar
  155. 155.
    Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66.PubMedCrossRefGoogle Scholar
  156. 156.
    Holtzman MJ, Byers DE, Alexander-Brett J, Wang X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol. 2014;14(10):686–98.PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Bernink JH, Germar K, Spits H. The role of ILC2 in pathology of type 2 inflammatory diseases. Curr Opin Immunol. 2014;31:115–20.PubMedCrossRefGoogle Scholar
  158. 158.
    Martinez-Gonzalez I, Steer CA, Takei F. Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 2015;36(3):189–95.PubMedCrossRefGoogle Scholar
  159. 159.
    Lloyd CM, Saglani S. Epithelial cytokines and pulmonary allergic inflammation. Curr Opin Immunol. 2015;34:52–8.PubMedCrossRefGoogle Scholar
  160. 160.
    Chang JE, Doherty TA, Baum R, Broide D. Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J Allergy Clin Immunol. 2014;133(3):899–901.PubMedCrossRefGoogle Scholar
  161. 161.
    Xue L, Salimi M, Panse I, Mjösberg JM, McKenzie AN, Spits H, et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol. 2014;133(4):1184–94.PubMedCentralPubMedCrossRefGoogle Scholar
  162. 162.
    Halim TY, Krauss RH, Sun AC, Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity. 2012;36(3):451–63.PubMedCrossRefGoogle Scholar
  163. 163.
    Chustz RT, Nagarkar DR, Poposki JA, Favoreto S Jr, Avila PC, Schleimer RP, et al. Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2011;45(1):145–53.PubMedCrossRefGoogle Scholar
  164. 164.
    Hsu J, Lanza DC, Kennedy DW. Antimicrobial resistance in bacterial chronic sinusitis. Am J Rhinol. 1998;12(4):243–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Jackson DJ, Makrinioti H, Rana BM, Shamji BW, Trujillo-Torralbo MB, Footitt J, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med. 2014;190(12):1373–82.PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Nagakumar P, Denney L, Fleming L, Bush A, Lloyd CM, Saglani S. Type 2 innate lymphoid cells in induced sputum from children with severe asthma. J Allergy Clin Immunol. 2016;137(2):624–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA, et al. National Heart, Lung, and Blood Institute Severe Asthma Research Program. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010;181(10):1033–41.PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612–9.PubMedCentralPubMedCrossRefGoogle Scholar
  169. 169.
    Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315–23.PubMedCrossRefGoogle Scholar
  170. 170.
    Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113(1):101–8.PubMedCrossRefGoogle Scholar
  171. 171.
    Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. 2011;128(3):508–15.PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Poon AH, Eidelman DH, Martin JG, Laprise C, Hamid Q. Pathogenesis of severe asthma. Clin Exp Allergy. 2012;42(5):625–37.PubMedCrossRefGoogle Scholar
  173. 173.
    Ordoñez CL, Shaughnessy TE, Matthay MA, Fahy JV. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biologic significance. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1185–90.PubMedCrossRefGoogle Scholar
  174. 174.
    Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007;132(6):1871–5.PubMedCrossRefGoogle Scholar
  175. 175.
    Woodruff PG, Khashayar R, Lazarus SC, Janson S, Avila P, Boushey HA, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol. 2001;108(5):753–8.PubMedCrossRefGoogle Scholar
  176. 176.
    Al-Ramli W, Préfontaine D, Chouiali F, Martin JG, Olivenstein R, Lemière C, et al. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.PubMedCrossRefGoogle Scholar
  177. 177.
    Pepe C, Foley S, Shannon J, Lemiere C, Olivenstein R, Ernst P, Ludwig MS, Martin JG, Hamid Q. Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol. 2005;116(3):544–9.PubMedCrossRefGoogle Scholar
  178. 178.
    Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemiere C, Foley S, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest. 2008;133(2):420–6.PubMedCrossRefGoogle Scholar
  179. 179.
    Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.PubMedCrossRefGoogle Scholar
  180. 180.
    Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.PubMedCentralPubMedCrossRefGoogle Scholar
  181. 181.
    Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J, et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674–7.PubMedCentralPubMedCrossRefGoogle Scholar
  182. 182.
    Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J, et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14(9):1583–9.PubMedCrossRefGoogle Scholar
  183. 183.
    Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41.PubMedCrossRefGoogle Scholar
  184. 184.
    Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y, et al. NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy. 2011;66(8):1047–57.PubMedCrossRefGoogle Scholar
  185. 185.
    Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol. 2008;181(6):3755–9.PubMedCrossRefGoogle Scholar
  186. 186.
    Gregory LG, Lloyd CM. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 2011;32(9):402–11.PubMedCentralPubMedCrossRefGoogle Scholar
  187. 187.
    Kim SR, Kim DI, Kim SH, Lee H, Lee KS, Cho SH, et al. NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation. Cell Death Dis. 2014;5:e1498.PubMedCentralPubMedCrossRefGoogle Scholar
  188. 188.
    Kim RY, Pinkerton JW, Essilfie AT, Robertson AA, Baines KJ, Brown AC, et al. Role for NLRP3 inflammasome-mediated, IL-1β -dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med. 2017;196(3):283-97.Google Scholar
  189. 189.
    Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017;49(2):pii:1602135. doi: 10.1183/13993003.02135–2016.CrossRefGoogle Scholar
  190. 190.
    Kips JC, Tavernier J, Pauwels RA. Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am Rev Respir Dis. 1992;145(2 Pt 1):332–6.PubMedCrossRefGoogle Scholar
  191. 191.
    Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354(7):697–708.PubMedCrossRefGoogle Scholar
  192. 192.
    Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax. 2008;63(7):584–91.PubMedCrossRefGoogle Scholar
  193. 193.
    Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlén SE, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549–58.PubMedCrossRefGoogle Scholar
  194. 194.
    Roussel L, Houle F, Chan C, Yao Y, Bérubé J, Olivenstein R, et al. IL-17 promotes p38 MAPK dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J Immunol. 2010;184(8):4531–7.PubMedCrossRefGoogle Scholar
  195. 195.
    Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143(2):494–501.PubMedCrossRefGoogle Scholar
  196. 196.
    Kim SR, Lee KS, Park SJ, Min KH, Lee KY, Choe YH, et al. PTEN down-regulates IL-17 expression in a murine model of toluene diisocyanate-induced airway disease. J Immunol. 2007;179(10):6820–9.PubMedCrossRefGoogle Scholar
  197. 197.
    Park SJ, Lee KS, Kim SR, Min KH, Choe YH, Moon H, et al. Peroxisome proliferator-activated receptor gamma agonist down-regulates IL-17 expression in a murine model of allergic airway inflammation. J Immunol. 2009;183(5):3259–67.PubMedCrossRefGoogle Scholar
  198. 198.
    Kim SR, Kim DI, Kang MR, Lee KS, Park SY, Jeong JS, et al. Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor-κB activation. J Allergy Clin Immunol. 2013;132(6):1397–408.PubMedCrossRefGoogle Scholar
  199. 199.
    Kim SR, Lee YC. Endoplasmic reticulum stress and the related signaling networks in severe asthma. Allergy Asthma Immunol Res. 2015;7(2):106–17.PubMedCrossRefGoogle Scholar
  200. 200.
    Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol. 2011;12(7):597–606.PubMedCrossRefGoogle Scholar
  201. 201.
    Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.PubMedCrossRefGoogle Scholar
  202. 202.
    Yu M, Eckart MR, Morgan AA, Mukai K, Butte AJ, Tsai M, et al. Identification of an IFN-gamma/mast cell axis in a mouse model of chronic asthma. J Clin Invest. 2011;121(8):3133–43.PubMedCentralPubMedCrossRefGoogle Scholar
  203. 203.
    Yoshida M, Leigh R, Matsumoto K, Wattie J, Ellis R, O’Byrne PM, et al. Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice. Am J Respir Crit Care Med. 2002;166(4):451–6.PubMedCrossRefGoogle Scholar
  204. 204.
    Yang M, Kumar RK, Foster PS. Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFN-gamma and TLR4/MyD88 pathways. J Immunol. 2009;182(8):5107–15.PubMedCrossRefGoogle Scholar
  205. 205.
    Dahlberg PE, Busse WW. Is intrinsic asthma synonymous with infection? Clin Exp Allergy. 2009;39(9):1324–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Ebensen T, Schulze K, Riese P, Link C, Morr M, Guzman CA. The bacterial second messenger cyclic diGMP exhibits potent adjuvant properties. Vaccine. 2007;25(8):1464–9.PubMedCrossRefGoogle Scholar
  207. 207.
    Nakanishi K, Tsutsui H, Yoshimoto T. Importance of IL-18-induced super Th1 cells for the development of allergic inflammation. Allergol Int. 2010;59(2):137–41.PubMedCrossRefGoogle Scholar
  208. 208.
    Voraphani N, Gladwin MT, Contreras AU, Kaminski N, Tedrow JR, Milosevic J, et al. An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma. Mucosal Immunol. 2014;7(5):1175–85.PubMedCentralPubMedCrossRefGoogle Scholar
  209. 209.
    Yamagata S, Tomita K, Sato R, Niwa A, Higashino H, Tohda Y. Interleukin-18-deficient mice exhibit diminished chronic inflammation and airway remodelling in ovalbumin-induced asthma model. Clin Exp Immunol. 2008;154(3):295–304.PubMedCentralPubMedCrossRefGoogle Scholar
  210. 210.
    Jin FY, Nathan C, Radzioch D, Ding A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell. 1997;88(3):417–26.PubMedCrossRefGoogle Scholar
  211. 211.
    Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H. T al. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med. 2000;6(10):1147–53.PubMedCrossRefGoogle Scholar
  212. 212.
    Makinde T, Murphy RF, Agrawal DK. The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol. 2007;85(5):348–56.PubMedCrossRefGoogle Scholar
  213. 213.
    Cockcroft DW, Davis BE. Airway hyperresponsiveness as a determinant of the early asthmatic response to inhaled allergen. J Asthma. 2006;43(3):175–8.PubMedCrossRefGoogle Scholar
  214. 214.
    van Anken E, Braakman I. Versatility of the endoplasmic reticulum protein folding factory. Crit Rev Biochem Mol Biol. 2005;40(4):191–228.PubMedCrossRefGoogle Scholar
  215. 215.
    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29.PubMedCrossRefGoogle Scholar
  216. 216.
    Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–30.PubMedCrossRefGoogle Scholar
  217. 217.
    Zhang K, Kaufman RJ. From endoplasmic reticulum stress to the inflammatory response. Nature. 2008;454(7203):455–62.PubMedCentralPubMedCrossRefGoogle Scholar
  218. 218.
    Malhotra D, Thimmulappa R, Vij N, Navas-Acien A, Sussan T, Merali S, et al. Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease: the role of Nrf2-regulated proteasomal activity. Am J Respir Crit Care Med. 2009;180(12):1196–207.PubMedCentralPubMedCrossRefGoogle Scholar
  219. 219.
    Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178(8):838–46.PubMedCentralPubMedCrossRefGoogle Scholar
  220. 220.
    Kim HJ, Jeong JS, Kim SR, Park SY, Chae HJ, Lee YC, et al. Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway. Sci Rep. 2013;3:1142.PubMedCentralPubMedCrossRefGoogle Scholar
  221. 221.
    Guo Q, Li H, Liu J, Xu L, Yang L, Sun Z, et al. Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma. J Asthma. 2017;54(2):125–33.PubMedCrossRefGoogle Scholar
  222. 222.
    Lee KS, Jeong JS, Kim SR, Cho SH, Kolliputi N, Ko YH, et al. Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress. Thorax. 2016;71(1):52–63.PubMedCrossRefGoogle Scholar
  223. 223.
    Cabanski M, Steinmüller M, Marsh LM, Surdziel E, Seeger W, Lohmeyer J. PKR regulates TLR2/TLR4-dependent signaling in murine alveolar macrophages. Am J Respir Cell Mol Biol. 2008;38(1):26–31.PubMedCrossRefGoogle Scholar
  224. 224.
    Kim SR, Lee YC, Kim DI, Park HJ. Effects of PKR inhibitor on poly (I:C)-induced exacerbation of severe asthma. Eur Respir J. 2016;48(suppl 60):PA1099.Google Scholar
  225. 225.
    Emelyanov VV. Mitochondrial connection to the origin of the eukaryotic cell. Eur J Biochem. 2003;270(8):1599–618.PubMedCrossRefGoogle Scholar
  226. 226.
    Cloonan SM, Choi AM. Mitochondria: commanders of innate immunity and disease? Curr Opin Immunol. 2012;24(1):32–40.PubMedCrossRefGoogle Scholar
  227. 227.
    Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, et al. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One. 2011;6(1):e16038.PubMedCentralPubMedCrossRefGoogle Scholar
  228. 228.
    d’Avila JC, Santiago AP, Amâncio RT, Galina A, Oliveira MF, Bozza FA. Sepsis induces brain mitochondrial dysfunction. Crit Care Med. 2008;36(6):1925–32.PubMedCrossRefGoogle Scholar
  229. 229.
    Archer SL. Mitochondrial dynamics–mitochondrial fission and fusion in human diseases. N Engl J Med. 2013;369(23):2236–51.PubMedCrossRefGoogle Scholar
  230. 230.
    Aravamudan B, Thompson MA, Pabelick CM, Prakash YS. Mitochondria in lung diseases. Expert Rev Respir Med. 2013;7(6):631–46.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Respiratory Medicine and Allergy, Department of Internal MedicineChonbuk National University Medical SchoolJeonjuSouth Korea

Personalised recommendations