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Pathogenesis of asthma

Mark Liu, MD
Section Editor
Bruce S Bochner, MD
Deputy Editor
Helen Hollingsworth, MD


The "classic" signs and symptoms of asthma are intermittent dyspnea, cough, and wheezing. This well-recognized syndrome is characterized by variable airflow limitation and by airway hyperresponsiveness, which represents an exaggerated contractile response of the airways to a variety of stimuli.

Atopy, or the genetic predisposition to develop specific IgE antibodies directed against common environmental allergens, is the strongest identifiable risk factor for the development of asthma [1]. While the association of asthma and atopy is undisputed, the pathways by which atopy is expressed as clinical asthma and by which asthma occurs in the absence of atopy are not as clearly defined [1]. Intrinsic abnormalities in airway smooth muscle function, airway remodeling in response to injury or inflammation, and interactions between epithelial and mesenchymal cells appear to modulate and add to the effects of airway inflammation in creating the clinical presentation of asthma. Different phenotypes of asthma that can be defined clinically reinforce the notion that asthma is really a syndrome with multiple underlying mechanisms [2].

The inflammatory, physiologic, and structural factors that contribute to the pathogenesis of asthma will be reviewed here, focusing on aspects that aid in the understanding of the clinical presentation of asthma and its treatment.

Discussions of the genetics, clinical risk factors (eg, atopy, allergen exposure, viral illness, gender, and smoking), diagnosis, and management of asthma are provided separately. (See "Genetics of asthma" and "Risk factors for asthma" and "Diagnosis of asthma in adolescents and adults" and "Asthma in children younger than 12 years: Initial evaluation and diagnosis".)


Airway biopsies obtained by bronchoscopy have demonstrated that inflammation in asthma generally involves the same cells that play prominent roles in the allergic response in the nasal passages and skin, whether the individual is atopic or not. This supports the belief that the consequences of mast cell activation, mediated by a variety of cells, cytokines, and other mediators, are key to the development of clinical asthma. (See "Pathogenesis of allergic rhinitis (rhinosinusitis)".)

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Literature review current through: Nov 2017. | This topic last updated: May 31, 2016.
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  1. National Asthma Education and Prevention Program: Expert panel report II: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute (NIH publication no. 97-4051), Bethesda, MD 1997.
  2. Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181:315.
  3. Liu MC, Hubbard WC, Proud D, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes. Am Rev Respir Dis 1991; 144:51.
  4. Riccio MM, Proud D. Evidence that enhanced nasal reactivity to bradykinin in patients with symptomatic allergy is mediated by neural reflexes. J Allergy Clin Immunol 1996; 97:1252.
  5. Peebles RS Jr, Permutt S, Togias A. Rapid reversibility of the allergen-induced pulmonary late-phase reaction by an intravenous beta2-agonist. J Appl Physiol (1985) 1998; 84:1500.
  6. Jahnsen FL, Moloney ED, Hogan T, et al. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 2001; 56:823.
  7. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323:1033.
  8. Wong CK, Cheung PF, Ip WK, Lam CW. Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. Am J Respir Cell Mol Biol 2007; 37:85.
  9. Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346:1699.
  10. Nakae S, Ho LH, Yu M, et al. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. J Allergy Clin Immunol 2007; 120:48.
  11. Stewart AG, Tomlinson PR, Fernandes DJ, et al. Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. Am J Respir Cell Mol Biol 1995; 12:110.
  12. Howarth PH, Babu KS, Arshad HS, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60:1012.
  13. Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697.
  14. Robinson DS. The role of the T cell in asthma. J Allergy Clin Immunol 2010; 126:1081.
  15. Mikhak Z, Fukui M, Farsidjani A, et al. Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation. J Allergy Clin Immunol 2009; 123:67.
  16. Xue L, Gyles SL, Wettey FR, et al. Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol 2005; 175:6531.
  17. Gyles SL, Xue L, Townsend ER, et al. A dominant role for chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2+ CD4+ Th2 lymphocytes in response to mast cell supernatants. Immunology 2006; 119:362.
  18. Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999; 103:779.
  19. Ingram JL, Kraft M. IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. J Allergy Clin Immunol 2012; 130:829.
  20. Kips JC, O'Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003; 167:1655.
  21. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176:1062.
  22. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360:985.
  23. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360:973.
  24. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380:651.
  25. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184:1125.
  26. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371:1198.
  27. Castro M, Zangrilli J, Wechsler ME, 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; 3:355.
  28. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189.
  29. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088.
  30. Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 2015; 70:748.
  31. Corren J, Busse W, Meltzer EO, et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med 2010; 181:788.
  32. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368:2455.
  33. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388:31.
  34. Akbari O, Faul JL, Hoyte EG, et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 2006; 354:1117.
  35. Vijayanand P, Seumois G, Pickard C, et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 2007; 356:1410.
  36. Redrup AC, Howard BP, MacGlashan DW Jr, et al. Differential regulation of IL-4 and IL-13 secretion by human basophils: their relationship to histamine release in mixed leukocyte cultures. J Immunol 1998; 160:1957.
  37. Holgate ST. The epithelium takes centre stage in asthma and atopic dermatitis. Trends Immunol 2007; 28:248.
  38. Hammad H, Chieppa M, Perros F, et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 2009; 15:410.
  39. Karta MR, Broide DH, Doherty TA. Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease. Curr Allergy Asthma Rep 2016; 16:8.
  40. Smith SG, Chen R, Kjarsgaard M, 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; 137:75.
  41. Nagakumar P, Denney L, Fleming L, et al. Type 2 innate lymphoid cells in induced sputum from children with severe asthma. J Allergy Clin Immunol 2016; 137:624.
  42. Tunon-De-Lara JM, Redington AE, Bradding P, et al. Dendritic cells in normal and asthmatic airways: expression of the alpha subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI -alpha). Clin Exp Allergy 1996; 26:648.
  43. van Rijt LS, Jung S, Kleinjan A, et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 2005; 201:981.
  44. Wenzel SE, Schwartz LB, Langmack EL, 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; 160:1001.
  45. Wenzel SE, Szefler SJ, Leung DY, et al. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997; 156:737.
  46. Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993; 148:713.
  47. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997; 155:1828.
  48. Roquet A, Dahlén B, Kumlin M, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 1997; 155:1856.
  49. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med 1999; 341:1966.
  50. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90:32.
  51. Djukanović R, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004; 170:583.
  52. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998; 158:1213.
  53. Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol 1996; 98:859.
  54. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356:2144.
  55. Holgate ST, Davies DE, Lackie PM, et al. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol 2000; 105:193.
  56. Zhang S, Smartt H, Holgate ST, Roche WR. Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: an in vitro co-culture model of airway remodeling in asthma. Lab Invest 1999; 79:395.
  57. Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir Cell Mol Biol 2001; 25:385.
  58. Hackett TL, Warner SM, Stefanowicz D, et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med 2009; 180:122.
  59. Puddicombe SM, Polosa R, Richter A, et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000; 14:1362.
  60. Wenzel SE, Balzar S, Cundall M, Chu HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol 2003; 111:1345.
  61. Kassel O, Schmidlin F, Duvernelle C, et al. Human bronchial smooth muscle cells in culture produce stem cell factor. Eur Respir J 1999; 13:951.
  62. Mullings RE, Wilson SJ, Puddicombe SM, et al. Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. J Allergy Clin Immunol 2001; 108:832.
  63. Mitchell HW, Sparrow MP. Increased responsiveness to cholinergic stimulation of small compared to large diameter cartilaginous bronchi. Eur Respir J 1994; 7:298.
  64. Adler A, Cowley EA, Bates JH, Eidelman DH. Airway-parenchymal interdependence after airway contraction in rat lung explants. J Appl Physiol (1985) 1998; 85:231.
  65. Wagner EM, Liu MC, Weinmann GG, et al. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990; 141:584.
  66. Brown RH, Mitzner W. The myth of maximal airway responsiveness in vivo. J Appl Physiol (1985) 1998; 85:2012.
  67. King GG, Carroll JD, Müller NL, et al. Heterogeneity of narrowing in normal and asthmatic airways measured by HRCT. Eur Respir J 2004; 24:211.
  68. de Lange EE, Altes TA, Patrie JT, et al. Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. Chest 2006; 130:1055.
  69. Liu MC, Bleecker ER, Lichtenstein LM, et al. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis 1990; 142:126.
  70. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 1995; 96:2393.
  71. Brown RH, Croisille P, Mudge B, et al. Airway narrowing in healthy humans inhaling methacholine without deep inspirations demonstrated by HRCT. Am J Respir Crit Care Med 2000; 161:1256.
  72. Brown RH, Scichilone N, Mudge B, et al. High-resolution computed tomographic evaluation of airway distensibility and the effects of lung inflation on airway caliber in healthy subjects and individuals with asthma. Am J Respir Crit Care Med 2001; 163:994.
  73. Limb SL, Brown KC, Wood RA, et al. Irreversible lung function deficits in young adults with a history of childhood asthma. J Allergy Clin Immunol 2005; 116:1213.
  74. Brown RH, Pearse DB, Pyrgos G, et al. The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol (1985) 2006; 101:30.
  75. Barbato A, Turato G, Baraldo S, et al. Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med 2006; 174:975.
  76. ten Brinke A, Zwinderman AH, Sterk PJ, et al. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med 2001; 164:744.
  77. Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339:1194.
  78. Grol MH, Gerritsen J, Vonk JM, et al. Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years. A 30-year follow-up study. Am J Respir Crit Care Med 1999; 160:1830.
  79. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964-1999. J Allergy Clin Immunol 2002; 109:189.
  80. Aysola RS, Hoffman EA, Gierada D, et al. Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology. Chest 2008; 134:1183.
  81. Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 2007; 357:1487.