Current Allergy and Asthma Reports

, Volume 7, Issue 1, pp 27–32 | Cite as

Etiology of exercise-induced asthma: Physical stress-induced transcription

  • Thomas Hilberg


Exercise-induced asthma (EIA) occurs with a high prevalence in both asthmatic and nonasthmatic individuals. Although understanding of the functional genomics (proteomics) in sports medicine remains limited, this review focuses on immunologic changes as reflected in transcriptional regulation in respect to EIA. Studies demonstrated that leukotrienes play a significant role in EIA. Exercise increases the distribution of leukotrienes and influences the leukotriene transcription pathway; it could be shown that the genes ALOX5 and ALOX5AP encoding for 5-lipooxygenase (5-LO) and 5-lipoxygenase—activating protein (FLAP) as well as activators for 5-LO, p38 mitogen-activated protein kinase (MAPK), and others, are enhanced after exercise in healthy subjects. Possibly EIA is triggered via leukotriene release if a predisposition or other conditions (eg, epithelial injury and repair) are present. Furthermore, exercise influences transcription factors such as nuclear factor-kappa B (NF-κB), activator protein-1 (AP1), cytokines, and chemokines and promotes cellular responses linked to EIA, which are possibly able to modify further the incidence or the severity of EIA.


Asthma Mast Cell Allergy Clin Immunol Montelukast Respir Crit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Hallstrand TS, Moody MW, Wurfel MM, et al.: Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2005, 172:679–686.PubMedCrossRefGoogle Scholar
  2. 2.
    Rundell KW, Jenkinson DM: Exercise-induced bronchospasm in the elite athlete. Sports Med 2002, 32:583–600.PubMedCrossRefGoogle Scholar
  3. 3.
    Storms WW: Review of exercise-induced asthma. Med Sci Sports Exerc 2003, 35:1464–1470.PubMedCrossRefGoogle Scholar
  4. 4.
    Anderson SD, Kippelen P: Exercise-induced bronchoconstriction: pathogenesis. Curr Allergy Asthma Rep 2005, 5:116–122.PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson SD: How does exercise cause asthma attacks? Curr Opin Allergy Clin Immunol 2006, 6:37–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Freed AN, Davis MS: Hyperventilation with dry air increases airway surface fluid osm olality in canine peripheral airways. Am J Respir Crit Care Med 1999, 159:1101–1107.PubMedGoogle Scholar
  7. 7.
    Ingenito EP, Pliss LB, Ingram RH Jr, Pichurko BM: Bronchoalveolar lavage cell and mediator responses to hyperpnea-induced bronchoconstriction in the guinea pig. Am Rev Respir Dis 1990, 141:1162–1166.PubMedGoogle Scholar
  8. 8.
    Omori C, Tagari P, Freed AN: Eicosanoids modulate hyperpnea-induced bronchoconstriction in canine peripheral airways. J Appl Physiol 1996, 81:1255–1263.PubMedGoogle Scholar
  9. 9.
    Jarjour NN, Calhoun WJ: Exercise-induced asthma is not associated with mast cell activation or airway inflammation. J Allergy Clin Immunol 1992, 89:60–68.PubMedCrossRefGoogle Scholar
  10. 10.
    Broide DH, Eisman S, Ramsdell JW, et al.: Airway levels of mast cell-derived mediators in exercise-induced asthma. Am Rev Respir Dis 1990, 141:563–568.PubMedGoogle Scholar
  11. 11.
    Mickleborough TD, Murray RL, Ionescu AA, Lindley MR: Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003, 168:1181–1189.PubMedCrossRefGoogle Scholar
  12. 12.
    Reiss TF, Hill JB, Harman E, et al.: Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997, 52:1030–1035.PubMedGoogle Scholar
  13. 13.
    Anderson SD, Brannan JD: Exercise-induced asthma: is there still a case for histamine? J Allergy Clin Immunol 2002, 109:771–773.PubMedCrossRefGoogle Scholar
  14. 14.
    Leff JA, Busse WW, Pearlman D, et al.: Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998, 339:147–152.PubMedCrossRefGoogle Scholar
  15. 15.
    Meltzer SS, Hasday JD, Cohn J, Bleecker ER: Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am J Respir Crit Care Med 1996, 153:931–935.PubMedGoogle Scholar
  16. 16.
    Dahlen B, Roquet A, Inman MD, et al.: Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction. J Allergy Clin Immunol 2002, 109:789–793.PubMedCrossRefGoogle Scholar
  17. 17.
    Caillaud C, Le Creff C, Legros P, Denjean A: Strenuous exercise increases plasmatic and urinary leukotriene E4 in cyclists. Can J Appl Physiol 2003, 28:793–806.PubMedGoogle Scholar
  18. 18.
    Peters-Golden M: Cell biology of the 5-lipoxygenase pathway. Am J Respir Crit Care Med 1998, 157:S227–231.Google Scholar
  19. 19.
    Werz O: 5-lipoxygenase: cellular biology and molecular pharmacology. Curr Drug Targets Inflamm Allergy 2002, 1:23–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Koshino T, Takano S, Houjo T, et al.: Expression of 5-lipoxygenase and 5-lipoxygenase-activating protein mRNAs in the peripheral blood leukocytes of asthmatics. Biochem Biophys Res Commun 1998, 247:510–513.PubMedCrossRefGoogle Scholar
  21. 21.
    Cowburn AS, Holgate ST, Sampson AP: IL-5 increases expression of 5-lipoxygenase-activating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J Immunol 1999, 163:456–465.PubMedGoogle Scholar
  22. 22.
    Hilberg T, Deigner HP, Moller E, et al.: Transcription in response to physical stress-clues to the molecular mechanisms of exercise-induced asthma. FASEB J 2005, 11:1492–1494.Google Scholar
  23. 23.
    Aoi W, Ichiishi E, Sakamoto N, et al.: Effect of exercise on hepatic gene expression in rats: a microarray analysis. Life Sci 2004, 75:3117–3128.PubMedCrossRefGoogle Scholar
  24. 24.
    Long YC, Widegren U, Zierath JR: Exercise-induced mitogen-activated protein kinase signalling in skeletal muscle. Proc Nutr Soc 2004, 63:227–232.PubMedCrossRefGoogle Scholar
  25. 25.
    Chan MH, McGee SL, Watt MJ, et al.: Altering dietary nutrient intake that reduces glycogen content leads to phosphorylation of nuclear p38 MAP kinase in human skeletal muscle: association with IL-6 gene transcription during contraction. FASEB J 2004, 18:1785–1787.PubMedGoogle Scholar
  26. 26.
    Widegren U, Ryder JW, Zierath JR: Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contraction. Acta Physiol Scand 2001, 172:227–238.PubMedCrossRefGoogle Scholar
  27. 27.
    Kumar S, Boehm J, Lee JC: p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003, 2:717–726.PubMedCrossRefGoogle Scholar
  28. 28.
    Adams JL, Badger AM, Kumar S, Lee JC: p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines. Prog Med Chem 2001, 38:1–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Barnes PJ: Transcription factors in airway diseases. Lab Invest 2006, 86:867–872.PubMedCrossRefGoogle Scholar
  30. 30.
    Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997, 336:1066–1071.PubMedCrossRefGoogle Scholar
  31. 31.
    Kumar A, Takada Y, Boriek AM, Aggarwal BB: Nuclear factor-kappaB: its role in health and disease. J Mol Med 2004, 82:434–438.PubMedCrossRefGoogle Scholar
  32. 32.
    Ji LL, Gomez-Cabrera MC, Steinhafel N, Vina J: Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle. FASEB J 2004, 18:1499–1506.PubMedCrossRefGoogle Scholar
  33. 33.
    Vider J, Laaksonen DE, Kilk A, et al.: Physical exercise induces activation of NF-kappaB in human peripheral blood lymphocytes. Antioxid Redox Signal 2001, 3:1131–1137.PubMedCrossRefGoogle Scholar
  34. 34.
    Weiss C, Bierhaus A, Kinscherf R, et al.: Tissue factor-dependent pathway is not involved in exercise-induced formation of thrombin and fibrin. J Appl Physiol 2002, 92:211–218.PubMedGoogle Scholar
  35. 35.
    Popescu FD: New asthma drugs acting on gene expression. J Cell Mol Med 2003, 7:475–486.PubMedCrossRefGoogle Scholar
  36. 36.
    Desmet C, Gosset P, Henry E, et al.: Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med 2005, 172:671–678.PubMedCrossRefGoogle Scholar
  37. 37.
    Hollander J, Fiebig R, Gore M, et al.: Superoxide dismutase gene expression is activated by a single bout of exercise in rat skeletal muscle. Pflugers Arch 2001, 442:426–434.PubMedCrossRefGoogle Scholar
  38. 38.
    Barnes PJ: Drugs for asthma. Br J Pharmacol 2006, 147(Suppl 1):S297–S303.PubMedCrossRefGoogle Scholar
  39. 39.
    Kips JC, Tournoy KG, Pauwels RA: New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J 2001, 17:499–506.PubMedCrossRefGoogle Scholar
  40. 40.
    Wynn TA: IL-13 effector functions. Annu Rev Immunol 2003, 21:425–456.PubMedCrossRefGoogle Scholar
  41. 41.
    Chavez J, Young HW, Corry DB, Lieberman MW: Interactions between leukotriene C4 and interleukin 13 signaling pathways in a mouse model of airway disease. Arch Pathol Lab Med 2006, 130:440–446.PubMedGoogle Scholar
  42. 42.
    Pedersen BK, Hoffman-Goetz L: Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev 2000, 80:1055–1081.PubMedGoogle Scholar
  43. 43.
    Suzuki K, Nakaji S, Kurakake S, et al.: Exhaustive exercise and type-1/type-2 cytokine balance with special focus on interleukin-12 p40/p70. Exerc Immunol Rev 2003, 9:48–57.PubMedGoogle Scholar
  44. 44.
    Peake JM, Suzuki K, Hordern M, et al.: Plasma cytokine changes in relation to exercise intensity and muscle damage. Eur J Appl Physiol 2005, 95:514–521.PubMedCrossRefGoogle Scholar
  45. 45.
    Tahan F, Karaaslan C, Aslan A, et al.: The role of chemokines in exercise-induced bronchoconstriction in asthma. Ann Allergy Asthma Immunol 2006, 96:819–825.PubMedCrossRefGoogle Scholar
  46. 46.
    Furuichi S, Hashimoto S, Gon Y, et al.: p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase regulate interleukin-8 and RANTES production in hyperosmolarity stimulated human bronchial epithelial cells. Respirology 2002, 7:193–200.PubMedCrossRefGoogle Scholar
  47. 47.
    Hashimoto S, Gon Y, Matsumoto K, et al.: Inhaltant corticosteroids inhibit hypersomolarity-induced, and cooling and rewarming-induced interleukin-8 and RANTES production by human bronchial epithelial cells. Am J Respir Crit Care Med 2000, 162:1075–1080.PubMedGoogle Scholar
  48. 48.
    Mucci P, Durand F, Lebel B, et al.: Interleukins 1-beta,-8, and histamine increases in highly trained, exercising athletes. Med Sci Sports Exerc 2000, 32:1094–1100.PubMedCrossRefGoogle Scholar
  49. 49.
    Sampson AP: The role of eosinophils and neutrophils in inflammation. Clin Exp Allergy 2000, 30(Suppl 1):22–27.PubMedCrossRefGoogle Scholar
  50. 50.
    Holgate ST: The role of mast cells and basophils in inflammation. Clin Exp Allergy 2000, 30(Suppl 1):28–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Thomas Hilberg
    • 1
  1. 1.Department of Sports MedicineFriedrich-Schiller-University, JenaJenaGermany

Personalised recommendations