Skip to main content

Advertisement

SpringerLink
Log in

Glucocorticoid-resistant asthma

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Glucocorticoids are currently the most effective anti-inflammatory therapy for asthma. However, a small subset of asthma sufferers do not respond to clinically relevant doses of glucocorticoids and are termed “glucocorticoid resistant.” These patients are characterized by increased bronchial hyperreactivity, lower morning peak expiratory flow rates, and a longer total duration of symptoms. The definition of glucocorticoid resistance is arbitrary, and a dosage and duration of oral glucocorticoid therapy that represent a completely adequate therapeutic trial have yet to be established. For research purposes, glucocorticoid-resistant asthma is defined on the basis of a lack of improvement in airway obstruction (FEV1) following a 2-week course of oral glucocorticoid therapy. Glucocorticoid resistance is associated with in vivo and in vitro alterations in cellular responses to exogenous glucocorticoids. We have implicated abnormal regulation of the activator protein 1 in the molecular mechanism of glucocorticoid resistance, a phenomenon that may be confined to T cells and monocytes. The identification of an alternatively spliced isoform of the glucocorticoid receptor (GRβ) has sparked interest in the functional role of this isoform and its potential involvement in the pathology of glucocorticoid resistance. Alternative therapies for this condition will have to await a better understanding of the mechanisms of glucocorticoid action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Schwartz HJ, Lowell FC, Melby JC: Steroid resistance in bronchial asthma. Ann Intern Med 1968, 69:493–499.

    PubMed  CAS  Google Scholar 

  2. Carmichael J, Paterson IC, Diaz P, et al.: Corticosteroid resistance in chronic asthma. Br Med J (Clin Res Ed) 1981, 282:1419–1422.

    CAS  Google Scholar 

  3. Coman E, Reinus JF: Cyclosporine use in steroid-resistant Crohn’s disease—grasping at new straws? Am J Gastroenterol 1990, 85:758–759.

    PubMed  CAS  Google Scholar 

  4. Curley RK, Holden CA: Steroid-resistant bullous pemphigoid treated with cyclosporin A. Clin Exp Dermatol 1991, 16:68–69.

    Article  PubMed  CAS  Google Scholar 

  5. Dundar S, Ozdemir O, Ozcebe O: Cyclosporin in steroidresistant auto-immune haemolytic anaemia. Acta Haematol 1991, 86:200–202.

    Article  PubMed  CAS  Google Scholar 

  6. Chrousos GP, Renquist D, Brandon D, et al.: Glucocorticoid hormone resistance during primate evolution: receptor-mediated mechanisms. Proc Natl Acad Sci U S A 1982, 79:2036–2040.

    Article  PubMed  CAS  Google Scholar 

  7. Chung KF: Approach to the management of difficult asthma. Eur Respir Rev 2001, 10:69–73. This article summarizes current management issues and the role of various pharmacologic agents in the treatment of this condition. Part of the Task Force Report on therapy-resistant asthma initiated by the European Respiratory Society in 1999.

    Google Scholar 

  8. Woolcock AJ: Corticosteroid-resistant asthma. Definitions. Am J Respir Crit Care Med 1996, 154(2 pt 2):S45-S48.

    PubMed  CAS  Google Scholar 

  9. Hearing SD, Norman M, Smyth C, et al.: Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J Clin Endocrinol Metab 1999, 84:4149–4154.

    Article  PubMed  CAS  Google Scholar 

  10. Corrigan CJ, Brown PH, Barnes NC, et al.: Glucocorticoid resistance in chronic asthma. Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Respir Dis 1991, 144:1026–1032.

    PubMed  CAS  Google Scholar 

  11. Corrigan CJ, Brown PH, Barnes NC, et al.: Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis 1991, 144:1016–1025.

    PubMed  CAS  Google Scholar 

  12. Lane SJ, Lee TH: Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid-resistant bronchial asthma. Am Rev Respir Dis 1991, 143(5 pt 1):1020–1024.

    PubMed  CAS  Google Scholar 

  13. Poznansky MC, Gordon AC, Douglas JG, et al.: Resistance to methylprednisolone in cultures of blood mononuclear cells from glucocorticoid-resistant asthmatic patients. Clin Sci (Lond) 1984, 67:639–645.

    CAS  Google Scholar 

  14. Kay AB, Diaz P, Carmicheal J, Grant IW: Corticosteroidresistant chronic asthma and monocyte complement receptors. Clin Exp Immunol 1981, 44:576–580.

    PubMed  CAS  Google Scholar 

  15. Wilkinson JR, Crea AE, Clark TJ, Lee TH: Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma. J Clin Invest 1989, 84:1930–1941.

    PubMed  CAS  Google Scholar 

  16. Lane SJ, Wilkinson JR, Cochrane GM, et al.: Differential in vitro regulation by glucocorticoids of monocyte-derived cytokine generation in glucocorticoid-resistant bronchial asthma. Am Rev Respir Dis 1993, 147:690–696.

    PubMed  CAS  Google Scholar 

  17. Wilkinson JR, Lane SJ, Lee TH: Effects of corticosteroids on cytokine generation and expression of activation antigens by monocytes in bronchial asthma. Int Arch Allergy Appl Immunol 1991, 94:220–221.

    PubMed  CAS  Google Scholar 

  18. Leung DY, Martin RJ, Szefler SJ, et al.: Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 1995, 181:33–40.

    Article  PubMed  CAS  Google Scholar 

  19. Sher ER, Leung DY, Surs W, et al.: Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest 1994, 93:33–39.

    PubMed  CAS  Google Scholar 

  20. Kam JC, Szefler SJ, Surs W, et al.: Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 1993, 151:3460–3466.

    PubMed  CAS  Google Scholar 

  21. Sousa AR, Lane SJ, Atkinson BA, et al.: The effects of prednisolone on the cutaneous tuberculin response in patients with corticosteroid-resistant bronchial asthma. J Allergy Clin Immunol 1996, 97:698–706.

    Article  PubMed  CAS  Google Scholar 

  22. Brown PH, Teelucksingh S, Matusiewicz SP, et al.: Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet 1991, 337:576–580.

    Article  PubMed  CAS  Google Scholar 

  23. Adcock IM, Lane SJ, Brown CR, et al.: Differences in binding of glucocorticoid receptor to DNA in steroidresistant asthma. J Immunol 1995, 154:3500–3505.

    PubMed  CAS  Google Scholar 

  24. Adcock IM, Lane SJ, Brown CR, et al.: Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med 1995, 182:1951–1958.

    Article  PubMed  CAS  Google Scholar 

  25. Lane SJ, Adcock IM, Richards D, et al.: Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 1998, 102:2156–2164.

    PubMed  CAS  Google Scholar 

  26. Ito K, Barnes PJ, Adcock IM: Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin- 1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000, 20:6891–6903. In this study, IL-1b and dexamethasone were observed to induce different patterns of histone acetylation in A549 human epithelial cells. The authors suggest that HAT and HDAC activity may be independently regulated by glucocorticoids and the balance of HAT/ HDAC activity may contribute to the overall effect of glucocorticoids on the transcription of proinflammatory genes.

    Article  PubMed  CAS  Google Scholar 

  27. Hollenberg SM, Weinberger C, Ong ES, et al.: Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 1985, 318:635–641.

    Article  PubMed  CAS  Google Scholar 

  28. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP: Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 1995, 95:2435–2441.

    Article  PubMed  CAS  Google Scholar 

  29. Sousa AR, Lane SJ, Cidlowski JA, et al.: Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol 2000, 105:943–950. The alternatively spliced version of the glucocorticoid receptor (GRb) has been implicated as a putative endogenous inhibitor to the transcriptionally active isoform (GRa). This study suggests that alterations in the GRa/GRb ratio may contribute to the glucocorticoid responsiveness in asthmatics. See also reference [31].

    Article  PubMed  CAS  Google Scholar 

  30. Strickland I, Kisich K, Hauk PJ, et al.: High constitutive glucocorticoid receptor beta in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids. J Exp Med 2001, 193:585–594.

    Article  PubMed  CAS  Google Scholar 

  31. Shahidi H, Vottero A, Stratakis CA, et al.: Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun 1999, 254:559–565.

    Article  PubMed  CAS  Google Scholar 

  32. Gagliardo R, Chanez P, Vignola AM, et al.: Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma. Am J Respir Crit Care Med 2000, 162:7–13.

    PubMed  CAS  Google Scholar 

  33. Corrigan CJ, Bungre JK, Assoufi B, et al.: Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents. Eur Respir J 1996, 9:2077–2086.

    Article  PubMed  CAS  Google Scholar 

  34. Haczku A, Alexander A, Brown P, et al.: The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 1994, 93:510–519.

    Article  PubMed  CAS  Google Scholar 

  35. 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, 356:2144–2148.

    Article  PubMed  CAS  Google Scholar 

  36. Kon OM, Sihra BS, Loh LC, et al.: The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur Respir J 2001, 18:45–52.

    Article  PubMed  CAS  Google Scholar 

  37. Corrigan CJ: The eotaxins in asthma and allergic inflammation: implications of therapy. Curr Opin Invest Drugs 2000, 1:321–328.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine and Allergy, Guy’s Hospital, 5th Floor, Thomas Guy House, St. Thomas Street, SE1 9RT, London, UK

    Tuck-Kay Loke MRCP, Ana R. Sousa PhD, Christopher J. Corrigan PhD, FRCP & Tak H. Lee MD, ScD, FRCP, FMedSci

Authors
  1. Tuck-Kay Loke MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana R. Sousa PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Corrigan PhD, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tak H. Lee MD, ScD, FRCP, FMedSci
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Loke, TK., Sousa, A.R., Corrigan, C.J. et al. Glucocorticoid-resistant asthma. Curr Allergy Asthma Rep 2, 144–150 (2002). https://doi.org/10.1007/s11882-002-0009-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-002-0009-y

Keywords

Search

Navigation