Glucocorticosteroids

Chapter
First Online:
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 237)

Abstract

Glucocorticosteroids are the most effective anti-inflammatory therapy for asthma but are relatively ineffective in COPD. Glucocorticoids are broad-spectrum anti-inflammatory drugs that suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in asthma by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to coactivator molecules and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex (trans-repression). At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects (trans-activation). Glucocorticoids also have post-transcriptional effects and decrease stability of some proinflammatory mRNAs. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with COPD. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve phosphorylation and other post-translational modifications of GR. HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress and pi3 kinase-δ inhibition, so that inflammation is resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids and selective GR modulators which show improved trans-repression over trans-activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance.

keywords

Anti-inflammatory Corticosteroid resistance Glucocorticoid receptor Glucocorticoid receptor-beta Histone deacetylase-2 p38 MAP kinase 
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References

  1. Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, Saklatvala J, Clark AR (2006) Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med 203(8):1883–1889CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adcock IM, Lane SJ, Brown CA, Lee TH, Barnes PJ (1995) Abnormal glucocorticoid receptor/AP-1 interaction in steroid resistant asthma. J Exp Med 182:1951–1958CrossRefPubMedGoogle Scholar
  3. Barnes PJ (2002) Scientific rationale for combination inhalers with a long-acting b2-agonists and corticosteroids. Eur Respir J 19:182–191CrossRefPubMedGoogle Scholar
  4. Barnes PJ (2005) Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets 9(6):1111–1121CrossRefPubMedGoogle Scholar
  5. Barnes PJ (2006) Corticosteroids: the drugs to beat. Eur J Pharmacol 533:2–14CrossRefPubMedGoogle Scholar
  6. Barnes PJ (2007) Scientific rationale for using a single inhaler for asthma control. Eur Respir Dis 29:587–595CrossRefGoogle Scholar
  7. Barnes PJ (2008) Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8:183–192CrossRefPubMedGoogle Scholar
  8. Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71:451–464. doi: 10.1146/annurev.physiol.010908.163257 CrossRefPubMedGoogle Scholar
  9. Barnes PJ (2010a) Inhaled corticosteroids in COPD: a controversy. Respiration 80(2):89–95. doi: 10.1159/000315416 CrossRefPubMedGoogle Scholar
  10. Barnes PJ (2010b) Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 120(2-3):76–85CrossRefPubMedGoogle Scholar
  11. Barnes PJ (2011) Glucocorticosteroids: current and future directions. Br J Pharmacol 163(1):29–43. doi: 10.1111/j.1476-5381.2010.01199.x CrossRefPubMedPubMedCentralGoogle Scholar
  12. Barnes PJ (2013a) Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol 131:636–645CrossRefPubMedGoogle Scholar
  13. Barnes PJ (2013b) New anti-inflammatory treatments for chronic obstructive pulmonary disease. Nat Rev Drug Discov 12:543–559CrossRefPubMedGoogle Scholar
  14. Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 342:1905–1917CrossRefGoogle Scholar
  15. Barnes PJ, Pedersen S, Busse WW (1998) Efficacy and safety of inhaled corticosteroids: an update. Am J Respir Crit Care Med 157:S1–S53CrossRefPubMedGoogle Scholar
  16. Belvisi MG, Wicks SL, Battram CH, Bottoms SE, Redford JE, Woodman P, Brown TJ, Webber SE, Foster ML (2001) Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity. J Immunol 166(3):1975–1982CrossRefPubMedGoogle Scholar
  17. Bergmann MW, Staples KJ, Smith SJ, Barnes PJ, Newton R (2004) Glucocorticoid inhibition of GM-CSF from T cells is independent of control by NF-kB and CLE0. Am J Respir Cell Mol Biol 30:555–563CrossRefPubMedGoogle Scholar
  18. Bhavsar P, Hew M, Khorasani N, Alfonso T, Barnes PJ, Adcock I, Chung KF (2008) Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared to non-severe asthma. Thorax 63:784–790CrossRefPubMedGoogle Scholar
  19. Black JL, Oliver BG, Roth M (2009) Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting beta-agonists. Chest 136(4):1095–1100. doi: 10.1378/chest.09-0354 CrossRefPubMedGoogle Scholar
  20. Charmandari E, Kino T, Chrousos GP (2013) Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity. Endocr Dev 24:67–85. doi: 10.1159/000342505 PubMedPubMedCentralGoogle Scholar
  21. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200:689–695CrossRefPubMedPubMedCentralGoogle Scholar
  22. Culpitt SV, Nightingale JA, Barnes PJ (1999) Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:1635–1639CrossRefPubMedGoogle Scholar
  23. Devereux G, Cotton S, Barnes P, Briggs A, Burns G, Chaudhuri R, Chrystyn H, Davies L, De Soyza A, Fielding S, Gompertz S, Haughney J, Lee AJ, McCormack K, McPherson G, Morice A, Norrie J, Sullivan A, Wilson A, Price D (2015) Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial. Trials 16:267. doi: 10.1186/s13063-015-0782-2 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Donn R, Berry A, Stevens A, Farrow S, Betts J, Stevens R, Clayton C, Wang J, Warnock L, Worthington J, Scott L, Graham S, Ray D (2007) Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII. FASEB J 21(2):402–414CrossRefPubMedGoogle Scholar
  25. Dostert A, Heinzel T (2004) Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des 10(23):2807–2816CrossRefPubMedGoogle Scholar
  26. Erin EM, Zacharasiewicz AS, Nicholson GC, Tan AJ, Neighbour H, Engelstatter R, Hellwig M, Minn KO, Barnes PJ, Hansel TT (2008) Rapid anti-inflammatory effect of inhaled ciclesonide in asthma: a randomised, placebo-controlled study. Chest 134:740–745CrossRefPubMedGoogle Scholar
  27. Evans DJ, Cullinan P, Geddes DM (2001) Cyclosporin as an oral corticosteroid sparing agent in stable asthma (Cochrane Review). Cochrane Database Syst Rev 2, CD002993Google Scholar
  28. Fakhri S, Tulic M, Christodoulopoulos P, Fukakusa M, Frenkiel S, Leung DY, Hamid QA (2004) Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model. Laryngoscope 114(5):887–892CrossRefPubMedGoogle Scholar
  29. Finney L, Berry M, Singanayagam A, Elkin SL, Johnston SL, Mallia P (2014) Inhaled corticosteroids and pneumonia in chronic obstructive pulmonary disease. Lancet Respir Med. doi: 10.1016/s2213-2600(14)70169-9 PubMedGoogle Scholar
  30. Ford PA, Durham AL, Russell REK, Gordon F, Adcock IM, Barnes PJ (2010) Treatment effects of low dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137:1338–1344CrossRefPubMedGoogle Scholar
  31. Galigniana MD, Piwien-Pilipuk G, Assreuy J (1999) Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol 55(2):317–323PubMedGoogle Scholar
  32. Garnock-Jones KP (2015) Roflumilast: a review in COPD. Drugs 75(14):1645–1656. doi: 10.1007/s40265-015-0463-1 CrossRefPubMedGoogle Scholar
  33. Goldfarb DS, Corbett AH, Mason DA, Harreman MT, Adam SA (2004) Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol 14(9):505–514CrossRefPubMedGoogle Scholar
  34. Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY (2006) Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 173(6):607–616CrossRefPubMedGoogle Scholar
  35. Hakim A, Barnes PJ, Adcock IM, Usmani OS (2013) Importin-7 mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity. FASEB J 27:4510–4519CrossRefPubMedGoogle Scholar
  36. Hakonarson H, Bjornsdottir US, Halapi E, Bradfield J, Zink F, Mouy M, Helgadottir H, Gudmundsdottir AS, Andrason H, Adalsteinsdottir AE, Kristjansson K, Birkisson I, Arnason T, Andresdottir M, Gislason D, Gislason T, Gulcher JR, Stefansson K (2005) Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci U S A 102(41):14789–14794CrossRefPubMedPubMedCentralGoogle Scholar
  37. Haque R, Hakim A, Moodley T, Torrego A, Essilfie-Quaye S, Jazrawi E, Johnson M, Barnes PJ, Adcock IM, Usmani OS (2013) Inhaled long-acting beta agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2013.07.038 PubMedGoogle Scholar
  38. Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, Schudt C, Tenor H (2010) The preclinical pharmacology of roflumilast – a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 23(4):235–256CrossRefPubMedGoogle Scholar
  39. Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, Adcock I, Chung KF (2006) Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med 174:134–141CrossRefPubMedPubMedCentralGoogle Scholar
  40. Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM (2002) p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 109(4):649–657CrossRefPubMedGoogle Scholar
  41. Ismaili N, Garabedian MJ (2004) Modulation of glucocorticoid receptor function via phosphorylation. Ann N Y Acad Sci 1024:86–101CrossRefPubMedGoogle Scholar
  42. Ito K, Barnes PJ, Adcock IM (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1b-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 20:6891–6903CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi M, Adcock IM, Hogg JC, Barnes PJ (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352:1967–1976CrossRefPubMedGoogle Scholar
  44. Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM (2006) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kB suppression. J Exp Med 203:7–13CrossRefPubMedPubMedCentralGoogle Scholar
  45. John S, Sabo PJ, Johnson TA, Sung MH, Biddie SC, Lightman SL, Voss TC, Davis SR, Meltzer PS, Stamatoyannopoulos JA, Hager GL (2008) Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell 29(5):611–624CrossRefPubMedGoogle Scholar
  46. Kadmiel M, Cidlowski JA (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 34(9):518–530. doi: 10.1016/j.tips.2013.07.003 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ (1997) Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 155:542–548CrossRefPubMedGoogle Scholar
  48. Kino T, Su YA, Chrousos GP (2009) Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology. Cell Mol Life Sci 66(21):3435–3448. doi: 10.1007/s00018-009-0098-z CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kleiman A, Tuckermann JP (2007) Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice. Mol Cell Endocrinol 275(1-2):98–108CrossRefPubMedGoogle Scholar
  50. Kobayashi Y, Mercado N, Barnes PJ, Ito K (2011) Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS One 6(12), e27627CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lane SJ, Arm JP, Staynov DZ, Lee TH (1994) Chemical mutational analysis of the human glucocortiocoid receptor cDNA in glucocorticoid-resistant bronchial asthma. Am J Respir Cell Mol Biol 11:42–48CrossRefPubMedGoogle Scholar
  52. Leaker BR, O’Connor B, Singh D, Barnes PJ (2015) The novel inhaled glucocorticoid receptor agonist GW870086X protects against adenosine-induced bronchoconstriction in asthma. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2015.01.034 PubMedGoogle Scholar
  53. Li LB, Goleva E, Hall CF, Ou LS, Leung DY (2004) 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 114(5):1059–1069CrossRefPubMedGoogle Scholar
  54. Mak JCW, Nishikawa M, Shirasaki H, Miyayasu K, Barnes PJ (1995) Protective effects of a glucocorticoid on down-regulation of pulmonary b2-adrenergic receptors in vivo. J Clin Invest 96:99–106CrossRefPubMedPubMedCentralGoogle Scholar
  55. Maneechotesuwan K, Supawita S, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ (2008) Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids. J Allergy Clin Immunol 121:43–50CrossRefPubMedGoogle Scholar
  56. Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJ (2009) Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med 6(5), e1000076CrossRefPubMedPubMedCentralGoogle Scholar
  57. Marwick JA, Caramori G, Stevenson CC, Casolari P, Jazrawi E, Barnes PJ, Ito K, Adcock IM, Kirkham PA, Papi A (2009) Inhibition of PI3Kd restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 179:542–548CrossRefPubMedGoogle Scholar
  58. Matthews JG, Ito K, Barnes PJ, Adcock IM (2004) Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J Allergy Clin Immunol 113(6):1100–1108CrossRefPubMedGoogle Scholar
  59. Medicherla S, Fitzgerald M, Spicer D, Woodman P, Ma JY, Kapoun AM, Chakravarty S, Dugar S, Protter AA, Higgins LS (2007) p38a Selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 324:921–929CrossRefPubMedGoogle Scholar
  60. Mercado N, To Y, Kobayashi Y, Adcock IM, Barnes PJ, Ito K (2011) p38 MAP kinase-g Inhibition by long-acting b2 adrenergic agonists reversed steroid insensitivity in severe asthma. Mol Pharmacol 80:1128–1135CrossRefPubMedPubMedCentralGoogle Scholar
  61. Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K (2012) Restoration of corticosteroid sensitivity by p38 mitogen activated Protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One 7(7), e41582CrossRefPubMedPubMedCentralGoogle Scholar
  62. Mitani A, Ito K, Vuppusetty C, Barnes PJ, Mercado N (2016) Inhibition of mTOR restores corticosteroid sensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 193(2):143–153Google Scholar
  63. Nannini LJ, Poole P, Milan SJ, Kesterton A (2013) Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 8, Cd006826. doi: 10.1002/14651858.CD006826.pub2
  64. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E (2010) The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75(1):1–12CrossRefPubMedGoogle Scholar
  65. O’Byrne PM, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, Lamm CJ, Pauwels RA (2006) Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma. Chest 129(6):1478–1485CrossRefPubMedGoogle Scholar
  66. Osoata G, Yamamura S, Ito M, Vuppusetty C, Adcock IM, Barnes PJ, Ito K (2009) Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophys Res Commun 384:366–371CrossRefPubMedGoogle Scholar
  67. Polosa R, Thomson NC (2012) Smoking and asthma: dangerous liaisons. Eur Respir J 41:716–726CrossRefPubMedGoogle Scholar
  68. Postma DS, Rabe KF (2015) The asthma-COPD overlap syndrome. N Engl J Med 373(13):1241–1249. doi: 10.1056/NEJMra1411863 CrossRefPubMedGoogle Scholar
  69. Prabhala P, Ammit AJ (2015) Tristetraprolin and its role in regulation of airway inflammation. Mol Pharmacol 87(4):629–638. doi: 10.1124/mol.114.095984 CrossRefPubMedGoogle Scholar
  70. Pujols L, Mullol J, Picado C (2007) Alpha and beta glucocorticoid receptors: relevance in airway diseases. Curr Allergy Asthma Rep 7(2):93–99CrossRefPubMedGoogle Scholar
  71. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, Haahtela T, Hurd SS, Inoue H, de Jongste JC, Lemanske RF Jr, Levy ML, O’Byrne PM, Paggiaro P, Pedersen SE, Pizzichini E, Soto-Quiroz M, Szefler SJ, Wong GW, FitzGerald JM (2015) A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 46(3):622–639. doi: 10.1183/13993003.00853-2015 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Roth M, Johnson PR, Rudiger JJ, King GG, Ge Q, Burgess JK, Anderson G, Tamm M, Black JL (2002) Interaction between glucocorticoids and b2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 360(9342):1293–1299CrossRefPubMedGoogle Scholar
  73. Sher ER, Leung YM, Surs W, Kam JC, Zieg G, Kamada AK, Szefler SJ (1994) Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest 93:33–39CrossRefPubMedPubMedCentralGoogle Scholar
  74. Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, Lafferty J, Chaudhuri R, Braganza G, Adcock IM, Barnes PJ, Wood S, Thomson NC (2009) Effect of theophylline plus beclometasone on lung function in smokers with asthma – a pilot study. Eur Respir J 33:1010–1017CrossRefPubMedGoogle Scholar
  75. Suissa S, Barnes PJ (2009) Inhaled corticosteroids in COPD: the case against. Eur Respir J 34(1):13–16CrossRefPubMedGoogle Scholar
  76. Tao T, Lan J, Lukacs GL, Hache RJ, Kaplan F (2006) Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells. Am J Respir Cell Mol Biol 35(6):668–680CrossRefPubMedGoogle Scholar
  77. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliot M, Hogg JC, Adcock IM, Barnes PJ (2010) Targeting phosphoinositide-3-kinase-d with theophylline reverses corticosteroid insensitivity in COPD. Am J Respir Crit Care Med 182:897–904CrossRefPubMedPubMedCentralGoogle Scholar
  78. Usmani OS, Ito K, Maneechotesuwan K, Ito M, Johnson M, Barnes PJ, Adcock IM (2005) Glucocorticoid receptor nuclear translocation in airway cells following inhaled combination therapy. Am J Respir Crit Care Med 172:704–712CrossRefPubMedGoogle Scholar
  79. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R (2013) Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. Am J Respir Crit Care Med 187:347–365CrossRefPubMedGoogle Scholar
  80. Weigel NL, Moore NL (2007) Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol 21(10):2311–2319CrossRefPubMedGoogle Scholar
  81. Yang IA, Clarke MS, Sim EH, Fong KM (2012) Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 7, CD002991Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Airway Disease SectionImperial College, National Heart and Lung InstituteLondonUK

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