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Glucocorticoids

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Pharmacology and Therapeutics of Asthma and COPD

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

Abstract

The most effective anti-inflammatory drugs used to treat patients with airways disease are topical glucocorticosteroids (GCs). These act on virtually all cells within the airway to suppress airway inflammation or prevent the recruitment of inflammatory cells into the airway. They also have profound effects on airway structural cells to reverse the effects of disease on their function. Glucorticosteroids act via specific receptors—the glucocorticosteroid receptor (GR)—which are a member of the nuclear receptor family. As such, many of the important actions of GCs are to modulate gene transcription through a number of distinct and complementary mechanisms. Targets genes include most inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. GCs delivered by the inhaled route are very effective for most patients and have few systemic side effects. However, in some patients, even high doses of topical or even systemic GCs fail to control their disease. A number of mechanisms relating to inflammation have been reported to be responsible for the failure of these patients to respond correctly to GCs and these provide insight into GC actions within the airways. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed for these patients. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.

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References

  • Accordini S, Corsico AG, Braggion M, Gerbase MW, Gislason D, Gulsvik A et al (2013) The cost of persistent asthma in Europe: an international population-based study in adults. Int Arch Allergy Immunol 160(1):93–101

    Article  PubMed  Google Scholar 

  • Adcock IM, Caramori G (2001) Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol 79(4):376–384

    Article  CAS  PubMed  Google Scholar 

  • Adcock IM, Gilbey T, Gelder CM, Chung KF, Barnes PJ (1996) Glucocorticoid receptor localization in normal and asthmatic lung. Am J Respir Crit Care Med 154(3 Pt 1):771–782

    Article  CAS  PubMed  Google Scholar 

  • Adcock IM, Caramori G, Chung KF (2008a) New targets for drug development in asthma. Lancet 372(9643):1073–1087

    Article  CAS  PubMed  Google Scholar 

  • Adcock IM, Caramori G, Chung KF (2008b) New targets for drug development in asthma. Lancet 372(9643):1073–1087

    Article  CAS  PubMed  Google Scholar 

  • Armstrong J, Harbron C, Lea S, Booth G, Cadden P, Wreggett KA, Singh D (2011) Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. J Pharmacol Exp Ther 338(3):732–740

    Article  CAS  PubMed  Google Scholar 

  • Avenant C, Kotitschke A, Hapgood JP (2010a) Glucocorticoid receptor phosphorylation modulates transcription efficacy through GRIP-1 recruitment. Biochemistry 49(5):972–985

    Article  CAS  PubMed  Google Scholar 

  • Avenant C, Ronacher K, Stubsrud E, Louw A, Hapgood JP (2010b) Role of ligand-dependent GR phosphorylation and half-life in determination of ligand-specific transcriptional activity. Mol Cell Endocrinol 327(1-2):72–88

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2006a) Corticosteroids: the drugs to beat. Eur J Pharmacol 533(1-3):2–14

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2006b) How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148(3):245–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes PJ (2009a) Intrinsic asthma: not so different from allergic asthma but driven by superantigens? Clin Exp Allergy 39(8):1145–1151

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2009b) Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 6(8):693–696

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2013) Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol 131(3):636–645

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ, Adcock IM (2003) How do corticosteroids work in asthma? Ann Intern Med 139(5 Pt 1):359–370

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373(9678):1905–1917

    Article  CAS  PubMed  Google Scholar 

  • Beck IM, Vanden Berghe W, Vermeulen L, Yamamoto KR, Haegeman G, De Bosscher K (2009) Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev 30(7):830–882 available from: PM:19890091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bel EH, Sousa A, Fleming L, Bush A, Chung KF, Versnel J, Wagener AH, Wagers SS, Sterk PJ, Compton CH (2011) Diagnosis and definition of severe refractory asthma: an international consensus statement from the

    Google Scholar 

  • Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID, Investigators SIRIUS (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371(13):1189–1197

    Article  PubMed  CAS  Google Scholar 

  • Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF (2010) Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J 35(4):750–756

    Article  CAS  PubMed  Google Scholar 

  • Biddie SC, John S, Sabo PJ, Thurman RE, Johnson TA, Schiltz RL, Miranda TB, Sung MH, Trump S, Lightman SL, Vinson C, Stamatoyannopoulos JA, Hager GL (2011) Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 43(1):145–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biddie SC, Conway-Campbell BL, Lightman SL (2012) Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology (Oxford) 51(3):403–412

    Article  CAS  Google Scholar 

  • Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE (2002) Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110(1):93–105

    Article  CAS  PubMed  Google Scholar 

  • Brompton Hospital/Medical Research Council Collaborative Trial (1974) Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma. Lancet 2(7876):303–307

    Google Scholar 

  • Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al (2007) Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 356(8):775–789

    Article  CAS  PubMed  Google Scholar 

  • Chang PJ, Bhavsar PK, Michaeloudes C, Khorasani N, Chung KF (2012) Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma. J Allergy Clin Immunol 130(4):877–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang PJ, Michaeloudes C, Zhu J, Shaikh N, Baker J, Chung KF, Bhavsar PK (2015) Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma. Am J Respir Crit Care Med 191(1):54–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Watson AM, Williamson CD, Rahimi M, Liang C, Colberg-Poley AM, Rose MC (2012) Glucocorticoid receptor and histone deacetylase-2 mediate dexamethasone-induced repression of MUC5AC gene expression. Am J Respir Cell Mol Biol 47(5):637–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, Fedorowicz G, Modrusan Z, Fahy JV, Woodruff PG, Arron JR (2011) Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Immunol 186(3):1861–1869

    Article  CAS  PubMed  Google Scholar 

  • Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P (2015) TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med 7(301):301

    Article  CAS  Google Scholar 

  • Chung KF (2005) The role of airway smooth muscle in the pathogenesis of airway wall remodeling in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2(4):347–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung KF (2011) p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest 139(6):1470–1479

    Article  CAS  PubMed  Google Scholar 

  • Chung KF, Adcock IM (2013) How variability in clinical phenotypes should guide research into disease mechanisms in asthma. Ann Am Thorac Soc 10(Suppl):S109–S117

    Article  PubMed  PubMed Central  Google Scholar 

  • Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43(2):343–373

    Article  CAS  PubMed  Google Scholar 

  • Clark TJ (1982) Safety of inhaled corticosteroids. Eur J Respir Dis Suppl 122:235–242

    CAS  PubMed  Google Scholar 

  • Clifford RL, Coward WR, Knox AJ, John AE (2011) Transcriptional regulation of inflammatory genes associated with severe asthma. Curr Pharm Des 17(7):653–666

    Article  CAS  PubMed  Google Scholar 

  • Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365(12):1088–1098

    Article  CAS  PubMed  Google Scholar 

  • Daley-Yates PT (2015) Inhaled corticosteroids: potency, dose equivalence and therapeutic index. Br J Clin Pharmacol 80(3):372–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies L, Karthikeyan N, Lynch JT, Sial EA, Gkourtsa A, Demonacos C, Krstic-Demonacos M (2008) Cross talk of signaling pathways in the regulation of the glucocorticoid receptor function. Mol Endocrinol 22(6):1331–1344

    Article  CAS  PubMed  Google Scholar 

  • Donnelly LE, Barnes PJ (2012) Defective phagocytosis in airways disease. Chest 141(4):1055–1062

    Article  PubMed  Google Scholar 

  • Durham AL, Caramori G, Chung KF, Adcock IM (2016) Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease. Transl Res 167(1):192–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Oefner PJ, Renner K (2011) Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. Biochim Biophys Acta 1807(6):719–725

    Article  CAS  PubMed  Google Scholar 

  • Farrow SN, Solari R, Willson TM (2012) The importance of chronobiology to drug discovery. Expert Opin Drug Discov 7(7):535–541

    Article  CAS  PubMed  Google Scholar 

  • Fenwick PS, Macedo P, Kilty IC, Barnes PJ, Donnelly LE (2015) Effect of JAK inhibitors on release of CXCL9, CXCL10 and CXCL11 from human airway epithelial cells. PLoS One 10(6):e0128757

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367(6):495–507

    Article  CAS  PubMed  Google Scholar 

  • Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ (2010) Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137(6):1338–1344

    Article  CAS  PubMed  Google Scholar 

  • Freedman ND, Yamamoto KR (2004) Importin 7 and importin alpha/importin beta are nuclear import receptors for the glucocorticoid receptor. Mol Biol Cell 15(5):2276–2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galliher-Beckley AJ, Williams JG, Cidlowski JA (2011) Ligand-independent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling. Mol Cell Biol 31(23):4663–4675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giembycz MA, Lindsay MA (1999) Pharmacology of the eosinophil. Pharmacol Rev 51(2):213–340

    CAS  PubMed  Google Scholar 

  • Global Initiative for Asthma (GINA) Global strategy for asthma management and prevention. NHLBI/WHO Workshop report 2002. NHI Publication 02-3659. http://www.ginasthma.com. Accessed 11 May 2015

  • GOLD (2016) Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, NHLBI/WHO workshop report 2001. National Heart, Lung and Blood Institute. NIH Publication 2701: 1-100. www.goldcopd.com. Accessed 10 Oct 2016

  • Goleva E, Hauk PJ, Hall CF, Liu AH, Riches DW, Martin RJ, Leung DY (2008) Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol 122(3):550–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goleva E, Li LB, Leung DY (2009) IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance. Am J Respir Cell Mol Biol 40(2):223–230

    Article  CAS  PubMed  Google Scholar 

  • Grant IW (1961) Corticosteroids in asthma. Br Med J 2(5269):1781

    Article  PubMed Central  Google Scholar 

  • Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P et al (2002) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360(9347):1715–1721

    Article  PubMed  Google Scholar 

  • Grunberg K, Sharon RF, Sont JK, In’t Veen JC, Van Schadewijk WA, de Klerk EP, Dick CR, van Krieken JH, Sterk PJ (2001) Rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection. Am J Respir Crit Care Med 164(10 Pt 1):1816–1822

    Article  CAS  PubMed  Google Scholar 

  • Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, Chan JH, Wright T, Punaro M, Bolland S, Soumelis V, Banchereau J, Coffman RL, Pascual V, Barrat FJ (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465(7300):937–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gustafson LM, Proud D, Hendley JO, Hayden FG, Gwaltney JM Jr (1996) Oral prednisone therapy in experimental rhinovirus infections. J Allergy Clin Immunol 97(4):1009–1014

    Article  CAS  PubMed  Google Scholar 

  • 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(11):4510–4519

    Article  CAS  PubMed  Google Scholar 

  • Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH (2008) Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 178(3):218–224

    Article  PubMed  PubMed Central  Google Scholar 

  • Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360(10):973–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hallett JM, Leitch AE, Riley NA, Duffin R, Haslett C, Rossi AG (2008) Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation. Trends Pharmacol Sci 29(5):250–257

    Article  CAS  PubMed  Google Scholar 

  • Heaney LG, Djukanovic R, Woodcock A, Walker S, Matthews JG, Pavord ID, Bradding P, Niven R, Brightling CE, Chaudhuri R, Arron JR, Choy DF, Cowan D, Mansur A, Menzies-Gow A, Adcock I, Chung KF, Corrigan C, Coyle P, Harrison T, Johnston S, Howarth P, Lordan J, Sabroe I, Bigler J, Smith D, Catley M, May R, Pierre L, Stevenson C, Crater G, Keane F, Costello RW, Hudson V, Supple D, Hardman T (2016) Research in progress: medical research council united kingdom refractory asthma stratification programme (RASP-UK). Thorax 71(2):187–189

    Article  PubMed  Google Scholar 

  • Heijink I, van Oosterhout A, Kliphuis N, Jonker M, Hoffmann R, Telenga E, Klooster K, Slebos DJ, ten Hacken N, Postma D, van den Berge M (2014) Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells. Thorax 69(1):5–13

    Article  PubMed  Google Scholar 

  • Hew M, Chung KF (2010) Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiology. Intern Med J 40(5):323–334

    Article  CAS  PubMed  Google Scholar 

  • Hewitt R, Farne H, Ritchie A, Luke E, Johnston SL, Mallia P (2016) The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma. Ther Adv Respir Dis 10(2):158–174

    Article  PubMed  Google Scholar 

  • Hochhaus G, Druzgala P, Hochhaus R, Huang MJ, Bodor N (1991) Glucocorticoid activity and structure activity relationships in a series of some novel 17 alpha-ether-substituted steroids: influence of 17 alpha-substituents. Drug Des Discov 8(2):117–125

    CAS  PubMed  Google Scholar 

  • Holgate ST, Arshad HS, Roberts GC, Howarth PH, Thurner P, Davies DE (2010) A new look at the pathogenesis of asthma. Clin Sci (Lond) 118(7):439–450

    Article  CAS  Google Scholar 

  • Hua G, Ganti KP, Chambon P (2016a) Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex. Proc Natl Acad Sci U S A 113(5):E635–E643

    Article  CAS  PubMed  Google Scholar 

  • Hua G, Paulen L, Chambon P (2016b) GR SUMOylation and formation of an SUMO-SMRT/NCoR1-HDAC3 repressing complex is mandatory for GC-induced IR nGRE-mediated transrepression. Proc Natl Acad Sci U S A 113(5):E626–E634

    Article  CAS  PubMed  Google Scholar 

  • 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):649–657

    Article  CAS  PubMed  Google Scholar 

  • Ishmael FT, Fang X, Galdiero MR, Atasoy U, Rigby WF, Gorospe M, Cheadle C, Stellato C (2008) Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. J Immunol 180(12):8342–8353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, Barnes PJ (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352(19):1967–1976

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Chung KF, Adcock IM (2006a) Update on glucocorticoid action and resistance. J Allergy Clin Immunol 117(3):522–543

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM (2006b) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med 203(1):7–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson DJ, Sykes A, Mallia P, Johnston SL (2011) Asthma exacerbations: origin, effect, and prevention. J Allergy Clin Immunol 128(6):1165–1174

    Article  PubMed  Google Scholar 

  • Johnson M (2004) Interactions between corticosteroids and beta2-agonists in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 1(3):200–206

    Article  CAS  PubMed  Google Scholar 

  • Kabesch M, Adcock IM (2012) Epigenetics in asthma and COPD. Biochimie 94(11):2231–2241

    Article  CAS  PubMed  Google Scholar 

  • Kadiyala V, Sasse SK, Altonsy MO, Berman R, Chu HW, Phang TL, Gerber AN (2016) Cistrome-based cooperation between airway epithelial glucocorticoid receptor and NF-ÎşB orchestrates anti-inflammatory effects. J Biol Chem 291(24):12673–12687

    Article  CAS  PubMed  Google Scholar 

  • Kaminska M, Foley S, Maghni K, Storness-Bliss C, Coxson H, Ghezzo H, Lemiere C, Olivenstein R, Ernst P, Hamid Q, Martin J (2009) Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J Allergy Clin Immunol 124(1):45–51

    Article  PubMed  Google Scholar 

  • Kanniess F, Richter K, Bohme S, Jorres RA, Magnussen H (2001) Effect of inhaled ciclesonide on airway responsiveness to inhaled AMP, the composition of induced sputum and exhaled nitric oxide in patients with mild asthma. Pulm Pharmacol Ther 14(2):141–147

    Article  CAS  PubMed  Google Scholar 

  • Kato A, Schleimer RP (2007) Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity. Curr Opin Immunol 19(6):711–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kielgast F, Schmidt H, Braubach P, Winkelmann VE, Thompson KE, Frick M, Dietl P, Wittekindt OH (2016) Glucocorticoids regulate tight junction permeability of lung epithelia by modulating claudin 8. Am J Respir Cell Mol Biol 54(5):707–717

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 3(107):ra8

    Google Scholar 

  • Kupczyk M, Wenzel S (2012) U.S. and. European severe asthma cohorts: what can they teach us about severe asthma? J Intern Med 272(2):121–132

    CAS  PubMed  Google Scholar 

  • Kupczyk M, Haque S, Middelveld RJ, Dahlen B, Dahlen SE (2013) Phenotypic predictors of response to oral glucocorticosteroids in severe asthma. Respir Med 107(10):1521–1530

    Article  PubMed  Google Scholar 

  • Lambrecht BN, Hammad H (2012) Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu Rev Immunol 30:243–270

    Article  CAS  PubMed  Google Scholar 

  • Langlais D, Couture C, Balsalobre A, Drouin J (2012) The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol Cell 47(1):38–49

    Article  CAS  PubMed  Google Scholar 

  • Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai MJ, O’Malley BW (1999) A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97(1):17–27

    Article  CAS  PubMed  Google Scholar 

  • Ledderose C, Mohnle P, Limbeck E, Schutz S, Weis F, Rink J, Briegel J, Kreth S (2012) Corticosteroid resistance in sepsis is influenced by microRNA-124—induced downregulation of glucocorticoid receptor-alpha. Crit Care Med 40(10):2745–2753

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Machin M, Russell KE, Pavlidis S, Zhu J, Barnes PJ, Chung KF, Adcock IM, Durham AL (2016) Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD. FASEB J 30(5):2014–2026

    Article  CAS  PubMed  Google Scholar 

  • 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):1059–1069

    Article  CAS  PubMed  Google Scholar 

  • Li LB, Leung DY, Martin RJ, Goleva E (2010) Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid resistant asthma. Am J Respir Crit Care Med 182(7):877–883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu NZ, Cidlowski JA (2006) Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 16(6):301–307

    Article  CAS  PubMed  Google Scholar 

  • Magiakou MA, Chrousos GP (2002) Cushing’s syndrome in children and adolescents: current diagnostic and therapeutic strategies. J Endocrinol Invest 25(2):181–194

    Article  CAS  PubMed  Google Scholar 

  • Maltby S, Plank M, Tay HL, Collison A, Foster PS (2016) Targeting MicroRNA function in respiratory diseases: mini-review. Front Physiol 7:21

    Article  PubMed  PubMed Central  Google Scholar 

  • Marwick JA, Caramori G, Stevenson CS, Casolari P, Jazrawi E, Barnes PJ, Ito K, Adcock IM, Kirkham PA, Papi A (2009) Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 179(7):542–548

    Article  CAS  PubMed  Google Scholar 

  • Mattishent K, Thavarajah M, Blanco P, Gilbert D, Wilson AM, Loke YK (2014) Meta-review: adverse effects of inhaled corticosteroids relevant to older patients. Drugs 74(5):539–547

    Article  CAS  PubMed  Google Scholar 

  • McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK (2008) TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 181(6):4089–4097 available from: PM:18768865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McNicholl DM, Stevenson M, McGarvey LP, Heaney LG (2012) The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med 186(11):1102–1108

    Article  PubMed  Google Scholar 

  • Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Yamamoto KR (2009) DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324(5925):407–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, Calhoun WJ, Castro M, Chung KF, Clark MP, Dweik RA, Fitzpatrick AM, Gaston B, Hew M, Hussain I, Jarjour NN, Israel E, Levy BD, Murphy JR, Peters SP, Teague WG, Meyers DA, Busse WW, Wenzel SE (2007) Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol 119(2):405–413

    Article  PubMed  PubMed Central  Google Scholar 

  • Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D’Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER (2010) Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 181(4):315–323

    Article  PubMed  Google Scholar 

  • Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O’Byrne PM (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360(10):985–993

    Article  CAS  PubMed  Google Scholar 

  • Nannini LJ, Poole P, Milan SJ, Holmes R, Normansell R (2013) Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 11:CD003794

    Google Scholar 

  • Ngkelo A, Hoffmann RF, Durham AL, Marwick JA, Brandenburg SM, de Bruin HG, Jonker MR, Rossios C, Tsitsiou E, Caramori G, Contoli M, Casolari P, Monaco F, Andò F, Speciale G, Kilty I, Chung KF, Papi A, Lindsay MA, Ten Hacken NH, van den Berge M, Timens W, Barnes PJ, van Oosterhout AJ, Adcock IM, Kirkham PA, Heijink IH (2015) Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD. Am J Physiol Lung Cell Mol Physiol 309(10):L1112–L1123

    CAS  PubMed  PubMed Central  Google Scholar 

  • O’Connor D, Adams WP, Chen ML, ey-Yates P, Davis J, Derendorf H, Ducharme MP, Fuglsang A, Herrle M, Hochhaus G, Holmes SM, Lee SL, Li BV, Lyapustina S, Newman S, Oliver M, Patterson B, Peart J, Poochikian G, Roy P, Shah T, Singh GJ, Sharp SS (2011) Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv 24(3):119–135

    Google Scholar 

  • Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P, Investigators MENSA (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371(13):1198–1207

    Article  PubMed  CAS  Google Scholar 

  • O’Shea JJ, Plenge R (2012) JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36(4):542–550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Osoata GO, 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(3):366–371

    Article  CAS  PubMed  Google Scholar 

  • Papi A, Contoli M, Adcock IM, Bellettato C, Padovani A, Casolari P, Stanciu LA, Barnes PJ, Johnston SL, Ito K, Caramori G (2013) Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor ÎşB and c-Jun N-terminal kinase activation. J Allergy Clin Immunol 132(5):1075–1085, e6

    Article  CAS  PubMed  Google Scholar 

  • Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID (2015) Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 12

    Google Scholar 

  • Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380(9842):651–659

    Article  CAS  PubMed  Google Scholar 

  • Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW, Wedzicha JA, Barnes NC (2016) Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax 71(2):118–125

    Article  PubMed  Google Scholar 

  • Perry MM, Baker JE, Gibeon DS, Adcock IM, Chung KF (2014) Airway smooth muscle hyperproliferation is regulated by microRNA-221 in severe asthma. Am J Respir Cell Mol Biol 50(1):7–17

    PubMed  PubMed Central  Google Scholar 

  • Perry MM, Durham AL, Austin PJ, Adcock IM, Chung KF (2015) BET bromodomains regulate transforming growth factor-β-induced proliferation and cytokine release in asthmatic airway smooth muscle. J Biol Chem 290(14):9111–9121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV; National Heart, Lung, and Blood Institute Severe Asthma Research Program (2016) Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med 4(7): 574–584

    Google Scholar 

  • Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV (2014) Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol 133(2):388–394

    Article  CAS  PubMed  Google Scholar 

  • Proud D, Leigh R (2011) Epithelial cells and airway diseases. Immunol Rev 242(1):186–204

    Article  CAS  PubMed  Google Scholar 

  • Psarra AM, Sekeris CE (2011) Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta 1813(10):1814–1821

    Article  CAS  PubMed  Google Scholar 

  • Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28(1):219–242

    Article  CAS  PubMed  Google Scholar 

  • Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353(16):1711–1723

    Article  CAS  PubMed  Google Scholar 

  • Savory JG, Hsu B, Laquian IR, Giffin W, Reich T, Hache RJ, Lefebvre YA (1999) Discrimination between NL1- and NL2-mediated nuclear localization of the glucocorticoid receptor. Mol Cell Biol 19(2):1025–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schacke H, Docke WD, Asadullah K (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96(1):23–43

    Article  CAS  PubMed  Google Scholar 

  • Schleimer RP (2004) Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium. Proc Am Thorac Soc 1(3):222–230

    Article  CAS  PubMed  Google Scholar 

  • Scott DA, Woods B, Thompson JC, Clark JF, Hawkins N, Chambers M, Celli BR, Calverley P (2015) Mortality and drug therapy in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Pulm Med 15:145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Smoak K, Cidlowski JA (2006) Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling. Mol Cell Biol 26(23):9126–9135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(5):1010–1017

    Article  CAS  PubMed  Google Scholar 

  • Su RC, Becker AB, Kozyrskyj AL, Hayglass KT (2009) Altered epigenetic regulation and increasing severity of bronchial hyperresponsiveness in atopic asthmatic children. J Allergy Clin Immunol 124(5):1116–1118

    Article  PubMed  Google Scholar 

  • To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliott WM, Hogg JC, Adcock IM, Barnes PJ (2010) Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 182(7):897–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Umland SP, Schleimer RP, Johnston SL (2002) Review of the molecular and cellular mechanisms of action of glucocorticoids for use in asthma. Pulm Pharmacol Ther 15(1):35–50 available from: PM:11969362

    Article  CAS  PubMed  Google Scholar 

  • Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabrysova L, Christensen J, Gupta A, Saglani S, Bush A, O’Garra A, Brown Z, Hawrylowicz CM (2012) The role of 1alpha,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3(+) and IL-10(+) CD4(+) T cells. Eur J Immunol 42(10):2697–2708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van den Berge M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev YO, Lenburg ME, Spira A, Postma DS (2014) Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax 69(1):14–23

    Article  PubMed  Google Scholar 

  • Vasavda N, Eichholtz T, Takahashi A, Affleck K, Matthews JG, Barnes PJ, Adcock IM (2006) Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma. J Allergy Clin Immunol 118(5):1090–1096

    Article  CAS  PubMed  Google Scholar 

  • Verhoog NJ, Du Toit A, Avenant C, Hapgood JP (2011) Glucocorticoid-independent repression of tumor necrosis factor (TNF) alpha-stimulated interleukin (IL)-6 expression by the glucocorticoid receptor: a potential mechanism for protection against an excessive inflammatory response. J Biol Chem 286(22):19297–19310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vockley CM, D’Ippolito AM, McDowell IC, Majoros WH, Safi A, Song L, Crawford GE, Reddy TE (2016) Direct GR binding sites potentiate clusters of TF binding across the human genome. Cell 166(5):1269–1281

    Article  CAS  PubMed  Google Scholar 

  • Weigel NL, Moore NL (2007) Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol 21(10):2311–2319

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ (1997) Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 156(3 Pt 1):737–743

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen SE, Holgate ST, Meyers DA, Rabe KF, Antczak A, Baker J, Horvath I, Mark Z, Bernstein D, Kerwin E, Schlenker-Herceg R, Lo KH, Watt R, Barnathan ES, Chanez P (2009) A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 179(7):549–558

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368(26):2455–2466

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN, Eckert L, Graham NM, Stahl N, Yancopoulos GD, Louis-Tisserand M, Teper A (2016) 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 388(10039):31–44

    Article  CAS  PubMed  Google Scholar 

  • Winkler J, Hochhaus G, Derendorf H (2004) How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc 1(4):356–363

    Article  CAS  PubMed  Google Scholar 

  • Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A 104(40):15858–15863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV (2009) T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180(5):388–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xavier AM, Anunciato AK, Rosenstock TR, Glezer I (2016) Gene expression control by glucocorticoid receptors during innate immune responses. Front Endocrinol (Lausanne) 7:31

    Google Scholar 

  • Yang IA, Clarke MS, Sim EH, Fong KM (2012) Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 7:CD002991

    Google Scholar 

  • Zhang N, Truong-Tran QA, Tancowny B, Harris KE, Schleimer RP (2007) Glucocorticoids enhance or spare innate immunity: effects in airway epithelium are mediated by CCAAT/enhancer binding proteins. J Immunol 179(1):578–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zijlstra GJ, Ten Hacken NH, Hoffmann RF, Van Oosterhout AJ, Heijink IH (2012) IL-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 39(2):439–445

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Research in the author’s laboratories is supported by the EU (IMI), MRC (UK), Wellcome Trust, BHF, Dunhill Medical Trust and by Asthma UK. The authors have no conflicts of interest. IMA is a principal investigator in the MRC/Asthma UK Centre for Asthma and Allergic Mechanisms and is supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

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Adcock, I.M., Mumby, S. (2016). Glucocorticoids. In: Page, C., Barnes, P. (eds) Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, vol 237. Springer, Cham. https://doi.org/10.1007/164_2016_98

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