Overcoming Steroid Insensitivity in Respiratory Disease

Ian Adcock, Professor of Respiratory Cell and Molecular Biology at the National Heart and Lung Institute, Royal Brompton Campus,?London, UK. K Fan Chung, Professor, Experimental Studies Group, NHLI, Royal Brompton Campus,?London, UK.

• Contents List of contributorsPreface1 Molecular Mechanisms of Glucocorticoid Receptor ActionPankaj Bhavsar and Ian M. Adcock1.1 Introduction1.2 Glucocorticoid receptor1.3 Gene induction by GR1.4 GR transactivation and histone acetylation1.5 Post-translational modifications of GR1.6 Repression of NF-êB-induced inflammatory gene expression by GR–NF-êB1.7 GR–NF-êB cross-talk1.8 Role of HDAC2 in glucocorticoid function1.9 Overexpression of HDAC2 restores glucocorticoid sensitivity in alveolar macrophages1.10 Acetylation of hsp90 and regulation of GR function1.11 Other mechanisms of GR action1.12 Conclusions2 Side Effects of Topical and Oral GlucocorticoidsHeike Schäcke, Khusru Asadullah and Wolf-Dietrich Döcke2.1 Introduction2.2 Glucocorticoid-induced side effects2.3 Summary3 Glucocorticoid Receptor Subtypes and Steroid SensitivityRobert H. Oakley and John A. Cidlowski3.1 Introduction3.2 Overview of classic GR function3.3 GR subtypes arising from alternative splicing3.4 GR subtypes arising from alternative translation initiation3.5 Conclusions4 Dissociated GlucocorticoidsIan M. Adcock4.1 Introduction4.2 Asthma and chronic obstructive pulmonary disease are chronic inflammatory diseases of the airways4.3 Regulation of inflammatory gene expression4.4 Effects on inflammation4.5 Mechanisms of glucocorticoid action4.6 Dissociated glucocorticoids4.7 GR cross-talk with other nuclear receptors and coactivators4.8 Overcoming steroid insensitivity4.9 Glucorticoid-sparing approaches to anti-inflammatory therapy 4.10 Conclusion5 Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular MechanismsEvangelia Charmandari, Tomoshige Kino and George P. Chrousos5.1 Introduction5.2 Molecular mechanisms of glucocorticoid resistance 5.3 Conclusions6 Corticosteroid Responsiveness in Asthma: Clinical AspectsKian Fan Chung6.1 Introduction6.2 Effects of corticosteroids in asthma6.3 Definition of corticosteroid insensitivity6.4 Oral CS responsiveness in asthma6.5 ICS responsiveness in asthma6.6 CS responsiveness in severe asthma6.7 Surrogates for CS responsiveness in asthma6.8 Pharmacokinetics of systemic CS in severe asthma 6.9 CS responsiveness in cigarette smokers and chronic obstructive pulmonary disease6.10 Other diseases of CS insensitivity6.11 Conclusions7 Glucocorticoid-insensitive Asthma: Molecular MechanismsJohn W. Bloom7.1 Introduction7.2 GR abnormalities7.3 GR nuclear translocation7.4 Cross-talk with transcription factors7.5 NF-kB, GR, histones and chromatin remodelling 7.6 Epigenetics and asthma7.7 Conclusions8 Cigarette Smoke, Oxidative Stress and Corticosteroid ResponsivenessIrfan Rahman and David Adenuga8.1 Oxidative stress8.2 Cigarette smoke/oxidative stress-induced NF-kB-mediated pro-inflammatory gene expression8.3 Histone acetylation and deacetylation8.4 Corticosteroids8.5 Histone deacetylases8.6 Reversing Glucocorticoids / Corticosteroid resistance8.7 Conclusion9 Regulation of Glucocorticoid Sensitivity by Macrophage Migration Inhibitory FactorEric F. Morand9.1 Introduction9.2 MIF as a pro-inflammatory factor9.3 Relationship between MIF and glucocorticoids 9.4 Conclusions10 Steroid-sparing Strategies: Long-acting Inhaled β2 -AgonistsAnna Miller-Larsson and Olof Selroos10.1 Introduction10.2 Why and when is a steroid-sparing effect of LABA important in asthma?10.3 Effects of lower dose ICS/LABA versus a higher dose ICS on lung function, symptoms and use of reliever medication10.4 Effects of lower dose ICS/LABA versus higher dose ICS on exacerbations10.5 Protocols with tapering ICS doses with and without LABA while maintaining asthma control10.6 Reducing ICS doses using an adjustable ICS/LABA dosing regimen10.7 Reducing ICS doses using Symbicort® maintenance and reliever therapy10.8 Does enhanced anti-inflammatory efficacy explain steroid-sparing effects in ICS/LABA therapy?10.9 Possible Mechanisms of Steroid-sparing Effects by Addition of LABA to ICS11 Steroid-sparing Strategies: Other CombinationsGaetano Caramori, Kazuhiro Ito and Alberto Papi11.1 Introduction11.2 Theophylline as steroid-sparing treatment in asthma and COPD11.3 Selective inhibitors of PDE411.4 Modulators of the synthesis or action of key inflammatory mediators11.5 Anticholinergics11.6 Leukotriene synthesis inhibitors and leukotriene receptor antagonists11.7 Anti-lgE therapy11.8 Macrolides/ketolides11.9 TNFá inhibitors11.10 Conclusions12 Kinases as Anti-inflammatory Targets for Respiratory DiseaseIain Kilty12.1 Introduction12.2 Pharmacological targeting of kinases12.3 Targeting NF-êB activation 12.4 Targeting the MAPKs12.5 Targeting PI3K12.6 Further potential kinase targets12.7 Conclusions13 Pharmacokinetic/Pharmacodynamic Factors and Steroid SensitivityGönther Hochhaus13.1 Introduction13.2 What factors are important for pulmonary efficacy and safety?13.3 Pharmacodynamic aspects13.4 Pharmacokinetic drug properties13.5 Conclusion14 Improved Lung Deposition: New Inhaler DevicesOmar S. Usmani14.1 Introduction14.2 Historical review of inhaled drug therapy14.3 Deposition of aerosols within the respiratory tract14.4 Assessing drug deposition in the lungs14.5 Aerosol generation devices for inhaled drug therapyIndex