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 contributors Preface 1 Molecular Mechanisms of Glucocorticoid Receptor Action Pankaj Bhavsar and Ian M. Adcock 1.1 Introduction 1.2 Glucocorticoid receptor 1.3 Gene induction by GR 1.4 GR transactivation and histone acetylation 1.5 Post-translational modifications of GR 1.6 Repression of NF-eB-induced inflammatory gene expression by GR-NF-eB 1.7 GR-NF-eB cross-talk 1.8 Role of HDAC2 in glucocorticoid function 1.9 Overexpression of HDAC2 restores glucocorticoid sensitivity in alveolar macrophages 1.10 Acetylation of hsp90 and regulation of GR function 1.11 Other mechanisms of GR action 1.12 Conclusions 2 Side Effects of Topical and Oral Glucocorticoids Heike Schacke, Khusru Asadullah and Wolf-Dietrich Docke 2.1 Introduction 2.2 Glucocorticoid-induced side effects 2.3 Summary 3 Glucocorticoid Receptor Subtypes and Steroid Sensitivity Robert H. Oakley and John A. Cidlowski 3.1 Introduction 3.2 Overview of classic GR function 3.3 GR subtypes arising from alternative splicing 3.4 GR subtypes arising from alternative translation initiation 3.5 Conclusions 4 Dissociated Glucocorticoids Ian M. Adcock 4.1 Introduction 4.2 Asthma and chronic obstructive pulmonary disease are chronic inflammatory diseases of the airways 4.3 Regulation of inflammatory gene expression 4.4 Effects on inflammation 4.5 Mechanisms of glucocorticoid action 4.6 Dissociated glucocorticoids 4.7 GR cross-talk with other nuclear receptors and coactivators 4.8 Overcoming steroid insensitivity 4.9 Glucorticoid-sparing approaches to anti-inflammatory therapy 4.10 Conclusion 5 Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms Evangelia Charmandari, Tomoshige Kino and George P. Chrousos 5.1 Introduction 5.2 Molecular mechanisms of glucocorticoid resistance 5.3 Conclusions 6 Corticosteroid Responsiveness in Asthma: Clinical Aspects Kian Fan Chung 6.1 Introduction 6.2 Effects of corticosteroids in asthma 6.3 Definition of corticosteroid insensitivity 6.4 Oral CS responsiveness in asthma 6.5 ICS responsiveness in asthma 6.6 CS responsiveness in severe asthma 6.7 Surrogates for CS responsiveness in asthma 6.8 Pharmacokinetics of systemic CS in severe asthma 6.9 CS responsiveness in cigarette smokers and chronic obstructive pulmonary disease 6.10 Other diseases of CS insensitivity 6.11 Conclusions 7 Glucocorticoid-insensitive Asthma: Molecular Mechanisms John W. Bloom 7.1 Introduction 7.2 GR abnormalities 7.3 GR nuclear translocation 7.4 Cross-talk with transcription factors 7.5 NF-kB, GR, histones and chromatin remodelling 7.6 Epigenetics and asthma 7.7 Conclusions 8 Cigarette Smoke, Oxidative Stress and Corticosteroid Responsiveness Irfan Rahman and David Adenuga 8.1 Oxidative stress 8.2 Cigarette smoke/oxidative stress-induced NF-kB-mediated pro-inflammatory gene expression 8.3 Histone acetylation and deacetylation 8.4 Corticosteroids 8.5 Histone deacetylases 8.6 Reversing Glucocorticoids / Corticosteroid resistance 8.7 Conclusion 9 Regulation of Glucocorticoid Sensitivity by Macrophage Migration Inhibitory Factor Eric F. Morand 9.1 Introduction 9.2 MIF as a pro-inflammatory factor 9.3 Relationship between MIF and glucocorticoids 9.4 Conclusions 10 Steroid-sparing Strategies: Long-acting Inhaled beta2 -Agonists Anna Miller-Larsson and Olof Selroos 10.1 Introduction 10.2 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 medication 10.4 Effects of lower dose ICS/LABA versus higher dose ICS on exacerbations 10.5 Protocols with tapering ICS doses with and without LABA while maintaining asthma control 10.6 Reducing ICS doses using an adjustable ICS/LABA dosing regimen 10.7 Reducing ICS doses using Symbicort(r) maintenance and reliever therapy 10.8 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 ICS 11 Steroid-sparing Strategies: Other Combinations Gaetano Caramori, Kazuhiro Ito and Alberto Papi 11.1 Introduction 11.2 Theophylline as steroid-sparing treatment in asthma and COPD 11.3 Selective inhibitors of PDE4 11.4 Modulators of the synthesis or action of key inflammatory mediators 11.5 Anticholinergics 11.6 Leukotriene synthesis inhibitors and leukotriene receptor antagonists 11.7 Anti-lgE therapy 11.8 Macrolides/ketolides 11.9 TNFa inhibitors 11.10 Conclusions 12 Kinases as Anti-inflammatory Targets for Respiratory Disease Iain Kilty 12.1 Introduction 12.2 Pharmacological targeting of kinases 12.3 Targeting NF-eB activation 12.4 Targeting the MAPKs 12.5 Targeting PI3K 12.6 Further potential kinase targets 12.7 Conclusions 13 Pharmacokinetic/Pharmacodynamic Factors and Steroid Sensitivity Gonther Hochhaus 13.1 Introduction 13.2 What factors are important for pulmonary efficacy and safety? 13.3 Pharmacodynamic aspects 13.4 Pharmacokinetic drug properties 13.5 Conclusion 14 Improved Lung Deposition: New Inhaler Devices Omar S. Usmani 14.1 Introduction 14.2 Historical review of inhaled drug therapy 14.3 Deposition of aerosols within the respiratory tract 14.4 Assessing drug deposition in the lungs 14.5 Aerosol generation devices for inhaled drug therapy Index