Overcoming Steroid Insensitivity in Respiratory Disease

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-êB-induced inflammatory gene expression by GR–NF-êB

1.7 GR–NF-êB 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 Schäcke, Khusru Asadullah and Wolf-Dietrich Döcke

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 β2 -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® 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 TNFá 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-êB 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

Gönther 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