Airway Smooth Muscle in Asthma and COPD: Biology and Pharmacology

List of Contributors xi

1 Biophysical basis of airway smooth muscle contraction and hyperresponsiveness in asthma 1
Steven S. An and Jeffrey J. Fredberg

1.1 Introduction 1

1.2 Airway hyperresponsiveness 2

1.3 Classical behaviour of airway smooth muscle and the balance of static forces 6

1.4 Shortening velocity and other manifestations of muscle dynamics 8

1.5 Biophysical characterization of airway smooth muscle: bronchospasm in culture? 10

1.6 Mechanical plasticity: a nonclassical feature of airway smooth muscle 14

1.7 Recent observations 18

1.8 Future directions 20

References 20

2 Dynamics of cytoskeletal and contractile protein organization: an emerging paradigm for airway smooth muscle contraction 31
Wenwu Zhang and Susan J. Gunst

2.1 Introduction 31

2.2 Molecular structure and organization of contractile and cytoskeletal filaments in the airway smooth muscle cell 33

2.3 Cytoskeletal dynamics and airway smooth muscle contraction 38

References 43

3 Airway smooth muscle: role in airway constrictor hyperresponsiveness 53
Melanie Brown and Julian Solway

3.1 What is airway constrictor hyperresponsiveness (AHR)? 53

3.2 Is AHR ever good? 55

3.3 Potential mechanisms leading to airflow obstruction 55

3.4 Potential abnormalities of airway smooth muscle (ASM) 60

3.5 If ASM is dysfunctional, how did it get that way? 63

3.6 Summary 64

Acknowledgements 64

References 64

4 Airway smooth muscle phenotypic and functional plasticity 71
Andrew J. Halayko, Reinoud Gosens and Thai Tran

4.1 Introduction 71

4.2 Historical perspective: smooth muscle phenotype plasticity 72

4.3 Features of phenotype plasticity 74

4.4 Mechanisms for phenotypic plasticity 76

4.5 Functional plasticity of airway smooth muscle: role in asthma pathogenesis 80

4.6 Concluding remarks 84

References 84

5 Airway smooth muscle proliferation: insights into mechanisms regulating airway smooth muscle mass 89
Reynold A. Panettieri, Jr.

5.1 Increases in airway smooth muscle (ASM) mass and the functional consequences 89

5.2 Growth factors, inflammatory mediators and cytokines modulate ASM proliferation 91
References 99

6 Airway smooth muscle bidirectional interactions with extracellular matrix 105
Jane E. Ward and Stuart J. Hirst

6.1 Overview 105

6.2 Introduction 106

6.3 Airway extracellular matrix (ECM) in health and disease 108

6.4 Integrins 110

6.5 Airway smooth muscle (ASM) as a modulator of airway ECM 111

6.6 Airway ECM as modulator of ASM function 113

6.7 Impact of anti-asthma therapy on ASM–ECM interactions 118

6.8 Conclusions 120

Acknowledgements 121

References 121

7 Airway smooth muscle interaction with mast cells 127
Roger Marthan, Patrick Berger, Pierre-Olivier Girodet and J. Manuel Tunon-de-Lara

7.1 Introduction 127

7.2 Mast cell mediators alter smooth muscle function 129

7.3 Smooth muscle cells induce mast cell chemotaxis 132

7.4 Mast cells can adhere to airway smooth muscle 134

7.5 Conclusion 135

Acknowledgements 136

References 136

8 Airway smooth muscle synthesis of inflammatory mediators 141
Alison E. John, Deborah L. Clarke, Alan J. Knox and Karl Deacon

8.1 Introduction 141

8.2 Lipid mediators 142

8.3 Chemokines 146

8.4 Growth and remodelling factors 149

8.5 Conclusions 152

References 152

9 Airway smooth muscle in experimental models 159
Anne-Marie Lauzon and James G. Martin

9.1 Introduction 159

9.2 Methods of assessment of airway smooth muscle (ASM) function 160

9.3 Potential mechanisms by which ASM properties may contribute to airway responsiveness 161

9.4 Experimental models 164

9.5 Conclusion 173

Acknowledgement 173

References 173

10 Altered properties of airway smooth muscle in asthma 181
Judith Black, Janette Burgess, Brian Oliver and Lyn Moir

10.1 Introduction 181

10.2 The extracellular matrix (ECM) and the airway smooth muscle (ASM) 182

10.3 ASM and integrins 190

10.4 The ASM cell and inflammation 191

10.5 The ASM cell and infection 193

References 194

11 The airway smooth muscle in chronic obstructive pulmonary disease (COPD) 201
Maria B. Sukkar and Kian Fan Chung

11.1 Introduction 201

11.2 Definition and assessment of COPD 202

11.3 Pathological features of COPD 203

11.4 COPD mechanisms 206

11.5 Conclusion 220

References 220

12 Glucocorticoid actions on airway smooth muscle 235
Ian M. Adcock, Loukia Tsaprouni and Pank Bhavsar

12.1 Introduction 235

12.2 Airway smooth muscle (ASM) in airways disease 236

12.3 Gene induction by glucocorticoid receptors (GR) 240

12.4 Actions of β2-agonists and glucocorticoids on growth, proliferation, and migration of ASM 245

12.5 Summary and conclusions 248

Acknowledgements 248

References 248

13 β2-Adrenergic receptors: effects on airway smooth muscle 255
Malcolm Johnson

13.1 The β2-adrenoceptor 255

13.2 β2-Receptor activation 257

13.3 β2-Receptor signalling pathways 257

13.4 Effects in airway smooth muscle (ASM) 258

13.5 β2-Receptor desensitization 260

13.6 Influence of polymorphisms of the β2-adrenoceptor in ASM 262

13.7 Non-bronchodilator effects of β2-agonists in ASM 264

13.8 Conclusion 271

References 271

14 Asthma treatments: effects on the airway smooth muscle 277
Kian Fan Chung

14.1 Introduction 277

14.2 Role and abnormalities of airway smooth muscle (ASM) in asthma and COPD 279

14.3 Treatment of asthma 283

14.4 Conclusion 293

References 293

Index 303