Molecular Basis of Pulmonary Disease (eBook)

Preface 6
Contents 8
Contributors 10
1 A Clinical Approach to Rare Lung Diseases 13
Introduction 13
Diagnostic Evaluation 15
History 15
Breathlessness 16
Chest Discomfort 16
Respiratory Sounds or Noises 17
Medical History 17
Family/Social History 17
Occupational/Environmental History 17
Review of Systems 18
Physical Examination 18
Inspection 18
Palpation and Percussion 18
Auscultation 19
Imaging Studies 19
Physiologic Studies 20
Other Studies 21
Pulmonary Differential Diagnosis of Rare or Unusual Conditions 22
References 41
2 Clinical Trials for Rare Lung Diseases 43
Introduction 44
A Hierarchy of Study Designs 46
Summary 49
References 49
3 Idiopathic and Familial Pulmonary Arterial Hypertension 51
Historical Review of Pulmonary Arterial Hypertension 52
Clinical History 52
Development of Clinical Classifications 52
Epidemiology of Pulmonary Arterial Hypertension 54
Incidence and Natural History 54
Prognostic Factors 54
Clinical Assessment of Pulmonary Arterial Hypertension 55
Defining Characteristics 55
Clinical History 55
Physical Examination Findings 55
Diagnostic Testing 56
Electrocardiography 56
Chest Radiography 57
Doppler Echocardiography 57
Evaluation of the Etiology of Pulmonary Hypertension 58
Pulmonary Function Testing 59
Evaluation for Thromboembolic Disease 59
Radiographic Testing 59
Serologic and Laboratory Testing 60
MRI 60
Confirmation of Presence of Pulmonary Arterial Hypertension (PAH) 60
Pathology 61
Genetics 63
History 63
Identification of BMPR2 Gene Mutations 64
Genetic Testing and Counseling 66
Potential Modifiers and Other Genes 66
Pathogenesis 67
Endothelial Dysfunction 68
Nitric Oxide 69
Prostacyclin 69
Thromboxane 70
Endothelin 70
Growth Factors 70
Serotonin 71
Bone Morphogenic Proteins (BMPs), Transforming Growth Factor- (TGF-), and Smad Signaling 71
Vasoactive Intestinal Peptide (VIP) 72
Tenascin-C (TN-C) 72
Elastase 73
S100A4 73
Inflammation 73
Viral Infection 73
Ion Channels 74
Rho-Kinase 74
Current Therapies for Pulmonary Hypertension 75
General Measures 75
Conventional Therapies 75
Calcium Channel Blockers 76
Targeted Pulmonary Arterial Hypertension Therapies 76
Prostanoids 76
Endothelin Receptor Antagonists 77
Phosphodiesterase Inhibitors 78
Interventional Procedures 78
Future Directions 79
Diagnosis and Management 79
Pharmacotherapies 79
Genetics 80
Pathobiology and Cell-Based Therapies 80
References 81
4 Lymphangioleiomyomatosis 97
Introduction 98
Epidemiology 98
Genetic Basis and Molecular Pathology 100
Overview 100
Tuberous Sclerosis Complex-Associated LAM 100
Sporadic LAM 101
LAM and the mTOR Signaling Cascade 102
The Cell of Origin of LAM 104
Why Does LAM Occur in Women? 105
Why Is LAM Associated with Cystic Lung Disease? 106
Clinical Presentation 107
Physical Examination 108
Diagnosis 108
Symptomatic Women Without a Prior Chest CT 108
Symptomatic or Asymptomatic Patient with Cystic Change on a High-Resolution Chest CT 109
Pathology 109
Physiology 111
Radiology 111
Clinical Course and Management 112
Pulmonary Function 112
Renal Angiomyolipomas, Lymphadenopathy, and Lymphagiomyomas 112
Pleural Complications 112
Screening and Follow-Up 113
Treatment 113
Clinical Trials 113
Transplantation 114
Challenges and Future Directions 115
Notes 115
References 116
5 Autoimmune Pulmonary Alveolar Proteinosis 123
Introduction and Definitions 124
Epidemiology 126
Molecular Pathogenesis 127
Animal Models 127
Disruption of Surfactant Homeostasis in Autoimmune PAP 129
Genetic Basis of Congenital PAP and Disorders of Surfactant Production 130
Clinical Presentation and Course 130
Diagnosis 131
Conventional Management and Treatment 134
Future Therapeutic Targets and Directions 135
GM-CSF Therapy 135
Other Approaches 136
References 137
6 Mutations in Surfactant Protein C and Interstitial Lung Disease 144
Introduction 145
Initial Clinical Evaluation of Diffuse Parenchymal Lung Disease 147
Epidemiology 147
Clinical Manifestations 148
Chest Imaging Studies 148
Physiological Studies 150
Pulmonary Function Testing 150
Gas Exchange 150
Pathology 150
Clinical Course 151
Treatment 151
Familial Pulmonary Fibrosis 152
Histopathology 153
Clinical Manifestations of SP-C Mutations Associated with ILD 154
Surfactant Protein C Structure/Function 156
SP-C Mutations and IIP 157
Molecular Pathogenesis of Disease 159
Protein Folding in the Endoplasmic Reticulum (ER) 159
ER Quality Control and the Unfolded Protein Response (UPR) 161
SFTPC Mutations: Cell Culture Data 162
Adaptation of Type II Cells to Misfolded SP-C? 163
SFTPC Mutations: Transgenic Mouse Data 163
Role of AEC Dysfunction/Apoptosis in Pathogenesis of Fibrosis 164
Animal Models of Pulmonary Fibrosis 164
Emerging Concepts: Role of Epithelial-to-Mesenchymal Transition (EMT) in Pulmonary Fibrosis 165
Possible Treatment Modalities for Patients with SFTPC Mutations 166
Conclusion 166
References 167
7 Hereditary Haemorrhagic Telangiectasia 178
Clinical HHT 178
Lung Disease in HHT 179
Pulmonary Hypertension in HHT 180
Variable Expression of HHT 181
Structural Basis of HHT 181
Classical Telangiectasia and AVMs 181
Non-criterion Manifestations of HHT 181
Genetic Basis of HHT 182
HHT Gene Mutations 183
ENG (Endoglin) Mutations 183
ACVRL1 (ALK1) Mutations 184
MADH4 (SMAD4) Mutations 185
Genotype--Phenotype Correlations 185
TGF- Family Signal Transduction Pathway 185
General Overview 185
ENDOGLIN 186
SMAD4 186
ALK1 187
Identity of ENG/ALK1 Ligands Pertinent to HHT: TGF- or BMP9? 188
Animal Models for HHT 188
Eng- or Alk1-Homozygous Mice 188
Eng-or Alk1-Heterozygous Mice 189
Conditional Knockout Mice for Alk1, Eng, and SMAD4 Genes 189
Implicated Roles of ENG and ALK1 in the Pathogenesis of HHT 189
Dysregulation of Angiogenesis 190
Perturbation of Arterial and Venous Identity 191
eNOS Uncoupling/Cox2 191
Future Directions of HHT Research 192
References 192
8 Hermansky-Pudlak Syndrome 200
Epidemiology 200
Genetic Basis and Molecular Pathogenesis 201
HPS-1 203
HPS-2 203
HPS-3 204
HPS-4 204
HPS-5 204
HPS-6 204
HPS-7 204
HPS-8 205
Heterozygotes 205
Clinical Presentation and Natural History 205
Albinism 205
Bleeding Diathesis 205
Inflammatory Bowel Disease 205
Interstitial Lung Disease (ILD) 206
Other Manifestations 208
Genotype--Phenotype Correlations 208
Diagnostic Approach 208
Management and Treatment 209
Disease Models 210
Other Potential Model Systems 211
Future Directions 212
References 212
9 Alpha-1 Antitrypsin Deficiency 219
AAT Synthesis and Regulation 219
AAT Structure and Mechanisms of Protease Inhibitory Activity 220
Genetic Modifications of the AAT Molecule 222
Posttranslational-Modified Molecular Forms of AAT 223
Clinical Lung Disease 225
Clinical Liver Disease 227
Other Diseases Associated with AATD 228
Clinical Testing 228
Summary 229
References 229
10 The Marfan Syndrome 235
Introduction 235
Prevalence 236
Genetic Basis 236
Animal Models and Molecular Pathogenesis 236
Marfan Mice Implicate Novel Functions for Fibrillin-1 237
Fibrillin-1 Deficiency -- Model of an Active Matrix in Lung Morphogenesis 238
Mechanism for TGFb Dysregulation in MFS 239
Airspace Septation Defects and Adult Emphysema 239
Fibrillin-1 Deficiency and Respiratory Muscle Dysfunction 240
Mouse Versus Human Lung Phenotype 240
Translation of Findings from the Marfan Lung 241
Losartan Studies 241
Fibrillin-1 Deficiency as a Paradigm for Emphysema and Disorders of Lung Prematurity 241
Clinical Presentation 242
Lung and Pleural Abnormalities 243
Spontaneous Pneumothorax, Subpleural Bullae, and Apical Pulmonary Fibrosis 243
Cystic Lung Disease 244
Pulmonary Tuberculosis 244
Airway Abnormalities 244
Bronchiectasis 244
Acquired Tracheobronchomegaly (TBM) 244
Tracheomalacia, Tracheal Compression, and Tracheal Collapse 244
Bronchial Hyperreactivity 245
Sleep Disturbances 245
Musculoskeletal and Developmental Abnormalities with Respiratory Consequences 246
Pectus Excavatum 246
Kyphoscoliosis 246
Myopathy with Respiratory Failure 247
Diaphragmatic Hernia and Eventration 247
Pulmonary Aplasia 247
Pulmonary Vascular Issues and Respiratory Failure 247
Pulmonary Function Abnormalities 248
Pulmonary Considerations in the MFS Patient Undergoing Surgery 248
Diagnostic Approach 248
Conventional Management and Treatment 249
Future Directions and Therapeutic Targets 250
Marfan Syndrome Patient Organizations 250
References 250
11 Surfactant Deficiency Disorders: SP-B and ABCA3 256
Introduction 256
Epidemiology 258
Genetic Basis and Molecular Pathogenesis 259
Animal Models 263
Clinical Presentations and Natural History 264
Diagnostic Approach 265
Conventional Management and Treatment 266
Future Therapeutic Targets and Directions 267
References 268
12 Pulmonary Capillary Hemangiomatosis 275
Introduction 275
Epidemiology/Genetics 276
Molecular Pathogenesis 276
Animal Models 278
Clinical Presentation 278
Diagnosis 278
Treatment 279
Future Directions 280
References 280
13 Anti-glomerular Basement Disease: Goodpasture's Syndrome 282
Introduction 283
History 283
Basement Membrane and Collagen Biochemistry 284
Basement Membrane 284
Collagen 284
Pathogenesis 286
Antigenic Determinants 286
Revelation of Cryptogenic Antigens 287
Autoantibody Production/Humoral Immune Response 287
Cellular Immune Response: Role of Th1 Response 288
Regulation of Antigen Tolerance 288
Genetic Susceptibility 289
Epidemiology 289
Clinical Manifestations 290
Renal 290
Pulmonary 290
Imaging and Physiologic Studies 291
Pathology 291
Renal 291
Pulmonary 291
Laboratory Studies 292
General 292
Renal 292
Pulmonary 292
Serologies: Sensitivity/Specificity of Assays 292
Acute 293
Maintenance 294
Experimental/New Therapies 294
Prognosis/Outcome 294
Summary 294
References 295
14 Primary Ciliary Dyskinesia 300
Introduction 300
Epidemiology 301
Genetic Basis and Molecular Pathogenesis of PCD 302
Animal Models 308
Clinical Manifestations of PCD 313
Diagnostic Approach 317
Management/Treatment of PCD 319
Future Therapeutic Targets and Directions 321
References 322
15 Pulmonary Alveolar Microlithiasis 331
History 331
Epidemiology 332
Frequency 332
Clinical Manifestation 332
Signs and Symptoms 332
Blood Study 332
Bronchoalveolar Lavage Fluid (BALF) 332
Respiratory Function 332
Radiological findings 333
Chest X-Ray 333
CT 333
Scintigram 334
Pathology 335
Diagnosis 335
Diagnosis 335
Complications 338
Mode of Detection and Age of Diagnosis 338
Procedures Used for Diagnosis 338
Prognosis 338
Therapies 338
The Gene Causing PAM 339
Mutation in the SLC34A2 Causes PAM 339
SLC34A2 and Phosphate Transport 339
Therapeutic Consideration 340
Population Genetics 341
Conclusion 342
References 342
16 Cystic Fibrosis 345
Introduction 345
Epidemiology 346
Genetic Basis and Molecular Pathogenesis 346
Animal Models 354
Clinical Presentation 355
Nutrition and Gastrointestinal Manifestations 357
Diagnostic Approach 360
Conventional Treatment 361
Further Therapeutic Targets and Direction 363
Pharmacological Approaches 363
References 365
17 Pulmonary Langerhans' Cell Histiocytosis - Advances in the Understanding of a True Dendritic Cell Lung Disease 375
Epidemiology and Demographics 377
Gross Pathology and Histologic Features 378
Pathogenesis 379
Pulmonary LCH a Neoplastic or Reactive Process? 382
Clinical Features 382
Radiographic Findings 383
Pulmonary Function Testing and Exercise Physiology 385
Diagnostic Evaluation of Individuals with Suspected Pulmonary LCH 386
Management 386
Outcomes and Prognosis 388
References 389
18 Sarcoidosis 395
Introduction 395
Epidemiology 396
Clinical Manifestations 396
Imaging 396
Laboratory Abnormalities 398
Pulmonary Function Studies 398
Diagnosis of Pulmonary Sarcoidosis 398
Pathology 399
Natural History of Pulmonary Sarcoidosis 399
Treatment 399
Lessons from Experiments of Nature and Unforeseen Consequences of Recently Introduced Therapeutic Strategies 400
Prevalence of Sarcoid in HIV Infection: Decrease with Active Infection and Increase with Effective Treatment 400
Sarcoid Associated with Interferon Therapy and Hepatitis C 402
TNF- Inhibition 403
Pathogenesis of Sarcoidosis 403
Immune Basis of the Pathogenesis of Sarcoidosis 404
Genetic Susceptibility to Sarcoidosis 407
Potential Etiologic Antigens in Sarcoidosis 408
References 409
19 Scleroderma Lung Disease 415
Introduction 415
Epidemiology 416
Genetic Basis and Molecular Pathogenesis 416
Animal Models 417
Clinical Presentation 418
Symptoms and Physical Exam 418
Physiologic Findings 419
Imaging 419
Histopathology 419
Bronchoalveolar Lavage 420
Diagnostic Approach 421
Conventional Management and Treatment 421
Future Therapeutic Targets and Directions 422
References 423
Subject Index 426