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Murray and Nadel's Textbook of Respiratory Medicine E-Book

Murray and Nadel's Textbook of Respiratory Medicine E-Book

Robert J. Mason | V.Courtney Broaddus | Thomas R Martin | Talmadge E King | Dean Schraufnagel | John F. Murray | Jay A. Nadel

(2010)

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Book Details

Abstract

Murray and Nadel’s Textbook of Respiratory Medicine has long been the definitive and comprehensive pulmonary disease reference. Robert J. Mason, MD now presents the fifth edition in full color with new images and highlighted clinical elements. The fully searchable text is also online at www.expertconsult.com, along with regular updates, video clips, additional images, and self-assessment questions. This new edition has been completely updated and remains the essential tool you need to care for patients with pulmonary disease.

    • Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability. Compatible with Kindle®, nook®, and other popular devices.
    • Master the scientific principles of respiratory medicine and its clinical applications.
    • Work through differential diagnosis using detailed explanations of each disease entity.
    • Learn new subjects in Pulmonary Medicine including Genetics, Ultrasound, and other key topics.
    • Grasp the Key Points in each chapter.
    • Search the full text online at expertconsult.com, along with downloadable images, regular updates, more than 50 videos, case studies, and self-assessment questions.
    • Consult new chapters covering Ultrasound, Innate Immunity, Adaptive Immunity, Deposition and Clearance, Ventilator-Associated Pneumonia.
    • Find critical information easily using the new full-color design that enhances teaching points and highlights challenging concepts.
    • Apply the expertise and fresh ideas of three new editors—Drs. Thomas R. Martin, Talmadge E. King, Jr., and Dean E. Schraufnagel.
    • Review the latest developments in genetics with advice on how the data will affect patient care.

    Table of Contents

    Section Title Page Action Price
    e9781416047100v1.pdf 1
    Front cover 1
    Murray and Nadel's Textbook of Respiratory Medicine 2
    Copyright page 5
    Dedication 6
    Contributors 8
    Preface to the Fifth Edition 20
    Preface to the First Edition 22
    Video Contents 24
    Table of Contents 26
    I Scientific Principles of Respiratory Medicine 32
    A Anatomy and Development of the Respiratory Tract 34
    1 Anatomy of the Lungs 34
    INTRODUCTION 34
    GROSS AND SUBGROSS ORGANIZATION 34
    AIRWAYS 37
    Cellular Complexity 38
    Bronchial Circulation 41
    PULMONARY CIRCULATION 41
    Pulmonary Vascular Endothelial Cells 43
    TERMINAL RESPIRATORY UNITS 44
    Type II Cell Structure 46
    Type II Cell Functions 47
    Type II Cell Proliferation 47
    Type I Cell Structure 47
    Type I Cell Functions 48
    Type I Cell Proliferation 49
    Relationship between Type II and Type I Cells In Vivo and In Vitro 49
    INNERVATION 49
    AIRSPACE MACROPHAGES, LYMPHATICS, LYMPHOID TISSUE, AND INNATE IMMUNITY 51
    References 52
    2 Lung Growth and Development 57
    INTRODUCTION 57
    STAGES OF LUNG DEVELOPMENT 57
    TISSUE INTERACTIONS AND LUNG DEVELOPMENT 60
    MOLECULAR REGULATION OF LUNG DEVELOPMENT 60
    Diffusible Mediators of Lung Development 60
    Fibroblast Growth Factors and Fibroblast Growth Factor Receptors 60
    Retinoic Acid 62
    Sonic Hedgehog 62
    TGF-β Superfamily 62
    Wnts and β-catenin 63
    Platelet-Derived Growth Factor 63
    VEGF 63
    Glucocorticoids 63
    Transcriptional Regulation of Lung Development 64
    Thyroid Transcription Factor 1 64
    FOX Family 64
    GATA-6 65
    SOX Family 65
    Summary 65
    References 66
    3 Mendelian Genetics, Disease Modifying or Associated Genes, and Epigenetics of Lung Disease 69
    INTRODUCTION 69
    Scope of the Problem 70
    Potential Impact of Human Genetics 70
    MOLECULAR CHARACTERIZATION OF GENETIC VARIATION 70
    Genomic Maps 71
    Comparative Genomics 72
    Public Databases 72
    GENETIC EPIDEMIOLOGY 73
    Genetic Markers and Their Inheritance 73
    Linkage and Positional Cloning 73
    Genetic Association and Candidate Genes 74
    Genome-Wide Association Studies 75
    Candidate Gene or Region-based Testing 75
    Gene by Environment Interaction 75
    EPIGENETICS 75
    APPLICATION TO PULMONARY DISEASES 77
    Asthma 77
    Chronic Obstructive Lung Disease 79
    Acute Respiratory Distress Syndrome 79
    Lung Cancer 79
    Interstitial Lung Disease 80
    THE PATH FORWARD 80
    ACKNOWLEDGMENTS 81
    References 81
    B Respiratory Physiology and Pharmacology 84
    4 Ventilation, Blood Flow, and Gas Exchange 84
    INTRODUCTION 84
    VENTILATION 84
    Lung Volumes 86
    Functional Residual Capacity, Residual Volume, and Total Lung Capacity 86
    Total and Alveolar Ventilation 87
    Total Ventilation 87
    Alveolar Ventilation 87
    Anatomic Dead Space 87
    Physiologic Dead Space 87
    Inequality of Ventilation 88
    Topographic Inequality 88
    Airway Closure 89
    Nontopographic Inequality 89
    BLOOD FLOW 89
    Pressures of the Pulmonary Circulation 89
    Pressure Inside Blood Vessels 90
    Pressures Outside Blood Vessels 90
    Pulmonary Vascular Resistance 91
    Pressure-Flow Relations 91
    Effect of Lung Volume 93
    Other Factors 93
    Distribution of Pulmonary Blood Flow 94
    Normal Distribution 94
    Three-Zone Model for the Distribution of Blood Flow 94
    The Effect of Lung Volume on the Distribution of Blood Flow—Zone 4 95
    Increased Acceleration and Weightlessness. 95
    Nongravitational Factors Influencing the Distribution of Pulmonary Blood Flow. 96
    Abnormal Patterns of Blood Flow 96
    Active Control of the Pulmonary Circulation 96
    Hypoxia 97
    Other Physiologic Substances 98
    Damage to Pulmonary Capillaries by High Wall Stresses 98
    Metabolic Functions of the Pulmonary Circulation 99
    GAS EXCHANGE 100
    Causes of Hypoxemia 101
    Hypoventilation 101
    Diffusion Limitation 102
    Oxygen Uptake along the Pulmonary Capillary 103
    Reaction Rates with Hemoglobin 104
    Diffusing Capacity 104
    Measurement. 105
    Interpretation. 106
    Shunt 106
    Ventilation-Perfusion Relationships 107
    Gas Exchange in a Single Lung Unit 107
    Pattern in the Normal Lung 108
    Traditional Assessment of Ventilation-Perfusion Inequality 109
    Distributions of Ventilation-Perfusion Ratios 111
    Multiple Inert Gas Elimination Technique. 111
    Distribution in Normal Subjects. 113
    Distributions in Lung Disease. 113
    Ventilation-Perfusion Inequality and Carbon Dioxide Retention 114
    Effect of Changes in Cardiac Output on Gas Exchange in the Presence of Ventilation-Perfusion Inequality 115
    Blood-Gas Transport 115
    Oxygen 115
    Carbon Dioxide 116
    References 117
    5 Respiratory System Mechanics and Energetics 120
    INTRODUCTION 120
    TERMINOLOGY 120
    Flow 120
    Volume 120
    Pressure 121
    Compliance and Resistance 122
    Time Constants 122
    RESPIRATORY MECHANICS IN STATIC CONDITIONS 123
    Elastic Recoil of the Lungs 123
    Lung Connective Tissue 123
    Alveolar Surface Forces and Surfactant 123
    Hysteresis and Stress Adaptation 125
    Recruitment Maneuvers in Acute Respiratory Distress Syndrome 125
    Elastic Recoil of the Chest Wall 125
    Respiratory Muscles 125
    Fatigue of Respiratory Muscles 127
    Respiratory Muscle Atrophy during Positive-Pressure Mechanical Ventilation 127
    Chest Wall Compliance 127
    Integration of Lung and Chest Wall Mechanics 128
    Calculation of Total Respiratory System Compliance from Lung and Chest Wall Compliance 129
    Clinical Applications 129
    The Impact of Positive End-Expiratory Pressure on Pleural Pressure 129
    Plateau Pressures in Patients Receiving Positive-Pressure Mechanical Ventilation 129
    THE RESPIRATORY SYSTEM IN DYNAMIC CONDITIONS 130
    Resistive Work Due to Gas Flow through Airways 130
    Laminar versus Turbulent Flow 130
    Reynold’s Number 130
    Clinical Effects of Heliox 131
    Flow Limitation 131
    Equal Pressure Point Theory (Fig. 5-20). 131
    The Bernoulli Effect and Wave Speed Theory. 132
    Other Resistive Work 132
    Auto-PEEP during Positive-Pressure Ventilation of COPD 132
    Measurement of Static Compliance and Resistance during Mechanical Ventilation 133
    ENERGETICS AND WORK OF BREATHING 134
    Measuring Work of Breathing Done by a Positive-Pressure Ventilator in a Paralyzed Patient 134
    Measuring Work of Breathing in a Spontaneously Breathing Patient 135
    Oxygen Cost of Breathing 135
    References 136
    6 Pulmonary Circulation and Regulation of Fluid Balance 139
    INTRODUCTION 139
    PULMONARY HEMODYNAMICS 139
    Pulmonary Vascular Pressures 140
    Pulmonary Vascular Resistance 140
    Vascular Resistance Profile 141
    Functional Description of Pulmonary Vessels 141
    Extra-Alveolar Vessels. 142
    Alveolar Vessels. 142
    Corner Vessels. 142
    Mechanical Effects on Pulmonary Vascular Resistance 142
    Transmural Pressure. 142
    Lung Volume. 143
    Viscosity. 143
    Pulmonary Vascular Compliance 143
    Pulmonary Vascular Pressure-Volume Curve 143
    Changes in Vascular Compliance 144
    Pulmonary Perfusion 144
    Distention and Recruitment 144
    Distribution of Pulmonary Blood Flow 144
    Mechanical Stress and Strain 145
    Shear Stress 145
    Cyclic Stretch 145
    Pulmonary Vascular Response to Hypoxia 145
    Response Elements 145
    Neural Regulation of Pulmonary Vascular Resistance 147
    Humoral Regulation of Pulmonary Vascular Resistance 147
    LUNG FLUID AND SOLUTE EXCHANGE 148
    Pathogenesis of Pulmonary Edema 148
    Sites of Fluid Accumulation 148
    Mechanisms of Pulmonary Edema 148
    Increased Pulmonary Capillary Pressure. 148
    Decreased Plasma Oncotic Pressure. 149
    Increased Lung Vascular Permeability. 149
    Lymphatic Insufficiency. 149
    Safety Factors in Lung Fluid Homeostasis. 149
    Transcapillary Exchange 150
    Fluid Flux Equation 150
    Solute Flux Equation 151
    Diffusion 152
    Sites of Fluid and Solute Exchange 152
    Capillary Endothelium 152
    Alveolar Epithelium 152
    Alveolar-Capillary Septum 152
    Pulmonary Lymphatic Vessels 153
    Lung Interstitium 153
    Interstitial Pressures 153
    Interstitial Compliance 154
    Transvascular Transport of Plasma Molecules 154
    Capillary Endothelial Permeability 154
    Pore Theory 154
    Mechanisms of Increased Endothelial Permeability 155
    Characteristics of Increased Vascular Endothelial Permeability. 155
    Intracellular Ca2+ Shifts. 156
    Protein Kinase C Activation and Other Barrier-Regulatory Signals. 157
    Basement Membrane and Matrix Components. 157
    Endothelial Water Permeability and Albumin Transcytosis. 157
    Strategies to Reverse Permeability and Restore Barrier Integrity 158
    PULMONARY VASCULAR GENOMICS 160
    References 161
    chapter 6 APPENDIX Endothelial Cell Function 165
    EFFECTS OF CELLULAR AND MOLECULAR CHARGE 165
    REGIONAL DIFFERENCES IN ENDOTHELIAL PERMEABILITY 165
    CYTOSKELETAL ALTERATIONS 166
    ANGIOGENESIS 167
    APOPTOSIS AND ENDOTHELIAL CELL DYSFUNCTION 168
    References 168
    7 Acid-Base Balance 171
    INTRODUCTION AND PHYSIOLOGY 171
    Choice of Respiratory and Metabolic Parameters 171
    The Strong Ion Approach 173
    Nomenclature of Acid-Base Disorders 175
    Compensations 176
    Respiratory Acidosis 176
    Respiratory Alkalosis 177
    Metabolic Acidosis 177
    Metabolic Alkalosis 177
    Role of the Kidney in Acid-Base Balance 177
    Response to Acidosis and Excretion of Acid 177
    Response to Alkalosis 178
    Intracellular Acid-Base Physiology 178
    METABOLIC ACIDOSIS 179
    Anion Gap Concept 179
    Causes 180
    Lactic Acidosis 180
    Diabetic Ketoacidosis 183
    Uremic Acidosis 184
    Toxic Forms of Anion Gap Acidosis 184
    Hyperchloremic Acidosis 185
    Renal Tubular Acidosis 185
    Type 1 Renal Tubular Acidosis. 185
    Type 2 Renal Tubular Acidosis. 186
    Type 3 Renal Tubular Acidosis. 186
    Type 4 Renal Tubular Acidosis. 186
    Acidosis of Progressive Renal Failure 186
    Gastrointestinal Causes of Hyperchloremic Acidosis 186
    Miscellaneous Causes of Hyperchloremic Acidosis 187
    Urine Net Charge and Osmolar Gap 187
    Dilutional Acidosis 187
    Clinical Manifestations 187
    Therapy 188
    METABOLIC ALKALOSIS 188
    Causes 189
    Chloride Responsive Alkalosis 189
    Gastrointestinal Losses. 189
    Renal Losses. 189
    Losses in Sweat. 189
    Chloride-Resistant Alkalosis 189
    Excessive Intake of 190
    Extracellular Fluid Contraction 190
    Clinical Manifestations 190
    Therapy 190
    RESPIRATORY ACIDOSIS 190
    General Considerations 190
    Causes 190
    Clinical Manifestations 191
    Therapy 191
    RESPIRATORY ALKALOSIS 192
    General Considerations 192
    Causes 192
    Clinical Manifestations 193
    Therapy 193
    References 193
    8 Pharmacologic Principles 196
    INTRODUCTION 197
    CELL INTERACTIONS IN THE LUNG 197
    Vascular Endothelium 197
    Airway Epithelium 197
    Inflammatory Cells 197
    Nerves 198
    RECEPTORS 198
    Receptor Classification 198
    G Protein–Coupled Receptors 198
    Rhodopsin as a Model Receptor 199
    Structure 199
    Receptor Dimerization 200
    G Proteins 200
    Second Messengers 202
    Adenylyl Cyclase 202
    Phosphodiesterases 202
    Phosphatidylinositol Hydrolysis 203
    Guanylyl Cyclase 204
    Ion Channel–Coupled Signaling 204
    Cytokine Receptors 204
    Chemokine Receptors 204
    Enzyme-Linked Receptors 205
    Receptor Tyrosine Kinases 205
    Signal Transduction 205
    MAPK Pathways 205
    Receptor Serine/Threonine Kinases 205
    Receptor Protein Tyrosine Phosphatases 206
    Ion Channel Receptors 206
    Intracellular Receptors 206
    Steroid Receptors 206
    Receptor Subtypes 207
    Receptor Interactions 208
    DRUG-RECEPTOR INTERACTIONS 209
    Radioligand Binding 209
    Agonists and Antagonists 209
    RECEPTOR REGULATION 210
    Desensitization 210
    G Protein–Receptor Kinases 210
    Arrestins 211
    Down-Regulation 211
    Steroid Modulation 211
    Receptor Ontogeny 212
    Pulmonary Diseases 212
    Transcriptional Control 212
    ION CHANNELS 212
    Calcium Channels 212
    Voltage-Gated Channels 212
    Receptor-Operated Channels 213
    ICRAC 213
    Potassium Channels 213
    Sodium Channels 214
    Chloride Channels 214
    ENZYMES 214
    Protein Kinases 214
    MAP Kinases 215
    Phosphoinositide 3-Kinases 215
    Protein Phosphatases 216
    PHARMACOKINETICS 216
    Absorption 216
    Distribution 216
    Clearance 216
    ROUTES OF DRUG DELIVERY 217
    Inhaled Route 217
    Particle Size 217
    Pharmacokinetics 217
    Delivery Devices 217
    Metered-Dose Inhalers. 217
    Spacer Chambers. 217
    Dry Powder Inhalers. 218
    Nebulizers. 218
    Oral Route 218
    Parenteral Route 218
    AUTONOMIC PHARMACOLOGY 218
    Overview of Airway Innervation 218
    Neural Interactions 219
    Cotransmission 219
    Afferent Nerves 219
    Slowly Adapting Receptors 220
    Rapidly Adapting Receptors 220
    C Fibers 220
    Defense Reflexes 220
    Cough 221
    Cholinergic Nerves 221
    Cholinergic Control of Airways 221
    Extraneuronal ACh 221
    Muscarinic Receptors 221
    Cholinergic Reflexes 222
    Neurogenic Inflammation 222
    Tachykinins 223
    Calcitonin Gene–Related Peptide 223
    Neurogenic Inflammation in Human Airways 223
    Neurotrophins 224
    Bronchodilator Nerves 224
    Sympathetic Nerves 224
    Circulating Catecholamines 224
    Adrenergic Receptors 224
    Inhibitory Nonadrenergic Noncholinergic Nerves 224
    Neural Control in Disease 225
    Asthma 225
    COPD 225
    INFLAMMATORY MEDIATORS 225
    Histamine 226
    Leukotrienes 226
    Prostaglandins 226
    Platelet-Activating Factor 226
    Endothelins 226
    Nitric Oxide 226
    Oxygen-Derived Free Radicals 226
    Adenosine 226
    Bradykinin 226
    Cytokines 227
    Chemokines 227
    Multiple Mediators 227
    Anti-inflammatory Mediators 228
    TRANSCRIPTION FACTORS 228
    Activator Protein-1 228
    Nuclear Factor-κB 229
    JAK-STAT 229
    GATA-3 230
    T-Bet 230
    CREB 230
    Glucocorticoid Receptors 230
    Nuclear Factor of Activated T Cells 230
    Coactivators 230
    Histone Modification 230
    References 232
    C Defense Mechanisms and Immunology 237
    9 Pulmonary Surfactant 237
    INTRODUCTION 237
    PHYSIOLOGIC FUNCTIONS OF PULMONARY SURFACTANT 238
    COMPOSITION 239
    Lipids 239
    Proteins 239
    Surfactant Protein A 240
    Synthesis and Secretion 240
    Structure and Function 241
    Binding to Infectious Organisms 241
    Viruses. 241
    Bacteria. 241
    Mycobacteria, Fungi, Mycoplasma, and Pneumocystis. 241
    Interaction with Phagocytic Cells 242
    Surfactant Protein B 242
    Surfactant Protein C 243
    Surfactant Protein D 243
    Structure and Function 244
    Binding to Infectious Organisms 244
    Viruses. 244
    Bacteria. 244
    Fungi, Mycobacteria, Mycoplasma, and Pneumocystis. 244
    Interactions with Phagocytic Cells 244
    SECRETION AND EXTRACELLULAR PROCESSING OF SURFACTANT 245
    SURFACTANT ABNORMALITIES IN LUNG DISEASE 246
    Primary Surfactant Deficiency of the Newborn 246
    Epidemiology and Clinical Features 246
    Treatment 246
    Hereditary Surfactant Protein B Deficiency 246
    Hereditary Surfactant Protein C Deficiency and Mutations 247
    Acute Respiratory Distress Syndrome 247
    Surfactant Alterations 247
    Mechanisms Leading to Surfactant Dysfunction 247
    Pneumonia 248
    Interstitial Lung Diseases 248
    Obstructive Lung Diseases 248
    Other Lung Diseases 248
    SURFACTANT THERAPY FOR ACUTE RESPIRATORY DISTRESS SYNDROME 249
    Surfactant Preparation and Dose 249
    Surfactant Delivery Methods 249
    Effects of Mechanical Ventilation 250
    Proposed Surfactant Treatment Strategies 250
    ACKNOWLEDGMENT 250
    References 250
    10 Alveolar and Distal Airway Epithelial Fluid Transport 254
    INTRODUCTION 254
    LUNG EPITHELIAL FLUID ABSORPTION 254
    EVIDENCE FOR ACTIVE FLUID TRANSPORT IN THE INTACT LUNG 255
    ION TRANSPORT IN ALVEOLAR AND DISTAL AIRWAY EPITHELIAL CELLS 255
    REGULATION OF LUNG EPITHELIAL FLUID TRANSPORT 256
    MECHANISMS THAT CAN IMPAIR THE RESOLUTION OF ALVEOLAR EDEMA 258
    ALVEOLAR FLUID TRANSPORT UNDER PATHOLOGIC CONDITIONS 259
    FUTURE DIRECTIONS 260
    References 261
    11 Airway Epithelial Mucins and Mucous Hypersecretion 263
    INTRODUCTION 263
    COMPONENTS OF MUCUS 263
    CHARACTERISTICS OF NORMAL AIRWAY MUCINS IN HEALTHY INDIVIDUALS 264
    MUCOUS HYPERSECRETORY DISEASES AND THEIR CLINICAL CONSEQUENCES 264
    IMPORTANCE OF MUCOUS HYPERSECRETION IN CHRONIC INFLAMMATORY AIRWAY DISEASES 264
    Cystic Fibrosis 265
    Asthma 266
    Chronic Bronchitis and Chronic Obstructive Pulmonary Disease 267
    EPITHELIAL SIGNALING PATHWAYS RESPONSIBLE FOR MUCIN PRODUCTION IN AIRWAYS 268
    Early Studies of Mucins 268
    Epidermal Growth Factor Receptor Activation Stimulates Mucin Production in Airways 268
    Metalloproteases Cleave Membrane-Bound Epidermal Growth Factor Receptor Ligands to Produce Mucins 269
    Roles of Reactive Oxygen Species in Airway Epithelial Mucin Production 269
    Toll-like Receptors 269
    THERAPEUTIC IMPLICATIONS 270
    References 271
    12 Aerosol Deposition and Clearance 273
    INTRODUCTION 273
    DEFINITION AND DESCRIPTION OF AN AEROSOL, 274
    PRINCIPLES OF DEPOSITION 274
    MEASUREMENTS OF PARTICLE SIZE 275
    Evaluation of Aerosol Particle Size 275
    Application of In Vitro Measurements of Particle Size to Clinical Studies,, 275
    GENERATION OF THERAPEUTIC AEROSOLS 275
    Dry Powder Devices,, 275
    Pressurized Metered-Dose Inhalers, 276
    Jet Nebulizers 277
    New Developments in Aerosol Delivery Systems 277
    PRINCIPLES OF ASSESSMENT OF DELIVERY SYSTEMS, 277
    The Inhaled Mass 277
    Deposition 278
    STRATEGIES TO OPTIMIZE DEPOSITION OF THERAPEUTIC AEROSOLS 279
    Getting Particles Past the Oropharynx 279
    Control of Breathing Pattern and Aerosol Deposition 279
    Expiration and Problems with Aerosol Deposition 280
    Deposition and Dose versus Response 280
    ADDITIONAL FACTORS INFLUENCING DEVELOPMENT OF THERAPEUTIC AEROSOLS 281
    Asthma 282
    Cystic Fibrosis 283
    Delivery of Inhaled Medications to Young Children 283
    Delivery of Therapeutic Aerosols to the Nasal Mucosa 283
    Aerosol Delivery during Mechanical Ventilation,, 285
    DIAGNOSTIC RADIOAEROSOLS 285
    MUCOCILIARY CLEARANCE AND DISEASE 285
    ALVEOLAR CLEARANCE 287
    ENVIRONMENTAL AEROSOLS 287
    References 289
    13 Innate Immunity in the Lungs 292
    INTRODUCTION 292
    OVERVIEW OF THE COMPONENTS OF LUNG INNATE IMMUNITY 293
    INNATE RECOGNITION IN THE LUNG 295
    Secreted Pattern Recognition Receptors 295
    Collectins 295
    Complement 296
    Pentraxins and Other Secreted Pattern Recognition Receptors 296
    Cellular Pattern Recognition Receptors 296
    Plasma Membrane and Endosomal Pattern Recognition Receptors 296
    Toll-like Receptors. 296
    Scavenger Receptors. 298
    C-Type Lectin Receptors. 298
    Cytoplasmic Pattern Recognition Receptors 300
    Nucleotide-Binding and Oligomerization Domain–like Receptors. 300
    Retinoic Acid–Inducible Gene-1–like Receptors. 301
    Summary 301
    EFFECTOR MECHANISMS 301
    Epithelium 301
    Neutrophils 302
    Mononuclear Phagocytes 306
    Resident Macrophages 306
    Functions of Resident and Interstitial Alveolar Macrophages. 306
    Recruitment of Mononuclear Phagocytes 308
    Functions of Recruited Monocytes and Macrophages. 308
    Dendritic Cells 309
    Mouse and Human Lung Dendritic Cell Subsets. 311
    Functions of Lung Dendritic Cells. 312
    SYSTEM INTEGRATION 313
    References 315
    14 Adaptive Immunity 322
    INTRODUCTION 322
    COMPONENTS OF THE IMMUNE SYSTEM: OVERVIEW 322
    IMMUNE RECOGNITION 325
    B Cells and Antibodies 325
    Structure of Immunoglobulin and the B-Cell Receptor for Antigen 325
    Genetic Mechanisms Involved in the Formation of the B-Cell Receptor Repertoire 325
    Isotype Switching and Function of the Different Immunoglobulin Classes 328
    B-Cell Development 329
    Immunoglobulin Interactions with Antigen 330
    T Cells and Antigen-Presenting Cells 330
    T-Cell Receptors 330
    Genetic Mechanisms Involved in T-Cell Receptor Structure and T-Cell Receptor Repertoire Formation 331
    Antigen-Presenting Cells and Molecules of the Major Histocompatibility Complex 332
    Genetics and Nomenclature for the Human Leukocyte Antigen System 333
    Presentation and T-Cell Recognition of Antigens 334
    CD3 Complex and Intracellular Signaling after T-Cell Activation 336
    T-Cell Accessory Molecules CD4 and CD8 336
    T-Cell Development and Selection of the T-Cell Repertoire 336
    T-Cell Tolerance: The Prevention of Self-Reactivity 337
    GENERATION OF THE IMMUNE RESPONSE 338
    T-Cell Activation and the Need for Co-stimulatory Molecules 338
    Subsets of T Helper Cells 340
    CD4+ T-Cell–B-Cell Collaboration and Regulation of Antibody Production 341
    Generation and Regulation of Cell-Mediated Immune Responses 342
    SPECIFIC IMMUNE RESPONSES IN THE LUNG 343
    Lymphocyte Populations and Trafficking in the Lung 343
    Antibody-Mediated Immune Responses in the Lung 344
    Immune Response to Extracellular Pathogens 344
    Immune Response to Autoantigens 345
    Immune Response in Allergic Disease 345
    Cell-Mediated Inflammatory Responses in the Lung 346
    Granulomatous Lung Disease 346
    Cytotoxic T-Cell Reactions in the Lung 346
    References 347
    D Respiratory Pathology and Inflammation 351
    15 General Features of Non-neoplastic Respiratory Pathology 351
    INTRODUCTION 351
    LUNG PROCESSING 352
    ACUTE LUNG PROCESSES 352
    Diffuse Alveolar Damage 353
    Acute Bronchopneumonia 353
    Diffuse Alveolar Hemorrhage 353
    Acute Eosinophilic Lung Processes 354
    Acute/Subacute Lymphocytic Lung Processes 354
    Organizing Pneumonia 355
    INTERSTITIAL LUNG FIBROTIC PATTERNS 355
    Acute Interstitial Pneumonitis 355
    Usual Interstitial Pneumonitis 355
    Desquamative Interstitial Pneumonitis 357
    Lymphocytic Interstitial Pneumonitis 357
    Nonspecific Interstitial Pneumonitis 357
    Other Forms of Idiopathic Interstitial Lung Pattern 357
    GRANULOMATOUS LUNG PATTERNS 358
    BRONCHIOLAR DISEASE PATTERNS 359
    Chronic Bronchiolitis 359
    Granulomatous Bronchiolitis 361
    Obliterative Bronchiolitis 361
    PULMONARY VASCULAR DISEASE PATTERNS 362
    TRANSBRONCHIAL BIOPSY 365
    References 365
    16 Injury and Repair of the Lung 367
    INTRODUCTION 367
    CONCEPTS OF LUNG INJURY AND REPAIR 367
    Lung Injury 368
    Lung Repair 368
    Repair and Homeostasis 368
    More Subtle Concepts of Injury and Repair 369
    Tissue Homeostasis and Cell Turnover 369
    Animal Models 369
    THE CLINICAL CONTEXT: HETEROGENEITY IN THE INJURY AND REPAIR PROCESS 369
    Representative Example: ALI/ARDS 370
    Characteristics of the Injurious Insult 370
    Characteristics of ALI/ARDS 370
    Preexisting Acquired Disorders 371
    Genetic Determinants 371
    Physiology, Cell Biology, and Immunology of ALI 372
    Common Pathway to ALI/ARDS 372
    Clinical and Pathologic Manifestations 372
    Distinct Phases of Injury 372
    Extent of Epithelial Injury Predicts Outcome 372
    CAUSES AND MECHANISMS OF LUNG INJURY 373
    Causes of Injury 373
    Mechanisms and Pathways of Lung Cell Injury 373
    Cell Death: Programmed Cell Death versus Toxic and Necrotic Cell Death 374
    Protection of Cells from Damage 374
    Assessing Programmed Cell Death 375
    Manifestations of Lung Injury: Loss of Structure Leads to Loss of Function 375
    Modeling Acute Lung Injury in Animals 375
    Feasible Assessment of Acute Lung Injury in Animal Models 375
    Abnormalities of Gas Exchange. 376
    Decreased Lung Compliance. 376
    Assessment of Increased Permeability of the Alveolar-Capillary Membrane. 376
    Histologic Assessment of Lung Injury. 376
    REPAIR OF THE LUNG 376
    Mechanisms and Pathways of Lung Cell Replacement 376
    Stem Cells, Constitutive Cell Turnover, and Reparative Cell Types 376
    Hierarchies of Reparative Cells 376
    Classical Stem Cell Hierarchy 377
    Cells Involved in Lung Repair 377
    Progenitor Cell. 377
    Tissue-Specific Stem Cells. 377
    Facultative Progenitor Cell Pools. 378
    Loss of Regenerative Potential: Depletion of the Facultative Progenitor Cell Pool 378
    Gene-Environment Interactions in Lung Injury and Repair 378
    Abnormal Cellular Repair 379
    Does Lung Repair Recapitulate Lung Development? 379
    References 380
    II Diagnosis and Evaluation of Respiratory Disease 384
    E Diagnosis 386
    17 History and Physical Examination 386
    INTRODUCTION 386
    Electronic Medical Record 386
    Communication Skills 387
    MEDICAL INTERVIEW 387
    Chief Complaint and Present Illness 387
    Major Pulmonary Symptoms 388
    Dyspnea 388
    Clinical Features. 388
    Cough 389
    Clinical Features. 389
    Hemoptysis 389
    e9781416047100v2 1209
    Front cover 1209
    Murray and Nadel's Textbook of Respiratory Medicine 1210
    Copyright page 1213
    Dedication 1214
    Contributors 1216
    Preface to the Fifth Edition 1228
    Preface to the First Edition 1230
    Video Contents 1232
    Table of Contents 1234
    III - Continued Clinical Respiratory Medicine 1240
    J Neoplasms of the Lung 1240
    45 Biology of Non–Small Cell Lung Cancer 1240
    INTRODUCTION 1240
    PREDISPOSITION TO LUNG CANCER 1241
    Smoking 1241
    Genetic Susceptibility and Familial Predisposition 1241
    EARLY EVENTS IN LUNG TUMORIGENESIS 1242
    Mucosal Response to Injury, the Emergence of Critical Mutations 1242
    Mutagens 1243
    The Field Cancerization Effect 1244
    Genomic Instability 1244
    Role of Inflammation in Lung Tumorigenesis 1245
    Role of Viruses in Lung Tumorigenesis 1246
    OTHER MOLECULAR ALTERATIONS DRIVING THE TUMOR PHENOTYPE 1246
    Chromosomal Changes 1246
    Epigenetic Alterations of Gene Expression in Lung Cancer 1247
    DNA Adducts 1247
    DNA Methylation 1248
    Histone Acetylation 1248
    Expression Arrays 1248
    RNA Regulation by miRNA 1249
    Proteomic Alterations 1249
    High-Throughput Profiling Techniques 1249
    Molecular Networks, Pathway Analyses 1249
    TRANSLATING LUNG CANCER BIOLOGY TO THE CLINIC 1250
    Biomarkers 1250
    Molecular Therapeutics 1251
    EGFR Antagonists 1251
    VEGF 1251
    p53 1252
    K-ras: Farnesyl Transferase Inhibitors 1252
    COX-2 Inhibition 1252
    References 1253
    46 Epidemiology of Lung Cancer 1258
    INTRODUCTION 1258
    PATTERNS OF OCCURRENCE 1258
    Temporal Trends 1258
    Race and Ethnicity 1259
    Geographic Patterns 1260
    Lung Cancer Occurrence by Histologic Type 1260
    THE ETIOLOGY OF LUNG CANCER: OVERVIEW 1262
    ENVIRONMENTAL AND OCCUPATIONAL AGENTS 1263
    Smoking 1263
    Overview 1263
    Quantitative Risks 1263
    Smoking Cessation 1263
    The Changing Cigarette 1263
    Passive Smoking 1265
    Diet 1265
    Environmental Exposures 1266
    Occupational Exposures 1266
    Asbestos 1266
    Radiation 1266
    High-LET Radiation: Radon. 1267
    Low-LET Radiation: X-Rays and Gamma-Rays. 1267
    Air Pollution 1267
    Atmospheric Air Pollution 1267
    Indoor Air Pollution 1268
    HOST FACTORS 1268
    Overview 1268
    Research Findings on the Genetic Basis of Lung Cancer 1268
    Presence of Human Immunodeficiency Virus 1270
    Presence of Acquired Lung Disease 1270
    Gender 1271
    FUTURE DIRECTIONS 1271
    References 1271
    47 Clinical Aspects of Lung Cancer 1276
    INTRODUCTION 1276
    SCREENING FOR LUNG CANCER 1277
    PRESENTATION 1278
    LUNG CANCER STAGING 1279
    NONINVASIVE STAGING TECHNIQUES 1280
    Chest Radiography 1280
    Computed Tomography of the Chest 1280
    Positron Emission Tomography 1281
    Magnetic Resonance Imaging 1282
    The Search for Metastatic Disease 1282
    Adrenal and Hepatic Imaging 1283
    Brain Imaging 1283
    Bone Imaging 1284
    Summary 1284
    INVASIVE DIAGNOSTIC AND STAGING TECHNIQUES 1284
    Sputum Cytology 1284
    Transthoracic Needle Aspiration 1284
    Fiberoptic Bronchoscopy 1284
    Submucosal and Peribronchial Lesions 1285
    Bronchoscopy for Staging Lung Cancer 1285
    Endoscopic Ultrasound 1285
    Endobronchial Ultrasound 1285
    Mediastinoscopy 1286
    TREATMENT OF LUNG CANCER 1286
    Prognostic Factors for Lung Cancer 1287
    Non–Small Cell Lung Cancer Treatment by Stage 1288
    Stage I 1288
    Stage II 1289
    Stage IIIA 1290
    Stage IIIB 1291
    Stage IV 1291
    Small Cell Lung Cancer 1292
    PALLIATIVE CARE 1293
    SPECIAL CONSIDERATIONS IN LUNG CANCER 1294
    Superior Sulcus Tumors and Pancoast’s Syndrome 1294
    Superior Vena Cava Syndrome 1294
    PARANEOPLASTIC SYNDROMES 1295
    Musculoskeletal Effects 1295
    Hematologic Effects 1295
    Hypercalcemia 1296
    Syndrome of Inappropriate Antidiuretic Hormone Secretion 1297
    Ectopic Corticotropin Syndrome 1298
    Neurologic Effects 1298
    References 1299
    48 Lymphoma, Lymphoproliferative Diseases, and Other Primary Malignant Tumors 1305
    INTRODUCTION 1305
    CHARACTERIZATION OF RARE LUNG TUMORS 1305
    PRIMARY PULMONARY LYMPHOMA AND OTHER LYMPHOPROLIFERATIVE DISEASES 1306
    Mucosa-Associated Lymphoid Tissue Lymphoma 1306
    Lymphomatoid Granulomatosis 1308
    Other Lymphomas and Lymphoproliferative Diseases 1309
    Amyloidosis 1309
    Nonamyloidotic Monoclonal Immunoglobulin Deposition Disease 1309
    CARCINOIDS AND OTHER NEUROENDOCRINE TUMORS 1310
    Pathologic Classification 1310
    Carcinoid Tumors 1310
    Large Cell Neuroendocrine Carcinoma 1311
    RARE MALIGNANT PRIMARY PULMONARY EPITHELIAL TUMORS 1311
    Mucoepidermoid Carcinoma 1311
    Pneumoblastoma 1311
    Sarcomatoid Carcinomas (Other Than Pneumoblastoma) 1312
    PRIMARY PULMONARY SARCOMAS 1313
    Parenchymal Sarcomas 1313
    Vascular Sarcomas 1313
    LESSONS LEARNED FOR THE MANAGEMENT OF RARE PRIMARY PULMONARY TUMORS 1315
    Specific Radioclinical Presentation 1315
    Specific Diagnostic Strategy 1315
    Distinguishing Primary Tumors from Metastases 1315
    General Therapeutic Management 1316
    References 1316
    49 Metastatic Malignant Tumors 1320
    INTRODUCTION 1320
    Epidemiology 1320
    Clinical History 1320
    MECHANISM OF METASTASIS TO THE LUNG 1321
    DIAGNOSIS 1322
    Differential Diagnosis 1322
    Distinguishing Metastases from Primary Lung Tumors 1322
    Pathology 1323
    Molecular Classification 1323
    Options for Obtaining a Tissue Diagnosis 1324
    Bronchoscopy 1324
    CT-Guided Biopsy 1324
    Surgery 1324
    TREATMENT OF LUNG METASTASES 1325
    Multimodality Therapy of Systemic Disease 1325
    Palliative Care 1325
    Radiofrequency Ablation of Metastases 1326
    Surgical Resection of Metastases 1326
    SPECIAL CASES 1328
    Airway Metastasis 1328
    Vascular Embolic Metastasis 1328
    References 1329
    50 Benign Lung Tumors 1331
    INTRODUCTION 1331
    Clinical Manifestations 1331
    BENIGN EPITHELIAL LESIONS 1331
    Papillomas and Adenomas 1331
    Solitary Papillomas 1331
    Recurrent Respiratory Papillomatosis 1332
    Adenomas 1333
    Micronodular Pneumocyte Hyperplasia 1335
    Sclerosing Hemangioma 1336
    BENIGN NONEPITHELIAL LESIONS 1337
    Hamartoma and Related Lesions 1337
    Inflammatory Myofibroblastic Tumor 1338
    Solitary Fibrous Tumor 1339
    Meningothelial-like Nodules and Intrapulmonary Meningioma 1340
    Miscellaneous 1340
    References 1342
    K Disorders of the Pulmonary Circulation 1346
    51 Pulmonary Thromboembolism 1346
    INTRODUCTION 1346
    PATHOGENESIS AND RISK FACTORS 1347
    NATURAL HISTORY: DEEP VENOUS THROMBOSIS 1349
    NATURAL HISTORY: PULMONARY EMBOLISM 1349
    CLINICAL PRESENTATION 1351
    DIAGNOSIS OF VENOUS THROMBOSIS 1352
    Contrast Venography 1352
    Duplex Ultrasonography 1352
    Impedance Plethysmography 1353
    Magnetic Resonance Imaging 1353
    Computed Tomography 1354
    Hemostaseologic Assays 1354
    Clinical Prediction Rules 1354
    DIAGNOSIS OF PULMONARY EMBOLISM 1354
    Standard Laboratory Evaluation 1355
    Echocardiography 1356
    Ventilation-Perfusion Scanning 1356
    Spiral (Helical) Computed Tomography 1357
    Lower Extremity Venous Evaluation 1359
    d-Dimer Testing 1359
    Pulmonary Angiography 1359
    Clinical Prediction Rules 1360
    PREVENTION OF VENOUS THROMBOEMBOLISM 1362
    Low-Dose Unfractionated Heparin 1362
    Low-Molecular-Weight Heparin 1362
    Pneumatic Compression Devices 1362
    Sodium Warfarin 1362
    Miscellaneous Agents 1363
    MANAGEMENT OF VENOUS THROMBOEMBOLISM 1363
    Heparin 1363
    Inferior Vena Cava Filters 1364
    MASSIVE PULMONARY EMBOLISM 1365
    Thrombolytic Therapy 1365
    Pulmonary Embolectomy 1366
    POSTEMBOLIC PROPHYLAXIS 1366
    CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION 1367
    Diagnosis 1367
    Treatment 1370
    OTHER FORMS OF EMBOLISM 1374
    Schistosomiasis 1374
    Air Embolism 1374
    Fat Embolism 1375
    Amniotic Fluid Embolism 1375
    Septic Embolism 1376
    Other Emboli 1376
    References 1376
    52 Pulmonary Hypertension 1384
    INTRODUCTION 1384
    CLASSIFICATION 1384
    EPIDEMIOLOGY 1384
    PATHOLOGY 1385
    PATHOGENESIS AND ETIOLOGY 1386
    OTHER FORMS OF PULMONARY ARTERIAL HYPERTENSION 1387
    SYMPTOMS 1388
    PHYSICAL FINDINGS 1389
    DIAGNOSIS 1389
    TREATMENT AND PROGNOSIS 1392
    Supportive Therapies 1392
    Exercise and Physical Activity 1392
    Avoidance of Altitude 1392
    Avoidance of Pregnancy 1392
    Warfarin 1392
    Supplemental Oxygen 1393
    Diuretics 1393
    Calcium Channel Antagonists 1394
    Targeted Therapies 1394
    Prostacyclin Analogues 1395
    Epoprostenal. 1395
    Treprostinil Sodium. 1396
    Iloprost. 1396
    Endothelin Receptor Antagonists 1396
    Bosentan. 1396
    Ambrisentan. 1397
    Phosphodiesterase Type 5 Inhibitors 1397
    Sildenafil. 1397
    Combination Therapy 1397
    Lung Transplantation 1398
    Overall Therapeutic Strategy: Challenges 1400
    Survival 1400
    Experimental Therapies 1400
    References 1401
    53 Pulmonary Vasculitis 1404
    INTRODUCTION 1404
    CLASSIFICATION 1404
    EPIDEMIOLOGY 1405
    NORMAL VASCULAR ANATOMY AND HISTOLOGY 1405
    HISTOPATHOLOGY OF VASCULITIS 1406
    PATHOGENESIS AND ETIOLOGY 1407
    THE INITIAL DIAGNOSIS 1407
    Clinical Scenarios Suggestive of Vasculitis 1407
    Destructive Upper Airway Lesions 1407
    Chest Imaging Findings of Cavitary or Nodular Disease 1408
    Diffuse Alveolar Hemorrhage 1408
    Acute Glomerulonephritis 1408
    Pulmonary-Renal Syndrome 1409
    Palpable Purpura 1409
    Mononeuritis Multiplex 1409
    Multisystem Disease 1409
    Specific Testing 1409
    Antinuclear Cytoplasmic Antibodies 1409
    Other Laboratory Studies 1410
    Chest Imaging 1410
    Bronchoscopy 1410
    Diagnostic Biopsy 1410
    SPECIFIC CLINICAL DISORDERS 1411
    Necrotizing Granulomatous Vasculitis (Formerly Wegener’s Granulomatosis) 1411
    Churg-Strauss Syndrome 1411
    Microscopic Polyangiitis 1414
    TREATMENT 1415
    General Principles 1415
    Remission-Induction 1415
    Limited Disease 1415
    Early Generalized Disease 1415
    Active Generalized Disease 1415
    Severe Disease 1416
    Refractory Disease 1416
    Maintenance 1416
    Monitoring for Complications 1416
    References 1417
    54 Pulmonary Arteriovenous Malformations and Other Vascular Abnormalities 1421
    INTRODUCTION 1421
    PULMONARY ARTERIOVENOUS MALFORMATIONS 1421
    Etiology 1422
    Hereditary Hemorrhagic Telangiectasia 1423
    Clinical Features and Diagnosis. 1423
    Genetics and Pathogenesis. 1423
    Phenotype-Genotype Correlations. 1424
    Cavopulmonary Shunts. 1424
    Pathophysiology 1425
    Anatomic Basis 1425
    Physiologic Attributes at Rest 1425
    Right-to-Left Shunt. 1425
    Pulmonary Hemodynamics. 1425
    Pulmonary Function. 1426
    Physiologic Consequences of Posture and Exercise 1426
    Posture. 1426
    Exercise. 1426
    Pulmonary Hypertension 1426
    Clinical Features 1427
    Respiratory Symptoms 1427
    Dyspnea. 1427
    Hemoptysis. 1427
    Chest Pain. 1427
    Strokes and Cerebral Abscess 1427
    Migraines 1428
    Pregnancy 1428
    Diagnosis 1428
    Radiology 1428
    Measurement of Right-to-Left Shunt 1429
    100% Oxygen Breathing. 1429
    Radiolabeled Particles. 1429
    Contrast Echocardiography. 1429
    Screening Patients 1431
    Management 1431
    Embolization 1431
    Long-Term Outcome. 1431
    Physiologic Outcome. 1432
    Clinical Outcome. 1432
    Risks of Embolization 1433
    Development of Systemic Arterial Supply. 1433
    Development of Pulmonary Hypertension. 1433
    Nonembolization Options 1433
    Surgery. 1433
    Medical Management 1434
    Dental Issues. 1434
    Pregnancy. 1434
    Thromboembolic Risks. 1434
    SYSTEMIC-TO-PULMONARY VASCULAR COMMUNICATIONS 1434
    Anatomy 1434
    Adult (Acquired) Systemic-to-Pulmonary Communications 1435
    Fetal- and Perinatal Systemic-to-Pulmonary Artery Collaterals 1435
    Aberrant Congenital Systemic-to-Pulmonary Communications 1435
    Cavopulmonary Anastomoses 1435
    Treatment 1435
    Managements of Hemoptysis 1436
    BRONCHOPULMONARY SEQUESTRATION 1436
    Classification 1436
    Pathogenesis 1436
    Clinical Features 1436
    Treatment 1437
    PULMONARY ARTERY ANEURYSMS 1437
    Etiology and Pathogenesis 1438
    Infection 1438
    Vascular Trauma 1438
    Weakness of the Arterial Wall 1438
    Diagnosis and Treatment 1438
    References 1439
    55 Pulmonary Edema and Acute Lung Injury 1444
    INTRODUCTION 1444
    PATHOPHYSIOLOGY OF PULMONARY EDEMA AND ACUTE LUNG INJURY 1444
    Increased Pressure Edema 1446
    Pathophysiology 1446
    Mechanisms 1448
    Increased Microvascular Hydrostatic Pressure. 1448
    Decreased Perimicrovascular Hydrostatic Pressure. 1450
    Decreased Transmural Osmotic Pressure Difference. 1450
    Alveolar Barrier Function. 1450
    Increased Permeability Edema and Acute Lung Injury 1451
    Pathophysiology 1452
    Mechanisms 1454
    Infection. 1455
    Inflammation. 1455
    Direct Toxicity. 1456
    Host Factors. 1457
    DIAGNOSIS 1457
    Clinical Assessment 1457
    Symptoms and Signs 1457
    Diagnostic Studies and Definitions 1458
    Chest Radiographs 1460
    Arterial Blood Studies 1460
    Pulmonary Edema Fluid Protein Concentration Measurement 1460
    Pulmonary Function Tests 1461
    Hemodynamic Measurements 1461
    Measurement of Lung Water and Barrier Function 1461
    Lung Density Methods 1461
    Tracer Methods 1462
    Multiple-Indicator Dilution Techniques. 1462
    Measurement of Barrier Function 1462
    Detection of Lung Injury 1462
    Changes in Metabolic Functions of the Lung 1462
    Biologic Markers of Lung Injury 1463
    TREATMENT 1464
    Immediate Therapy 1464
    Hydrostatic Pulmonary Edema 1464
    Major Options 1464
    Vasodilators 1465
    Diuretics 1466
    Inotropic Agents 1466
    Therapeutic Strategy 1467
    Increased Pressure Edema 1468
    Increased Permeability Edema 1468
    Lung-Protective Ventilator Strategies. 1469
    Specific Pharmacologic Therapies. 1470
    Corticosteroids. 1471
    Surfactant. 1471
    Antioxidants. 1472
    Pentoxifylline. 1472
    Treatments for Sepsis. 1472
    Prostaglandin E1 and Inhaled Nitric Oxide. 1473
    OUTCOME 1473
    Resolution of Edema 1473
    Increased Pressure Edema 1474
    Increased Permeability Edema 1475
    overview 1476
    References 1477
    56 Cor Pulmonale 1487
    INTRODUCTION 1487
    PULMONARY CIRCULATION 1487
    Pulmonary Artery Pressure 1489
    Pulmonary Artery Wedge Pressure 1489
    PATHOPHYSIOLOGY OF THE PULMONARY CIRCULATION 1490
    Hypoxic Pulmonary Vasoconstriction 1490
    Pulmonary Vascular Remodeling 1491
    RIGHT VENTRICLE 1492
    LEFT VENTRICLE 1494
    NEUROHORMONES 1495
    Angiotensin II 1496
    NATRIURETIC PEPTIDES 1496
    ENDOTHELIN-1 1497
    SYMPTOMS AND SIGNS 1497
    Chest Radiograph 1498
    Electrocardiogram 1498
    Echocardiography 1499
    Computed Tomography 1500
    Magnetic Resonance Imaging 1501
    Hemodynamics 1501
    DIFFERENTIAL DIAGNOSIS 1501
    TREATMENT 1502
    Oxygen 1504
    Vasodilators 1504
    Endothelin Receptor Antagonists 1505
    Prostacyclin and Its Analogues 1506
    Oral Phosphodiesterase V Inhibitors 1507
    Nitric Oxide 1508
    Angiotensin-Converting Enzyme Inhibitors 1509
    Natriuretic Peptides 1509
    Nonglycoside Inotropes 1509
    Surgery 1509
    Atrial Septostomy 1510
    NATURAL HISTORY 1510
    References 1512
    L Infiltrative and Interstitial Lung Diseases 1517
    57 Idiopathic Interstitial Pneumonias 1517
    INTRODUCTION 1517
    CLINICAL AND HISTOLOGIC CLASSIFICATION OF INTERSTITIAL LUNG DISEASE 1517
    CLINICAL, RADIOLOGIC, AND PHYSIOLOGIC FEATURES OF INTERSTITIAL LUNG DISEASES 1519
    Past History 1519
    Occupational History 1519
    Drug History 1520
    Smoking History 1520
    Family History 1520
    Gender 1520
    Symptoms 1520
    Physical Findings 1520
    Radiographic Features 1520
    Plain Roentgenography 1521
    Alveolar Filling Pattern (Table 57-4). 1521
    Interstitial Pattern. 1522
    Nodular Pattern. 1522
    Linear or Reticular. 1522
    Other Radiographic Features. 1523
    Computed Tomography 1524
    Functional Assessment 1526
    Ventilatory Function 1526
    Elastic Resistance 1526
    Flow Resistance 1527
    Gas Exchange 1527
    Exercise 1528
    Laboratory Findings 1529
    Bronchoalveolar Lavage 1529
    Histologic Diagnosis 1530
    Transbronchial Biopsy 1530
    Surgical Lung Biopsy 1530
    DIAGNOSIS AND MANAGEMENT OF THE IDIOPATHIC INTERSTITIAL PNEUMONIAS 1530
    Idiopathic Pulmonary Fibrosis 1531
    Clinical Features 1531
    Blood and Serologic Studies 1532
    Chest Imaging Studies 1532
    Chest Roentgenography. 1532
    Computed Tomography Scan. 1532
    Other Imaging Techniques 1533
    Gallium Scanning. 1533
    Ventilation-Perfusion Lung Scanning. 1533
    Magnetic Resonance Imaging for Differentiating Inflammation and Fibrosis 1534
    Imaging of Fibrogenesis by Positron Emission Tomography. 1534
    Pulmonary Function Tests 1534
    Pulmonary Hemodynamics 1535
    Abnormalities during Sleep 1535
    Histopathology 1536
    Etiologic Factors and Pathogenic Mechanisms 1537
    Diagnosis 1538
    Staging of Disease Activity and Predicting Outcome 1539
    Clinical Features. 1539
    Serum Studies. 1539
    Chest Roentgenography and High-Resolution Computed Tomography Scanning. 1539
    Pulmonary Physiologic Tests. 1539
    Bronchoalveolar Lavage. 1539
    Histopathology. 1540
    Prediction Models. 1540
    Outcome and Causes of Death. 1540
    Therapeutic Approach 1541
    Corticosteroids. 1541
    Immunomodulatory and Antifibrotic Agents. 1541
    Azathioprine. 1541
    N-Acetylcysteine. 1541
    Cyclophosphamide. 1541
    Other Agents. 1541
    New Therapeutic Approaches. 1542
    Interferon-γ. 1542
    Pirfenidone. 1542
    Endothelin-Receptor Antagonists. 1542
    Etanercept. 1542
    Lung Transplantation 1542
    Rehabilitation 1543
    Acute Exacerbations of Interstitial Pulmonary Fibrosis 1543
    Familial Pulmonary Fibrosis 1544
    Nonspecific Interstitial Pneumonia 1544
    Clinical Features 1544
    Chest Imaging Studies 1544
    Chest Roentgenography. 1544
    Computed Tomography Scan. 1544
    Pulmonary Function Tests 1545
    Pathologic Features 1545
    Differential Diagnosis 1545
    Clinical Course and Outcome 1546
    Respiratory Bronchiolitis–Associated Interstitial Lung Disease/Desquamative Interstitial Pneumonia 1546
    Clinical Features 1546
    Chest Imaging Studies 1546
    Chest Roentgenography. 1546
    Computed Tomography Scan. 1546
    Bronchoalveolar Lavage 1546
    Pulmonary Function Tests 1546
    Pathologic Features 1547
    Clinical Course and Outcome 1548
    Acute Interstitial Pneumonia 1548
    Clinical Features 1548
    Chest Imaging Studies 1548
    Chest Roentgenography. 1548
    Computed Tomography Scan. 1548
    Pulmonary Function Tests 1548
    Pathologic Features 1548
    Clinical Course and Outcome 1549
    Cryptogenic Organizing Pneumonia 1549
    Clinical Features 1549
    Chest Imaging Studies 1549
    Chest Roentgenography. 1549
    Computed Tomography Scan. 1549
    Pulmonary Function Tests 1550
    Bronchoalveolar Lavage 1550
    Pathologic Features 1550
    Clinical Course and Outcome 1550
    Lymphocytic Interstitial Pneumonia 1551
    Clinical Features 1551
    Chest Imaging Studies 1551
    Chest Roentgenography. 1551
    Computed Tomography Scan. 1551
    Pulmonary Function Tests 1552
    Bronchoalveolar Lavage 1552
    Pathologic Features 1552
    Clinical Course and Outcome 1552
    Conclusion 1552
    References 1553
    58 The Lungs and Connective Tissue Diseases 1559
    INTRODUCTION 1559
    SYSTEMIC SCLEROSIS (SCLERODERMA) 1559
    Epidemiology and Risk Factors 1559
    Chemically Induced Scleroderma-like Disorders 1560
    Pulmonary Manifestations 1561
    Interstitial Pulmonary Fibrosis 1561
    Pathogenesis. 1561
    Predisposition. 1561
    Inflammation Amplification. 1561
    Fibrogenetic Factors. 1561
    Clinical Features. 1562
    Imaging. 1562
    Lung Function Tests. 1562
    Bronchoalveolar Lavage. 1563
    Biopsy. 1563
    Serologic Investigations. 1564
    Prognosis. 1565
    Treatment. 1565
    Pulmonary Vascular Disease in Systemic Sclerosis 1566
    Other Pulmonary Complications 1566
    RHEUMATOID ARTHRITIS 1567
    Epidemiology and Risk Factors 1567
    Pulmonary Manifestations 1567
    Interstitial Pulmonary Fibrosis 1567
    Organizing Pneumonia 1568
    Obliterative Bronchiolitis 1569
    Follicular Bronchiolitis 1570
    Bronchiectasis 1570
    Pulmonary Vasculitis 1570
    Pulmonary Rheumatoid Nodules 1570
    Pleural Disease 1571
    Other Pulmonary Complications 1571
    Drug-Induced Pulmonary Disease 1571
    Pulmonary Function Tests 1571
    Radiologic Features 1571
    Treatment of Pulmonary Complications 1572
    SYSTEMIC LUPUS ERYTHEMATOSUS 1572
    Epidemiology and Risk Factors 1572
    Pulmonary Manifestations 1572
    Diffuse Lung Disease 1573
    Interstitial Pneumonia. 1573
    Acute Lupus Pneumonitis. 1573
    Extrapulmonary Restriction 1573
    Diffuse Alveolar Hemorrhage 1573
    Pulmonary Hypertension 1574
    Pleural Disease 1574
    SJÖGREN’S SYNDROME 1574
    Epidemiology and Risk Factors 1574
    Pulmonary Manifestations 1574
    Diffuse Lung Disease 1575
    Tracheobronchial Disease 1575
    POLYMYOSITIS AND DERMATOMYOSITIS 1576
    Epidemiology and Risk Factors 1576
    Pulmonary Manifestations 1576
    Diffuse Lung Disease 1576
    Clinical Features. 1576
    Imaging. 1577
    Pulmonary Function. 1577
    Bronchoalveolar Lavage. 1577
    Laboratory Tests. 1577
    Other Pulmonary Manifestations 1577
    Treatment of Pulmonary Complications 1578
    MIXED CONNECTIVE TISSUE DISEASE 1578
    UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE 1578
    RELAPSING POLYCHONDRITIS 1578
    BEHÇET’S SYNDROME 1580
    ANKYLOSING SPONDYLITIS 1581
    MARFAN SYNDROME 1581
    References 1582
    59 Sarcoidosis 1588
    INTRODUCTION 1588
    BACKGROUND 1588
    EPIDEMIOLOGY 1588
    ETIOLOGY AND PATHOGENESIS 1589
    Environment 1589
    Spatial and Temporal Clustering 1589
    Infectious Agents 1589
    Immunology 1590
    Autoantigens 1590
    Immune Response 1590
    Fibrosis 1591
    Anergy 1591
    Genetics 1591
    Familial Clustering 1591
    HLA Class II Associations 1591
    Other Candidate Genes 1592
    CLINICAL PRESENTATION 1592
    Acute Sarcoidosis 1592
    Chronic Sarcoidosis 1592
    CLINICAL FEATURES AND DIAGNOSIS 1592
    Pulmonary Sarcoidosis 1592
    Extrapulmonary Sarcoidosis 1596
    Ears, Nose, and Throat 1596
    Peripheral Lymph Nodes 1597
    Heart 1597
    Skin 1597
    Eyes 1597
    Nervous System 1597
    Endocrine Glands 1598
    Parotid Gland 1598
    Liver and Spleen 1598
    Joints 1598
    Blood 1598
    Other Sites 1598
    DIFFERENTIAL DIAGNOSIS 1598
    EVALUATION AND MANAGEMENT 1600
    TREATMENT 1601
    Corticosteroids 1601
    Other Immunosuppressive Agents 1603
    Methotrexate 1603
    Cyclosporin A 1603
    Azathioprine 1603
    Antimalarials 1603
    Cyclophosphamide 1604
    Anti–Tumor Necrosis Factor-α Therapy 1604
    Combination Treatment Regimens 1604
    Management of Treatment Complications: Aspergilloma 1605
    Lung Transplantation 1605
    References 1606
    60 Diffuse Alveolar Hemorrhage and Rare Infiltrative Disorders of the Lung 1610
    INTRODUCTION 1610
    DIFFUSE ALVEOLAR HEMORRHAGE 1610
    DEFINITION 1610
    CLINICAL PRESENTATION 1611
    History and Physical Examination 1611
    Radiology and Laboratory Evaluation 1611
    Physiology 1611
    CLASSIFICATION SCHEMA 1612
    DIAGNOSTIC APPROACH 1613
    Diagnosis of Diffuse Alveolar Hemorrhage 1613
    Diagnosis of Underlying Cause 1613
    Role of Surgical Lung Biopsy 1613
    SPECIFIC CAUSES OF DIFFUSE ALVEOLAR HEMORRHAGE 1615
    Vasculitis 1615
    Wegener’s Granulomatosis 1615
    Microscopic Polyangiitis 1616
    Isolated Pulmonary Capillaritis 1616
    Mixed Cryoglobulinemia 1616
    Behçet’s Syndrome 1616
    Henoch-Schönlein Purpura 1617
    Pauci-immune Glomerulonephritis 1617
    Immunologic 1617
    Goodpasture’s Syndrome 1617
    Connective Tissue Disease 1618
    Immune Complex–Related Crescentic Glomerulonephritis 1619
    Acute Pulmonary Allograft Rejection 1619
    Coagulation Disorders 1619
    Idiopathic Pulmonary Hemosiderosis 1619
    Other Causes of Diffuse Alveolar Hemorrhage 1620
    Drugs/Toxins 1620
    Diffuse Alveolar Damage 1620
    Mitral Stenosis 1621
    Pulmonary Veno-occlusive Disease 1621
    Pulmonary Capillary Hemangiomatosis 1621
    Lymphangioleiomyomatosis and Tuberous Sclerosis 1622
    RARE INFILTRATIVE DISORDERS OF THE LUNG 1622
    Neurofibromatosis 1622
    Hermansky-Pudlak Syndrome 1622
    Dyskeratosis Congenita 1623
    Gaucher’s Disease 1623
    Niemann-Pick Disease 1623
    Pulmonary Alveolar Microlithiasis 1623
    References 1625
    61 Eosinophilic Lung Diseases 1630
    INTRODUCTION 1630
    EOSINOPHIL BIOLOGY 1630
    GENERAL FEATURES OF EOSINOPHILIC PNEUMONIAS 1632
    Historical Perspective 1632
    Clinical Presentation 1632
    Pathology 1632
    Diagnosis 1633
    EOSINOPHILIC LUNG DISEASE OF UNDETERMINED CAUSE 1634
    Idiopathic Chronic Eosinophilic Pneumonia 1634
    Clinical Features 1634
    Imaging 1634
    Laboratory Studies 1635
    Bronchoalveolar Lavage 1635
    Differential Diagnosis 1635
    Lung Function Tests 1635
    Treatment and Prognosis 1635
    Idiopathic Acute Eosinophilic Pneumonia 1636
    Clinical Features 1636
    Imaging 1636
    Laboratory Studies 1637
    Bronchoalveolar Lavage 1637
    Lung Function Tests 1637
    Lung Biopsy 1637
    Treatment and Prognosis 1637
    Churg-Strauss Syndrome 1637
    Clinical Features 1638
    Imaging 1638
    Laboratory Studies 1638
    Pathogenesis 1639
    Diagnosis 1640
    Differential Diagnosis 1640
    Treatment and Prognosis 1641
    Hypereosinophilic Syndrome 1641
    Pathogenensis 1641
    Clinical Features 1642
    Imaging 1642
    Laboratory Studies 1643
    Treatment and Prognosis 1643
    EOSINOPHILIC LUNG DISEASE OF DETERMINED CAUSE 1643
    Eosinophilic Pneumonias of Parasitic Origin 1643
    Tropical Eosinophilia 1643
    Clinical Features. 1643
    Pathogenesis. 1643
    Laboratory Studies. 1643
    Treatment. 1644
    Ascaris Pneumonia 1644
    Eosinophilic Pneumonia in Larva Migrans Syndrome 1644
    Strongyloides stercoralis Infection 1644
    Eosinophilic Pneumonias in Other Parasitic Infections 1645
    Eosinophilic Pneumonias of Other Infectious Causes 1645
    Allergic Bronchopulmonary Aspergillosis and Related Syndromes 1645
    Allergic Bronchopulmonary Aspergillosis 1645
    Pathogenesis. 1645
    Clinical Features. 1646
    Imaging. 1646
    Treatment. 1646
    Other Allergic Bronchopulmonary Syndromes Associated with Fungi or Yeasts 1647
    Bronchocentric Granulomatosis 1647
    Drug, Toxic Agents, and Radiation-Induced Eosinophilic Pneumonias 1647
    Drugs 1647
    Toxic Oil Syndrome 1647
    Radiation Therapy 1648
    MISCELLANEOUS LUNG DISEASES WITH ASSOCIATED EOSINOPHILIA 1648
    Organizing Pneumonia 1648
    Asthma and Eosinophilic Bronchitis 1649
    Idiopathic Interstitial Pneumonias 1649
    Langerhans Cell Granulomatosis 1649
    Lung Transplantation 1649
    Other Lung Diseases with Occasional Eosinophilia 1649
    References 1650
    62 Lymphangioleiomyomatosis 1657
    INTRODUCTION 1657
    EPIDEMIOLOGY 1657
    GENETIC AND MOLECULAR BASIS OF TUBEROUS SCLEROSIS COMPLEX AND LYMPHANGIOLEIOMYOMATOSIS 1658
    Inheritance 1658
    Molecular Pathogenesis 1659
    Tumor Suppressor Proteins Control Cell Growth 1659
    The Tuberous Sclerosis Complex Proteins Regulate Signaling through the Akt Pathway 1659
    Tuberous Sclerosis Complex Mutations Are Found in the Lung and Kidney Lesions of Patients with Sporadic Lymphangioleiomyomatosis 1659
    Genetic Evidence Suggests That Lymphangioleiomyomatosis is a Metastatic Neoplasm 1660
    Role of Lymphangiogenesis and Lymphatic Spread in Dissemination of Lymphangioleiomatosis 1661
    Mechanisms of Matrix Remodeling in Lymphangioleiomyomatosis 1661
    Preclinical Evidence and Human Trials 1661
    Estrogen 1661
    Sirolimus 1661
    CLINICAL FEATURES 1662
    PHYSICAL EXAMINATION 1663
    IMAGING STUDIES 1663
    PULMONARY FUNCTION TESTING 1665
    PATHOLOGY 1665
    DIAGNOSIS 1667
    Clinical Diagnosis 1667
    Differential Diagnosis 1667
    Lung Biopsy 1668
    TREATMENT 1668
    General Recommendations 1668
    Pregnancy 1669
    Air Travel 1669
    Pleural Disease 1670
    Pulmonary Transplantation 1670
    Angiomyolipomas 1670
    PROGRESSION AND PROGNOSIS 1670
    FUTURE CLINICAL TRIALS IN LYMPHANGIOLEIOMYOMATOSIS 1671
    References 1672
    63 Pulmonary Alveolar Proteinosis Syndrome 1677
    INTRODUCTION 1677
    PATHOGENESIS 1678
    Surfactant Composition and Homeostasis 1678
    Granulocyte-Macrophage Colony-Stimulating Factor 1678
    Murine Models of Disordered Surfactant Homeostasis 1678
    Historical Overview of Human Disorders of Surfactant Homeostasis 1679
    Role of GM-CSF Autoantibodies 1680
    Genetic Factors 1681
    Disease Associations 1682
    Environmental Factors 1683
    Mechanisms of Disruption of Surfactant Homeostasis 1683
    NOMENCLATURE AND CLASSIFICATION 1684
    EPIDEMIOLOGY 1685
    CLINICAL PRESENTATION 1686
    EVALUATION AND DIFFERENTIAL DIAGNOSIS 1686
    Radiographic Appearance 1686
    Pulmonary Function Testing 1687
    Bronchoscopy, Bronchoalveolar Lavage, and Transbronchial Biopsy 1687
    Surgical Lung Biopsy 1688
    Laboratory Studies 1689
    Approach to Diagnosis 1690
    NATURAL HISTORY 1690
    Secondary Infections 1690
    Pulmonary Fibrosis 1690
    Spontaneous Resolution 1690
    TREATMENT 1690
    Autoimmune PAP 1691
    Whole-Lung Lavage 1691
    Granulocyte-Macrophage Colony-Stimulating Factor 1692
    Other Approaches 1692
    Familial PAP 1693
    Secondary PAP 1693
    Surfactant Metabolic Dysfunction Disorders 1693
    GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS 1693
    Etiology 1693
    Clinical Practice Guidelines 1693
    Novel Therapeutic Approaches 1693
    Conclusion 1693
    References 1694
    M Environmental and Occupational Disorders 1698
    64 Asthma in the Workplace and Occupational Asthma 1698
    INTRODUCTION 1698
    DEFINITION AND CLASSIFICATION 1698
    HISTORICAL ASPECTS 1699
    ETIOLOGIC AGENTS 1700
    GENETIC, PHYSIOPATHOLOGIC ASPECTS, AND ANIMAL MODELS 1700
    Genetics 1700
    Physiopathology 1701
    Occupational Asthma with a Latency Period 1701
    Immunologic, Immunoglobulin E–Mediated. 1702
    Immunologic, Non–Immunoglobulin E– Mediated. 1702
    Occupational Asthma without a Latency Period 1702
    Role of Irritant Exposure in Sensitization 1703
    Animal Models 1703
    Occupational Asthma with a Latency Period 1703
    Occupational Asthma without a Latency Period 1704
    FREQUENCY 1704
    DIAGNOSIS 1706
    EXPOSURE AND ENVIRONMENTAL MONITORING 1707
    MEDICOLEGAL ASPECTS AND COMPENSATION ISSUES 1708
    PREVENTION AND SURVEILLANCE 1708
    Primary Prevention 1708
    Secondary Prevention 1709
    Tertiary Prevention 1709
    IRRITANT-INDUCED ASTHMA AND REACTIVE AIRWAY DYSFUNCTION SYNDROME 1709
    ACKNOWLEDGMENTS 1710
    References 1711
    65 Pneumoconioses and Other Mineral Dust–Related Diseases 1715
    INTRODUCTION 1716
    Definitions 1716
    Accumulation of Dust in the Lung and Tissue Reactions 1716
    Exposure-Response Relationships 1716
    Chest Imaging 1716
    Clinical Issues, Lung Function, and Principles of Management 1717
    Epidemiology and Implications for Clinical Practice 1718
    SILICOSIS 1719
    Definition 1719
    Industries and Occupations Still at Risk 1719
    Pathology 1719
    Pathogenesis 1720
    Epidemiology: Secular Trends and Their Implications for the Clinician 1721
    Tuberculosis 1722
    Airflow Obstruction and Chronic Bronchitis 1722
    Connective Tissue Diseases and Renal Disease 1722
    Lung Cancer 1722
    Clinical Features 1722
    Radiographic Features 1723
    Lung Function 1724
    Diagnosis and Complications 1724
    Management and Control 1724
    COAL WORKERS’ PNEUMOCONIOSIS 1725
    Definition and Occupations at Risk 1725
    Pathology 1725
    Pathogenesis 1727
    Epidemiology and Natural History 1727
    Rheumatoid Pneumoconiosis 1727
    Role of Silica 1727
    Airflow Obstruction and Chronic Bronchitis 1728
    Tuberculosis and Cancer 1728
    Clinical Features 1728
    Chest Radiography 1728
    Lung Function 1729
    Diagnosis, Complications, and Management 1729
    ASBESTOS-RELATED FIBROSIS OF THE LUNGS (ASBESTOSIS) AND PLEURA 1729
    Asbestos Minerals 1729
    History and Uses 1729
    Sources of Human Exposure 1731
    The Fate of Inhaled Fibers 1731
    Exposure versus Dose-Response Relationships 1732
    Asbestosis (Pulmonary Parenchymal Fibrosis) 1732
    Pathology and Pathogenesis 1732
    Epidemiology and Natural History 1733
    Clinical Features 1733
    Radiographic Features 1733
    Lung Function 1734
    Diagnosis and Complications 1734
    Asbestosis, Asbestos Exposure, Lung Cancer, and Mesothelioma 1734
    Pleural Plaques 1736
    Pathology and Pathogenesis 1736
    Clinical Features 1736