E-Book, Englisch, Band 1, 682 Seiten
Reihe: Molecular Pathology Library
Zander / Popper / Jagirdar Molecular Pathology of Lung Diseases
2008
ISBN: 978-0-387-72430-0
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark
E-Book, Englisch, Band 1, 682 Seiten
Reihe: Molecular Pathology Library
ISBN: 978-0-387-72430-0
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark
This major work, complete with 150 illustrations, many of them in color, bridges the gap between clinical pulmonary pathology and basic molecular science. Through a highly visual approach that features an abundance of tables and diagrams, the book offers a practical disease-based overview. The first two sections of the volume provide the reader with general concepts, terminology and procedures in molecular pathology. The remainder of the volume is subdivided into neoplastic and non-neoplastic lung diseases with detailed chapters covering the current molecular pathology of specific diseases. The book will be essential reading for pathologists, pulmonologists, thoracic surgeons and other health care providers interested in lung disease.
Autoren/Hrsg.
Weitere Infos & Material
1;Series Preface;6
2;Preface;8
3;Table of Contents;9
4;Contributors;14
5;Section 1 Basic Concepts of Molecular Pathology;21
5.1;1 Genes, Gene Products, and Transcription Factors;22
5.1.1;Introduction;22
5.1.2;Nucleic Acids, Genes, and Gene Products;22
5.1.3;Posttranslational Modifications of Gene Products;24
5.1.4;Phosphorylation and Acetylation;24
5.1.5;Protein Degradation and Ubiquitinylation;24
5.1.6;Transcription Factors;24
5.1.7;References;25
5.2;2 Receptors, Signaling Pathways, Cell Cycle, and DNA Damage Repair ;30
5.2.1;Cell Surface Receptors and Signal Transduction;30
5.2.2;Signaling Pathways;30
5.2.3;The Cell Cycle;32
5.2.4;DNA Damage Repair;33
5.2.5;References;34
5.3;3 Cell Adhesion Molecules;41
5.3.1;Introduction;41
5.3.2;Integrins;41
5.3.2.1;a3ß1-Integrin and Small Cell Lung Carcinoma;42
5.3.2.2;CXCR4 Chemokine Receptors;42
5.3.2.3;Cyclooxygenase-2;42
5.3.2.4;Focal Adhesion Kinase;43
5.3.2.5;Other Integrin-Related Research;43
5.3.3;Cadherins;44
5.3.3.1;E-Cadherin;44
5.3.3.2;Cadherins and Cyclooxygenase-2;45
5.3.3.3;Cadherins and Epidermal Growth Factor Receptor;45
5.3.3.4;H-Cadherin;46
5.3.3.5;Other Cadherin-Related Research;46
5.3.4;Selectins;48
5.3.5;Immunoglobulin-Like Cell Adhesion Molecules;49
5.3.6;CD44;51
5.3.7;Conclusion;52
5.3.8;References;52
5.4;4 Apoptosis and Cell Death: Relevance to Lung;59
5.4.1;Introduction;59
5.4.2;Apoptosis and Other Forms of Cell Death;59
5.4.2.1;Necrosis;59
5.4.2.2;Autophagy;60
5.4.2.3;Paraptosis;61
5.4.2.4;Autoschizis;61
5.4.2.5;Apoptosis;61
5.4.3;Mechanisms of Apoptosis;61
5.4.3.1;Caspases;61
5.4.3.2;Extrinsic Death Pathway;62
5.4.3.3;Intrinsic Death Pathway;63
5.4.3.4;Regulators of Caspases;64
5.4.3.4.1;Adapter Proteins;64
5.4.3.4.2;The Bcl-2 Family of Proteins;65
5.4.3.4.3;Inhibitors of Apoptosis Proteins;65
5.4.3.4.4;Other Regulators;66
5.4.3.5;Protein Targets of Caspases;66
5.4.4;Apoptosis and the Pathogenesis of Lung Diseases;66
5.4.4.1;Acute Lung Injury/Acute Respiratory Distress Syndrome;66
5.4.4.2;Chronic Obstructive Pulmonary Disease;67
5.4.4.3;Asthma;67
5.4.4.4;Pulmonary Fibrosis;67
5.4.4.5;Lung Cancer;67
5.4.5;Conclusion;67
5.4.6;References;68
5.5;5 Roles of Mutation and Epimutation in the Development of Lung Disease ;72
5.5.1;Introduction;72
5.5.2;Pathogenesis of Lung Disease;72
5.5.3;Mutations and Epimutations;72
5.5.3.1;Genetic Alterations;72
5.5.3.2;Epigenetic Alterations;73
5.5.4;Neoplastic Lung Diseases;73
5.5.4.1;Pathogenesis of Lung Cancer;73
5.5.4.2;Chromosomal Alterations in Lung Cancer;73
5.5.4.2.1;Amplification of the c-Myc Protooncogene in Lung Cancer;74
5.5.4.2.2;Common Chromosomal Deletions in Lung Cancer ;74
5.5.4.2.3;Complex Chromosomal Rearrangements in Lung Cancer ;74
5.5.4.3;Gene Mutations in Lung Cancer;75
5.5.4.3.1;The ras Gene Family;75
5.5.4.3.2;Tumor Suppressor p53;75
5.5.4.3.3;Tumor Suppressor p16INK4A;75
5.5.4.4;Epimutations in Lung Cancer;75
5.5.5;Obstructive Lung Diseases;76
5.5.5.1;Pathogenesis of Emphysema;76
5.5.5.2;Gene Mutations in Emphysema;76
5.5.5.3;Pathogenesis of Cystic Fibrosis;76
5.5.5.4;Gene Mutations in Cystic Fibrosis;76
5.5.5.5;Epimutations in Cystic Fibrosis;77
5.5.6;References;77
6;Section 2 Techniques and Experimental Systems in Molecular Pathology;81
6.1;6 Bioinformatics and Omics;82
6.1.1;Introduction;82
6.1.2;Bioinformatics;82
6.1.3;Omics;82
6.1.3.1;Genomics;82
6.1.3.2;Transcriptomics;82
6.1.3.3;Proteomics;83
6.1.3.4;Metabolomics;83
6.1.3.5;DNA Microarrays;83
6.1.4;Conclusion;83
6.1.5;References;83
6.2;7 General Approach to Molecular Pathology;87
6.2.1;Introduction;87
6.2.2;Nucleic Acid Extraction;87
6.2.3;Amplification Technologies;88
6.2.3.1;Target Amplification;88
6.2.3.1.1;Polymerase Chain Reaction;88
6.2.3.1.2;Other Target Amplification Techniques;89
6.2.3.2;Signal Amplification;89
6.2.4;Restriction Fragment Analysis and Southern Blotting;91
6.2.4.1;Restriction Fragment-Length Polymorphism;91
6.2.4.2;Southern Blotting;91
6.2.5;Sequencing;91
6.2.5.1;Sanger Sequencing;91
6.2.5.2;Real-time Sequencing;92
6.2.5.3;Advanced Sequencing;92
6.2.6;Methylation Detection Methods;92
6.2.7;Fluorescence In Situ Hybridization and Microarrays;92
6.2.7.1;Fluorescence In Situ Hybridization;92
6.2.7.2;Chromosomal Microarrays;92
6.2.7.3;Oligonucleotide Microarrays;93
6.2.8;Liquid Bead Microarrays;93
6.2.9;Mass Spectrometry;93
6.2.10;Systems Biology Approaches;93
6.2.10.1;Implementing Molecular Pathology;94
6.2.10.2;Laboratory Design Considerations;94
6.2.10.3;Laboratory Staffing;94
6.2.11;References;94
6.3;8 Applications of Molecular Tests in Anatomic Pathology;95
6.3.1;Introduction;95
6.3.2;Anatomic Pathology Testing to Detector Characterize Neoplasia;96
6.3.2.1;Oncogenes;96
6.3.2.2;Tumor Suppressor Genes;97
6.3.2.3;Molecular Anatomic Testing for Targeted Therapies in Lung Cancer;97
6.3.3;Anatomic Pathology Testing forInfectious Agents;97
6.3.4;References;98
6.4;9 Polymerase Chain Reaction and Reverse Transcription–Polymerase Chain Reaction;100
6.4.1;Polymerase Chain Reaction;100
6.4.1.1;Theory;100
6.4.1.2;Principles;100
6.4.1.3;Practical Polymerase Chain Reaction;103
6.4.1.3.1;Denaturation Step Programming;103
6.4.1.3.2;Annealing Step Programming and Primer Design;103
6.4.1.4;Polymerase Chain Reaction Components;104
6.4.1.4.1;Thermostable Polymerase;104
6.4.1.4.2;Deoxynucleotides;104
6.4.1.4.3;Polymerase Chain Reaction Buffer;105
6.4.1.4.4;Magnesium;105
6.4.1.5;Polymerase Chain Reaction Set-Up;105
6.4.1.6;Postprocedure Analysis;105
6.4.1.7;Variations;106
6.4.1.8;Real-Time Polymerase Chain Reaction;106
6.4.2;Reverse Transcription;109
6.4.3;References;111
6.5;10 Array Comparative Genomic Hybridization in Pathology ;114
6.5.1;Principle of Comparative Genomic Hybridization;114
6.5.2;Array Comparative Genomic Hybridization Platforms;114
6.5.2.1;Arrays Based on Clone Inserts;114
6.5.2.1.1;cDNA Arrays;114
6.5.2.1.2;Large-Insert Clone Arrays;114
6.5.2.2;Repeat-Free and Nonredundant Sequence Arrays;116
6.5.2.3;Oligonucleotide Arrays Using Presynthesized Oligonucleotides;117
6.5.2.4;Oligonucleotide Arrays Based on In Situ Synthesis;117
6.5.3;General Platform Considerations;117
6.5.4;DNA Preparation and Hybridization;118
6.5.4.1;DNA Isolation and Quality;118
6.5.4.2;Microdissection and DNA Amplification;118
6.5.4.3;Reference DNA;119
6.5.4.4;DNA Labeling;120
6.5.4.5;Hybridization;120
6.5.5;Data Analysis;120
6.5.5.1;Image Processing;121
6.5.5.2;Background Subtraction;121
6.5.5.3;Normalization;121
6.5.5.4;Identifying an Aberration;121
6.5.6;Conclusion;122
6.5.7;References;123
6.6;11 Loss of Heterozygosity in Lung Diseases;125
6.6.1;Introduction;125
6.6.2;What Is Loss of Heterozygosity?;125
6.6.3;Detecting Loss of Heterozygosity;125
6.6.4;Tobacco Smoke and Loss of Heterozygosity;126
6.6.5;Other Factors Influencing Loss of Heterozygosity;126
6.6.5.1;Asbestos;126
6.6.5.2;Pathogens;126
6.6.6;Patterns of Loss of Heterozygosity in Lung Cancer;127
6.6.6.1;Loss of Heterozygosity at 1p;128
6.6.6.2;Loss of Heterozygosity at 3p;128
6.6.6.3;Loss of Heterozygosity at 5q;128
6.6.6.4;Loss of Heterozygosity at 8p;128
6.6.6.5;Loss of Heterozygosity at 9p;129
6.6.6.6;Loss of Heterozygosity at 10q;129
6.6.6.7;Loss of Heterozygosity at 13q;129
6.6.6.8;Loss of Heterozygosity at 15q;129
6.6.6.9;Loss of Heterozygosity at 17p;129
6.6.6.10;Loss of Heterozygosity at 19p;129
6.6.6.11;Loss of Heterozygosity on the X Chromosome;129
6.6.7;Loss of Heterozygosity in Benign Lung Diseases;130
6.6.7.1;Idiopathic Pulmonary Fibrosis;130
6.6.7.2;Sarcoidosis;130
6.6.7.3;Chronic Obstructive Pulmonary Disease and Asthma;130
6.6.8;Conclusion;130
6.6.9;References;130
6.7;12 In Situ Hybridization: Principles and Applications for Pulmonary Medicine;134
6.7.1;Introduction;134
6.7.2;In Situ Hybridization:General Principles;134
6.7.2.1;DNA Composition and Structure;134
6.7.2.2;Principles of Base Pairing;134
6.7.2.3;Denaturation, Renaturation, and Influencing Factors;135
6.7.3;Probes;136
6.7.3.1;Types of Probes;136
6.7.3.1.1;Chromosome Enumeration Probes;136
6.7.3.1.2;Locus-Specific Probes;137
6.7.3.1.3;Telomeric Probes;137
6.7.3.1.4;Chromosomal Paints;137
6.7.4;Probe Preparation;137
6.7.4.1;Directly Labeled Probes;137
6.7.4.2;Indirectly Labeled Probes;137
6.7.4.3;In-House Developed Probes;137
6.7.5;Fluorescence In Situ Hybridization;137
6.7.5.1;Procedure;137
6.7.5.2;Specimens;139
6.7.5.3;Prehybridization;139
6.7.5.4;Denaturation and Hybridization;139
6.7.5.5;Removing Nonspecifically Bound Probe;139
6.7.5.6;Fluorescence Microscopy;140
6.7.6;Chromogenic In Situ Hybridization;140
6.7.7;Other Techniques That Utilize In Situ Hybridization;141
6.7.7.1;Comparative Genomic Hybridization;141
6.7.8;Multicolor Whole-Chromosome Painting;142
6.7.9;Clinical Applications;143
6.7.9.1;Oncology;143
6.7.9.1.1;Tumor Detection;143
6.7.9.1.2;Tumor Typing;143
6.7.9.1.3;Prognostication and Guiding Treatment;144
6.7.9.2;Infectious Disease;144
6.7.9.3;Inherited Diseases;144
6.7.10;Conclusion;144
6.7.11;References;145
6.8;13 Proteomics;147
6.8.1;Omics;147
6.8.1.1;Genomics and Transcriptomics;147
6.8.1.2;Proteomics;147
6.8.2;Proteomics: A New Diagnostic Tool for Lung Diseases;148
6.8.2.1;The Ideal Proteomics;148
6.8.2.2;Shotgun and Protein Profiling;148
6.8.2.3;Protein Identification;149
6.8.2.4;Data Validation;149
6.8.3;Proteomics Instrumentation;149
6.8.3.1;Two-Dimensional Gel Electrophoresis;149
6.8.3.1.1;Methodologic Obstacles of PAGE;149
6.8.3.1.1.1;Protein Staining;150
6.8.3.1.1.2;Enzymatic and Nonenzymatic Digestion;150
6.8.3.1.2;Mass Spectrometry;151
6.8.3.1.2.1;Matrix-Assisted Laser Desorption/Ionization;151
6.8.3.1.2.2;Imaging Mass Spectrometry;151
6.8.3.1.2.3;Surface-Enhanced Laser Desorption/Ionization Mass Spectrometry;152
6.8.3.1.2.4;Other Types of Spectrometry;152
6.8.3.1.2.5;A “Dream Team” Mass Spectrometry System;152
6.8.4;Proteomics Protocols;153
6.8.4.1;Protein Identification;153
6.8.4.1.1;Mass Fingerprinting Identification;153
6.8.4.1.2;Sequence-Based Identification;153
6.8.4.1.3;Database Searching;154
6.8.4.1.4;Validation of Protein Match;154
6.8.4.2;Protein Quantification;155
6.8.4.2.1;Detection of Posttranslational Modification;155
6.8.4.3;Protein Complexes and Protein Interactions;156
6.8.5;Applications to Pulmonary Pathology;156
6.8.5.1;Noninfectious Inflammatory Diseases of the Lung ;156
6.8.5.2;Infectious Diseases of the Lung;157
6.8.5.3;Transplant Rejection Versus Infection;157
6.8.5.4;Neoplastic Diseases of the Lung;157
6.8.6;References;159
6.9;14 Animal Models of Lung Disease;161
6.9.1;Introduction;161
6.9.2;Transgenic Mouse Models;161
6.9.3;Nonneoplastic Diseases;161
6.9.3.1;Chronic Bronchitis and Emphysema;161
6.9.3.2;Asthma;162
6.9.3.3;Cystic Fibrosis;162
6.9.3.4;Interstitial Lung Diseases;162
6.9.4;Animal Models of Lung Cancer;163
6.9.4.1;Knockout Mouse Models;163
6.9.5;Animal Models of Mesothelioma;164
6.9.6;Conclusion;164
6.9.7;References;164
6.10;15 Tissue Culture Models;167
6.10.1;Introduction;167
6.10.2;History of Tissue Culture;167
6.10.3;Types of Tissue Culture;168
6.10.4;Advantages and Limitations of Tissue Culture;169
6.10.5;Cell Culture and the Study of Disease Processes;169
6.10.6;Biology of the Cultured Cell;169
6.10.6.1;Culture Environment;169
6.10.6.2;Cell Adhesion;170
6.10.6.3;Development of Continuous Cell Lines;170
6.10.6.4;Dedifferentiation;170
6.10.6.5;Functional Environment;170
6.10.7;Lung Tissue Cell Lines: Establishment and Significance;171
6.10.7.1;Normal Human Bronchial Epithelial Cells;171
6.10.7.2;Pulmonary Endothelial Cells;171
6.10.7.3;Airway Smooth Muscle and Asthma;172
6.10.7.4;Lung Cancer Tissue and the Development of Novel Therapeutics;172
6.10.7.5;Infectious Diseases;173
6.10.7.6;Human Type II Alveolar Pneumocytes and Acute Lung Injury/Acute Respiratory Distress Syndrome;173
6.10.8;Three-Dimensional Biology;173
6.10.8.1;Conventional Bioreactors and Three-Dimensionality: The Origins of Three-Dimensional Culture;173
6.10.8.2;Three-Dimensional Models for Physiological Study;175
6.10.8.3;Three-Dimensional Models of Lung Disease;175
6.10.8.3.1;Lung Cancer;175
6.10.8.4;Rotating-Wall Vessel Tumor Models;177
6.10.8.4.1;Rotating-Wall Vessel Normal Human Tissue Models as Disease Targets;177
6.10.9;Conclusion;179
6.10.10;References;179
7;Section 3 Molecular Pathology of Pulmonary and Pleural Neoplasms: General Principles;183
7.1;16 Molecular Oncogenesis of Lung Cancer;184
7.1.1;Introduction;184
7.1.2;Oncogene Activation;184
7.1.2.1;K-ras Activation;185
7.1.2.2;Erb Family Activation: ErbB1 (EGFR) and ErbB2 (HER2/neu);185
7.1.2.3;Myc Activation;185
7.1.2.4;Other Alterations: Vascular Endothelial Growth Factor, Bcl-2, Myb, Fms, Rlf,Kit/SCR, GRP/GRPR, Raf;186
7.1.3;Alterations of Tumor Suppressor Genes in Lung Cancers;186
7.1.3.1;The p53 Pathway;186
7.1.3.2;The Retinoblastoma Pathway: Rb and P16INK4;187
7.1.3.3;Other Chromosomal Deletions;187
7.1.4;Gene Silencing by MicroRNA;188
7.1.5;Perspectives;188
7.1.6;References;188
7.2;17 Genetic Susceptibility;191
7.2.1;Lung Cancer Risk;191
7.2.1.1;Familial Lung Cancer Risk;191
7.2.1.2;Lung Cancer Risk in Women and Men;192
7.2.1.3;Xenobiotic-Metabolizing Enzymes;192
7.2.1.4;DNA Adducts and Lung Cancer;193
7.2.1.5;Polymorphisms and DNA Adduct Levels;193
7.2.1.6;Investigations of Specific Polymorphismsand Susceptibility to Lung Cancer;194
7.2.2;Xenobiotic-Metabolizing Genes;194
7.2.2.1;Cytochrome P450 Polymorphisms and Lung Cancer Susceptibility;194
7.2.2.2;CYP2A6;195
7.2.2.3;Other CYP Alleles;195
7.2.2.4;Aryl Hydrocarbon Receptor;195
7.2.2.5;Microsomal Epoxide Hydrolase;195
7.2.2.6;Glutathione-S-Transferase and Lung Cancer Susceptibility;195
7.2.2.7;Other Phase II Xenobiotic Enzymes;195
7.2.2.8;Multiple Xenobiotic-Metabolizing Enzymes;195
7.2.2.9;DNA Repair Gene Polymorphisms and Lung Cancer Susceptibility;196
7.2.2.10;Nucleotide Excision Repair Pathway Polymorphisms;196
7.2.2.11;Other DNA Repair Genes;197
7.2.2.12;Multiple DNA Repair Genes;197
7.2.3;References;197
7.3;18 Prognostic Markers;208
7.3.1;Prognostic Markers;208
7.3.2;Non–Small Cell Lung Cancers;208
7.3.2.1;c-erbB2;208
7.3.2.2;Bcl-2;209
7.3.2.3;p53;209
7.3.2.4;p63;210
7.3.2.5;Retinoblastoma Protein;210
7.3.2.6;Cell Cycle Proteins;210
7.3.2.7;Epidermal Growth Factor Receptor;210
7.3.2.8;Murine Double Minute 2;211
7.3.2.8.1;ras;211
7.3.2.8.2;L-Myc;211
7.3.3;Neuroendocrine Lung Cancers;211
7.3.4;Conclusion;212
7.3.5;References;212
7.4;19 Pulmonary Angiogenesis in Neoplasticand Nonneoplastic Disorders;215
7.4.1;Introduction;215
7.4.2;The CXC Chemokines;215
7.4.2.1;CXCR2 Is the Receptor for Angiogenic ELR+ CXC Chemokine-Mediated Angiogenesis;216
7.4.2.2;Virally Encoded Chemokine Receptorsand Angiogenesis;217
7.4.2.3;CXCR3 Is the Major Receptor for CXC Chemokines That Inhibit Angiogenesis;217
7.4.3;Endothelin-1 and Angiogenesis;218
7.4.4;Angiogenesis and Pulmonary Hypertension;218
7.4.5;Angiogenesis and Fibroproliferation in the Lung;219
7.4.6;Chemokines and Angiogenesis in Lung Cancer;220
7.4.7;Non-ELR+ CXC Chemokines Attenuate Angiogenesis Associated with Tumorigenesis;220
7.4.8;Molecular Mechanisms of Angiogenesis;221
7.4.9;The Duffy Antigen Receptor for Chemokines and Tumor Angiogenesis;223
7.4.10;Possible Nonreceptor-Mediated Inhibition of Angiogenesis;223
7.4.11;Conclusion;224
7.4.12;References;224
7.5;20 Lung Cancer Stem Cells;228
7.5.1;Stem Cells;228
7.5.2;Cancer Stem Cells;228
7.5.3;Cancer Stem Cell Regulation;229
7.5.4;Clinical Implications of Cancer Stem Cells;230
7.5.5;Lung Cancer Stem Cells;230
7.5.6;References;231
7.6;21 Gene Therapy Approaches for Lung Cancer;234
7.6.1;Introduction;234
7.6.2;Mechanism of p53 Tumor Suppression and Rationale for p53 Gene Therapy;234
7.6.3;Preclinical Studies of p53 Gene Replacement;235
7.6.4;Clinical Trials of p53 Gene Replacement;235
7.6.5;Gene Replacement in Combination with Conventional DNA-Damaging Agents in Non–Small Cell Lung Cancer;236
7.6.6;Preclinical Studies;236
7.6.7;Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy;236
7.6.8;Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy;236
7.6.9;Systemic Gene Therapy;237
7.6.10;Conclusion;238
7.6.11;References;238
7.7;22 Response to Conventional Therapy and Targeted Molecular Therapy;241
7.7.1;Traditional Therapy;241
7.7.2;Predictors of Response to Traditional Therapy;241
7.7.3;Targeted Therapies;242
7.7.3.1;Epidermal Growth Factor Receptor-Targeted Therapies;242
7.7.3.1.1;Monoclonal Antibodies;242
7.7.3.1.2;Tyrosine Kinase Inhibitors;242
7.7.3.2;Antiangiogenesis Therapy;243
7.7.3.3;Other Potential Targeted Therapies;244
7.7.3.3.1;Trastuzumab;244
7.7.3.3.2;Pertuzumab;244
7.7.3.3.3;Farnesyltransferase Inhibitor Sch66336;244
7.7.3.3.4;Retinoids and Rexinoids;244
7.7.3.3.5;Antimethylation;244
7.7.4;Small Cell Lung Carcinoma;244
7.7.5;Conclusion;245
7.7.6;References;245
7.8;23 Environmental Agents in Lung and Pleural Neoplasms;248
7.8.1;Introduction;248
7.8.2;Mechanisms of Action of Environmental Carcinogens;248
7.8.3;Asbestos: A Unique Carcinogen;249
7.8.3.1;Properties of Asbestos;249
7.8.3.2;Asbestos-Associated Lung Cancers;250
7.8.3.3;Asbestos-Associated Mesothelioma;250
7.8.3.4;Mechanisms of Asbestos-Induced Carcinogenesis;250
7.8.3.5;Mechanisms of Asbestos-Induced CellSignaling In Mitogenesis, TumorPromotion, and Progression;250
7.8.3.6;General Concepts of Mitogen-Activated Protein Kinase Signaling;251
7.8.3.7;Mitogen-Activated Protein Kinase Signaling, Fos/Jun Proteins, and Activator Protein-1 Activation;251
7.8.3.8;Asbestos and Mitogen-Activated Protein Kinase Signaling;252
7.8.3.9;Nuclear Factor-.B Signaling by Asbestos;252
7.8.3.10;Phosphatidylinositol-3 Kinase/AktSignaling by Asbestos;252
7.8.4;Conclusion;252
7.8.5;References;253
7.9;24 Viral Oncogenesis;255
7.9.1;Introduction;255
7.9.2;Mechanisms of Tumorigenesis;256
7.9.3;Cell Proliferation and Carcinogenesis;257
7.9.4;Viruses in Human Tumors;257
7.9.5;Conclusion;260
7.9.6;References;260
8;Section 4 Molecular Pathology of Pulmonary and Pleural Neoplasms: Specific Histologic Types;263
8.1;25 Adenocarcinoma and Its Precursor Lesions;264
8.1.1;Why Is Adenocarcinoma Now the Most Common Lung Carcinoma?;264
8.1.2;Cigarette Smoke, FilteredVersus Unfiltered Cigarettes,and Their Carcinogens;265
8.1.3;The Architecture of Bronchi,Bronchioles, and Alveoli andTheir Cellular Constituents;265
8.1.4;Regeneration and Its Implications;265
8.1.5;Atypical Adenomatous Hyperplasia,Bronchiolar Columnar Cell Dysplasia, Atypical Goblet Cell Hyperplasia, and Other Lesions?;266
8.1.6;The Role of Cancer Stem Cells;266
8.1.7;The Bronchoalveolar Carcinoma Story:Is There Room for a Noninvasive Adenocarcinoma?;267
8.1.8;Genomic Aberrations in Adenocarcinoma;267
8.1.9;Specific Gene Loci in Adenocarcinomas;268
8.1.10;RNA Expression in Adenocarcinoma;271
8.1.11;Proteomics of Adenocarcinoma;273
8.1.12;Regulatory Pathwaysin Adenocarcinoma;274
8.1.12.1;The Epidermal Growth Factor Receptor System;274
8.1.12.2;The Platelet-Derived Growth Factor System;275
8.1.12.3;The Histone Deacetylase System;275
8.1.12.4;Insulin-Like Growth Factor System;276
8.1.12.5;The Vascular Endothelial Growth Factor and Angiogenesis System;277
8.1.12.6;The Nuclear Factor-.B Pathway;277
8.1.12.7;The Hepatocyte Growth Factor Pathway;278
8.1.13;From Invasion to Metastasis;279
8.1.14;References;279
8.2;26 Molecular Pathology of Squamous Cell Carcinoma and Its Precursors;283
8.2.1;Introduction;283
8.2.2;Chromosomal Abnormalities:Loss of Heterozygosity;284
8.2.3;p53 Mutations;285
8.2.4;The p16/Cyclin D1/Cyclin-Dependent Kinase 4/Retinoblastoma Pathway and Aberrant Methylation;286
8.2.5;The PTEN/MMAC1 Tumor Suppressor Gene;286
8.2.6;Telomerase Dysregulation and Upregulation;286
8.2.7;Amplification of Oncogenes;287
8.2.8;Epidermal Growth Factor Receptorand Tyrosine Kinase Inhibitors;287
8.2.9;Autocrine Growth Factors;288
8.2.10;Conclusion;288
8.2.11;References;289
8.3;27 Molecular Pathology of Large Cell Carcinoma and Its Precursors;292
8.3.1;Introduction;292
8.3.2;Molecular Studies:Immunohistochemical Markers;294
8.3.2.1;Lineage Specific Markers;294
8.3.2.1.1;Large Cell Carcinoma;294
8.3.2.1.2;Large Cell Neuroendocrine Carcinoma;294
8.3.2.1.3;Basaloid Carcinoma;294
8.3.2.1.4;Lymphoepithelioma-Like Carcinoma;295
8.3.2.1.5;Large Cell Carcinoma with Rhabdoid Phenotype;295
8.3.2.2;Molecular Pathway and Prognostic Markers;295
8.3.2.3;Large Cell Carcinoma and Large Cell Neuroendocrine Carcinoma;295
8.3.2.4;Basaloid Carcinoma;295
8.3.3;Studies of Single Genes;299
8.3.3.1;Large Cell Carcinoma;299
8.3.3.2;Large Cell Neuroendocrine Carcinoma;300
8.3.3.3;Lymphoepithelioma-Like Carcinoma;300
8.3.4;Chromosomal Studies and Large Cell Carcinoma;300
8.3.5;Cytogenetic Studies of Large Cell Carcinoma;300
8.3.6;Comparative Genomic Hybridization;300
8.3.6.1;Large Cell Carcinoma;300
8.3.6.2;Large Cell Neuroendocrine Carcinoma;300
8.3.7;Loss of Heterozygosity Studies;301
8.3.7.1;Large Cell Carcinoma;301
8.3.7.2;Large Cell Neuroendocrine Carcinoma;301
8.3.8;Gene Expression Profiling Studies;301
8.3.9;Proteomics;302
8.3.10;Conclusion;303
8.3.11;References;303
8.4;28 Small Cell Carcinoma;306
8.4.1;Introduction;306
8.4.2;Molecular Pathology;306
8.4.2.1;Signature of Cell Differentiation;306
8.4.2.2;The Molecular Genetics Alterations Related to Small Cell Lung Carcinoma Pathogenesis: Proliferation and Progression;307
8.4.2.2.1;Chromosomal Imbalances;307
8.4.2.2.2;The Sonic Hedgehog Pathway;307
8.4.2.2.3;Human Achaete-Scute Homolog 1 Expression;307
8.4.2.2.4;p53 Pathway Alterations;307
8.4.2.2.5;Retinoblastoma Alterations in Lung Cancer;308
8.4.2.2.6;Alteration of Upstream Regulators of p53:p14ARF and MDM2;308
8.4.2.2.7;E2F1 Overexpression;309
8.4.2.2.8;Chromosome 3p Deletion;309
8.4.2.2.9;Telomerase Expression;309
8.4.2.2.10;Angiogenic Factors;310
8.4.2.2.11;Cadherin–Catenin Complex Proteins;310
8.4.2.3;Tyrosine-Kinase Growth Factor and Receptors;310
8.4.3;References;311
8.5;29 Neuroendocrine Carcinomas and Precursors;314
8.5.1;Introduction;314
8.5.2;Histopathologic Defi nitions;314
8.5.3;Molecular Pathology: Differentiation Signs;315
8.5.4;Molecular Alterations Reflecting Malignant Proliferation;315
8.5.4.1;Carcinoids (Typical and Atypical);315
8.5.4.1.1;Somatic Genetics: Cytogenetics and Comparative Genomic Hybridization;315
8.5.4.1.2;p53 Pathway Alterations;315
8.5.4.1.3;The Retinoblastoma Pathway;315
8.5.4.1.4;Upstream p53 Pathway Alterations;316
8.5.4.1.5;The Fas Pathway of Apoptosis;316
8.5.4.1.6;Telomerase Inactivation;316
8.5.4.1.7;Angiogenic Factors, Growth Factors, and Migration Factors;316
8.5.4.2;Large Cell Neuroendocrine Carcinoma;316
8.5.4.2.1;Somatic Genetics: Cytogenetics and Comparative Genomic Hybridization;316
8.5.4.2.2;Molecular Pathology: The p53 and Retinoblastoma Pathways;317
8.5.4.2.3;Apoptotic Factors;317
8.5.4.2.4;Fas and Fas Ligand;317
8.5.4.2.5;Angiogenic Factors;317
8.5.4.2.6;Growth Factors and Receptors;317
8.5.4.2.7;Adhesion Molecule of E-Cadherin–b-Catenin Complex;317
8.5.5;Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Tumorlets;318
8.5.6;References;318
8.6;30 Pulmonary Lymphomas;320
8.6.1;Introduction;320
8.6.2;Mucosa-Associated Lymphoid Tissue Lymphoma;320
8.6.2.1;Case 30.1;321
8.6.3;Diffuse Large B-Cell Lymphoma;323
8.6.3.1;Posttransplantation Lymphoma;323
8.6.3.2;Pulmonary Lymphoma in Acquired Immunodeficiency Syndrome;323
8.6.3.2.1;Case 30.2;324
8.6.4;Lymphomatoid Granulomatosis;325
8.6.5;Conclusion;326
8.6.6;References;326
8.7;31 Posttransplantation Lymphoproliferative Disorder;328
8.7.1;Introduction;328
8.7.2;Classification;328
8.7.3;Incidence and Risk Factors;329
8.7.4;Lung Transplantation and Posttransplantation Lymphoproliferative Disorder;329
8.7.5;Pathogenesis;330
8.7.5.1;Virology of Epstein-Barr Virus;330
8.7.5.2;In Vitro Epstein-Barr Virus Infection;332
8.7.5.3;In Vivo Epstein-Barr Virus Infection;333
8.7.5.4;Persistence of Infection;333
8.7.5.5;Cellular Signaling Pathway;335
8.7.6;Immunosurveillance and Evasionof the Immune System;336
8.7.6.1;Restricted Gene Expression During Latent Infection;336
8.7.6.2;Interference with Cytokines;336
8.7.6.3;Cytotoxic Activity;336
8.7.7;Patterns of Epstein-Barr Virus Latency and Related Diseases;337
8.7.8;Molecular Histogenesis;338
8.7.9;Genetic Profi le;340
8.7.10;Diagnosis and Evaluation;341
8.7.11;Treatment and Management;342
8.7.12;Prophylaxis;343
8.7.12.1;Epstein-Barr Viral Load in Immunocompromised Hosts;343
8.7.12.2;Epstein-Barr Virus–Negative Disease;343
8.7.13;Prognosis;344
8.7.14;References;344
8.8;32 Unusual Benign and Malignant Neoplasms of Lung: Molecular Pathology;347
8.8.1;Sclerosing Hemangioma;347
8.8.2;Lymphangioleiomyomatosis;348
8.8.3;Solitary Fibrous Tumor;348
8.8.4;Lipomatous Neoplasms;349
8.8.5;Myxoid Liposarcoma;350
8.8.6;Chondroma and Chondrosarcoma;350
8.8.7;Vascular Lesions;351
8.8.7.1;Epithelioid Hemangioendothelioma and Angiosarcoma;351
8.8.8;Other Sarcomas;351
8.8.8.1;Pulmonary Synovial Sarcoma;351
8.8.8.2;Pulmonary Artery Sarcoma;351
8.8.8.3;Alveolar Soft Part Sarcoma;352
8.8.9;References;352
8.9;33 Primary Versus Metastatic Cancer: Gene Expression Profiling;354
8.9.1;General Comments;354
8.9.2;Background: Value of Immunohistochemistry;354
8.9.3;Molecular Markers in the Differential Diagnosis of Primary Versus Metastatic Tumor to the Lung: Are We There?;355
8.9.4;Molecular Markers in the Differentiation of Synchronous and Metachronous Lung Lesions Versus Recurrence/Metastases;357
8.9.5;References;357
8.10;34 Diffuse Malignant Mesothelioma: Genetic Pathways and Mechanisms of Oncogenesis of Asbestos and Other Agents That Cause Mesotheliomas;360
8.10.1;Introduction;360
8.10.2;Mechanisms of Oncogenesis in Mesothelioma;360
8.10.2.1;Asbestos-Induced Oncogenesis;360
8.10.2.2;Viruses;361
8.10.2.3;Radiation;361
8.10.2.4;Other Etiologic Factors;361
8.10.3;Cytogenetics, Deletion Mapping, and Gene Profiling in Mesothelioma ;361
8.10.3.1;Karyotypic Analysis Studies;361
8.10.3.2;Comparative Genomic Hybridization Studies;361
8.10.3.3;Deletion Mapping;362
8.10.3.4;Gene Profi ling and Mesothelioma;362
8.10.4;Polymorphisms in Genes as Risk Factors for Asbestos-Related Malignant Mesothelioma;363
8.10.5;Tumor Suppressor Gene Inactivation in Mesothelioma;364
8.10.5.1;Loss of Cyclin-Dependent Kinase Inhibitor Function;364
8.10.5.2;The p53 Gene;364
8.10.5.3;The NF2 Gene;365
8.10.6;Tumor Suppressor Gene Methylation in Mesothelioma;365
8.10.7;Simian Virus 40 and Human Mesothelioma;365
8.10.8;Wilms’ Tumor 1 Susceptibility Gene;366
8.10.9;Abnormal Expression of Growth Factors and Cytokines;367
8.10.10;Conclusion;367
8.10.11;References;367
8.11;35 Molecular Pathology of Pediatric Tumors of the Lung;371
8.11.1;Introduction;371
8.11.2;Pleuropulmonary Blastoma;371
8.11.2.1;Immunohistochemistry;372
8.11.2.2;Cytogenetic and Molecular Studies;372
8.11.2.3;Relationship of Pleuropulmonary Blastoma to Congenital Cystic Adenomatoid Malformation;372
8.11.3;Inflammatory Myofibroblastic Tumor ;374
8.11.4;Cytogenetic and Molecular Studies;374
8.11.4.1;Prognostic Signifi cance of ALK Expression;375
8.11.4.2;Etiologic Role of Infectious Agents;375
8.11.5;Malignant Small Round Cell Tumor of the Thoracopulmonary Region;376
8.11.5.1;Cytogenetic and Molecular Studies in Ewing’s Family of Tumors;376
8.11.6;References;377
9;Section 5 Molecular Pathology of Pulmonary Infections;380
9.1;36 Basis of Susceptibility to Lung Infection;381
9.1.1;Introduction;381
9.1.2;Lung Anatomy and Function;381
9.1.2.1;Unique Aspects of the Lung Microcirculation;381
9.1.2.2;Epithelial Cilia and Airway Surface Fluid;382
9.1.2.3;Cough Reflex;382
9.1.2.4;Innate Immunity;382
9.1.2.5;Complement;382
9.1.2.6;Surfactant;383
9.1.2.7;Lung Epithelial Cells;383
9.1.2.8;Alveolar Macrophages;384
9.1.2.9;Neutrophils;384
9.1.3;Adaptive Immunity;386
9.1.3.1;T Lymphocytes;387
9.1.3.2;Natural Killer and Natural Killer T Cells;390
9.1.3.3;Dendritic Cells;390
9.1.3.4;Humoral Immunity (B Lymphocytes and Antibodies);390
9.1.4;Conclusion;391
9.1.5;References;391
9.2;37 Molecular Pathology of Viral Respiratory Diseases;394
9.2.1;Introduction;394
9.2.2;General Principles;395
9.2.2.1;Structure and Invasion;395
9.2.2.2;Envelope;395
9.2.2.3;Genome;396
9.2.2.4;Recombination;396
9.2.2.5;Viral Pathogenesis;396
9.2.2.6;Classification;397
9.2.3;Viral Respiratory Diseases;399
9.2.3.1;Orthomyxoviridae;399
9.2.3.2;Paramyxoviridae;399
9.2.3.3;Adenoviruses;401
9.2.3.4;Coronaviruses;401
9.2.3.5;Severe Adult Respiratory Distress Syndrome;402
9.2.3.6;Bunyaviridae (Hantaviruses);402
9.2.3.7;Picornaviruses;402
9.2.4;Conclusion;404
9.2.5;References;404
9.3;38 Molecular Pathology of Rickettsial Lung Infections;409
9.3.1;Introduction;409
9.3.2;Rickettsial Infections That Impact Lung Structure and Function;409
9.3.3;Rocky Mountain Spotted Fever;410
9.3.3.1;Clinical Disease and Pathophysiology;410
9.3.3.2;Early Events in the Rickettsia–Endothelial Cell Interaction;410
9.3.3.3;Cellular and Tissue Injury;410
9.3.3.4;Host Innate and Adaptive Immune Responses to Infection;412
9.3.3.5;Diagnosis;413
9.3.4;Human Monocytic Ehrlichiosis;413
9.3.4.1;Clinical Disease and Pathophysiology;413
9.3.4.2;Early Events in the Ehrlichia–Mononuclear Phagocyte Interaction;415
9.3.4.3;Cellular and Tissue Injury;415
9.3.4.4;Host Innate and Adaptive Immune Responses to Infection;415
9.3.4.5;Diagnosis;416
9.3.5;Conclusion;416
9.3.6;References;416
9.4;39 Bacteria;419
9.4.1;Introduction;419
9.4.2;Bacterial Causes of Pneumonia;419
9.4.3;Pathogenesis of Pneumonia;419
9.4.4;Pathology;419
9.4.5;Clinical Features;420
9.4.6;Diagnosis;420
9.4.6.1;Streptococcus pneumoniae;421
9.4.6.1.1;Pathogenesis;421
9.4.6.1.2;Clinical Features;421
9.4.6.1.3;Antimicrobial Resistance;421
9.4.6.1.4;Diagnostic Testing;421
9.4.6.2;Haemophilus influenzae;422
9.4.6.2.1;Pathogenesis;422
9.4.6.2.2;Clinical Features;422
9.4.6.2.3;Antimicrobial Resistance;422
9.4.6.2.4;Diagnostic Testing;422
9.4.6.3;Moraxella catarrhalis;422
9.4.6.3.1;Pathogenesis;422
9.4.6.3.2;Clinical Features;423
9.4.6.3.3;Antimicrobial Resistance;423
9.4.6.3.4;Diagnostic Testing;423
9.4.6.4;Legionella pneumophila;423
9.4.6.4.1;Pathogenesis;423
9.4.6.4.2;Clinical Features;423
9.4.6.4.3;Antimicrobial Resistance;424
9.4.6.4.4;Diagnostic Testing;424
9.4.6.5;Chlamydophila pneumoniae;424
9.4.6.5.1;Pathogenesis;424
9.4.6.5.2;Clinical Features;424
9.4.6.5.3;Antimicrobial Resistance;424
9.4.6.5.4;Diagnostic Testing;424
9.4.6.6;Mycoplasma pneumoniae;425
9.4.6.6.1;Pathogenesis;425
9.4.6.6.2;Clinical Features;425
9.4.6.6.3;Antimicrobial Resistance;425
9.4.6.6.4;Diagnostic Testing;425
9.4.6.7;Bordetella pertussis;426
9.4.6.7.1;Pathogenesis;426
9.4.6.7.2;Clinical Features;426
9.4.6.7.3;Antimicrobial Resistance;426
9.4.6.7.4;Diagnostic Testing;426
9.4.6.8;Staphylococcus aureus;426
9.4.6.8.1;Pathogenesis;427
9.4.6.8.2;Clinical Features;427
9.4.6.8.3;Antimicrobial Resistance;427
9.4.6.8.4;Diagnostic Testing;427
9.4.7;Agents with Bioterrorism Potential;427
9.4.7.1;Pathogenesis;427
9.4.7.2;Clinical Features;427
9.4.7.3;Antimicrobial Resistance;428
9.4.7.4;Diagnostic Testing;428
9.4.8;References;428
9.5;40 Immunopathology of Tuberculosis;431
9.5.1;Introduction: Magnitude of Disease;431
9.5.2;Primary and Secondary Tuberculosis Pathology;431
9.5.3;Immune Response to Tuberculosis;434
9.5.4;Conclusion;437
9.5.5;References;437
9.6;41 Molecular Pathology of Fungal Lung Infection;441
9.6.1;Introduction;441
9.6.2;Innate Immunity;441
9.6.2.1;Cellular Component of Immunity;441
9.6.2.2;Complement Component;442
9.6.3;Adaptive Immunity;442
9.6.3.1;Cell-Mediated Immunity and Cytokines;442
9.6.3.2;Dendritic Cells;442
9.6.3.3;Humoral Immunity;443
9.6.4;Pathology and Pathogenesis of Fungal Infections;443
9.6.4.1;Aspergillus;443
9.6.4.2;Coccidioides;444
9.6.4.3;Histoplasma;444
9.6.4.4;Molecular Basis of Pathogenesis;444
9.6.4.5;Pathology;447
9.6.5;Diagnosis;448
9.6.5.1;Molecular Diagnostic Techniques;449
9.6.5.1.1;Serologic Diagnosis;449
9.6.5.1.2;Polymerase Chain Reaction;449
9.6.6;Molecular Basis of Therapy;450
9.6.7;Conclusion;450
9.6.8;References;451
9.7;42 Parasites;454
9.7.1;Introduction;454
9.7.2;Principles of Parasitic Molecular Pathogenesis;454
9.7.2.1;Adaptive Immune Response;455
9.7.2.2;Parasitic Proteases and Their Role in Pathogenesis;456
9.7.3;Molecular Pathogenesis of Pulmonary Protozoan Pathogens;458
9.7.3.1;Toxoplasmosis;458
9.7.3.2;Amebiasis;459
9.7.3.3;Microsporidiosis;459
9.7.3.4;Cryptosporidiosis;460
9.7.4;Molecular Pathogenesis of Pulmonary Helminthic Pathogens;461
9.7.4.1;Nematodes;461
9.7.4.1.1;Filariasis;461
9.7.4.1.2;Strongyloidiasis;461
9.7.4.2;Trematodes;462
9.7.4.2.1;Paragonomiasis;462
9.7.4.2.2;Schistosomiasis;463
9.7.4.3;Cestodes: Echinococcosis;464
9.7.5;Conclusion;464
9.7.6;References;464
10;Section 6 Molecular Pathology of Other Nonneoplastic Pulmonary Diseases: General Principles;469
10.1;43 Inflammation;470
10.1.1;The Inflammatory Response;470
10.1.2;Harmful Effects of Inflammation;471
10.1.3;Innate Immunity: Toll-Like Receptors;471
10.1.4;Acquired Immunity: Macrophages, Dendritic Cells and Antigen Presentation;472
10.1.5;Variants of Inflammation;474
10.1.5.1;Granulomatous Inflammation;474
10.1.5.2;Interstitial Inflammation;475
10.1.6;Human Leukocyte Antigen–Linked Lung Disease;476
10.1.7;Conclusion;478
10.1.8;References;478
10.2;44 Oxidants and Antioxidants;481
10.2.1;Introduction;481
10.2.2;Oxidants in the Lung;481
10.2.2.1;Reactive Oxygen Species;481
10.2.2.2;Reactive Nitrogen Species;482
10.2.3;Antioxidants in the Lung;482
10.2.3.1;Nonenzymatic Antioxidants;482
10.2.3.2;Enzymatic Antioxidants;482
10.2.4;Redox-Sensitive Transcription Factors;483
10.2.5;Oxidative Stress-Associated Lung Disease/Injury;484
10.2.6;References;485
10.3;45 Epithelial Repair and Regeneration;487
10.3.1;Introduction;487
10.3.2;Steady-State Kinetics of Lung Epithelial Cells;487
10.3.3;Steps in Injury and Repair;487
10.3.3.1;Formation of A Provisional Matrix;489
10.3.3.1.1;Loss of Normal Basement Membrane;489
10.3.3.1.2;Functions of the Provisional Matrix;489
10.3.3.2;Restitution of the Epithelial Barrier;489
10.3.3.2.1;Epithelial Cell Dedifferentiation;489
10.3.3.2.2;Signals for Dedifferentiation;490
10.3.3.2.3;Epithelial Cell Migration;490
10.3.3.2.4;Matrix–Epithelial Cell Interactions During Migration;490
10.3.3.2.5;Protease Functions in Epithelial Cell Migration;490
10.3.3.2.6;Reestablishment of the Normal Basement Membrane;490
10.3.3.3;Reconstitution of Epithelial Cell Density;491
10.3.3.3.1;Epithelial Cell Proliferation;491
10.3.3.3.2;Lung Progenitor and Lung Epithelial Stem Cells Roles;491
10.3.3.3.3;Bone Marrow Stem Cells in Repair;492
10.3.3.3.4;Growth Factor Functions in Epithelial Cell Reconstitution;492
10.3.3.4;Epithelial Cell Redifferentiation;492
10.3.3.4.1;Epithelial Cell Redifferentiation and Transdifferentiation;492
10.3.3.4.2;Developmental Signaling Pathways Mediating Differentiation;492
10.3.3.4.3;Transcription Factors Mediating Differentiation Following Injury;493
10.3.4;Metaplasia and Compensatory Apoptosis of Epithelial Cell Populations;493
10.3.5;Roles for Growth Factors in Epithelial Cell Repair;493
10.3.5.1;Epidermal Growth Factor Family;493
10.3.5.2;Transforming Growth Factor-ß Family;493
10.3.5.3;Fibroblast Growth Factor;493
10.3.5.4;Hepatocyte Growth Factor;494
10.3.6;Epithelial Cell Repair Following Prototypic Injuries;494
10.3.6.1;Airway Epithelial Cell Repair Following Respiratory Virus Infection;494
10.3.6.1.1;Morphologic Events Following Respiratory Virus Infection;494
10.3.6.1.2;Molecular Correlates of Morphologic Events;494
10.3.6.1.3;Mucous Cell Metaplasia Following Respiratory Virus Infection;495
10.3.6.2;Alveolar Epithelial Cell Repair Following Acute Respiratory Distress Syndrome;495
10.3.6.3;Establishment of a Provisional Matrix in Acute Respiratory Distress Syndrome;496
10.3.6.4;Restitution and Reconstitution of the Epithelial Cell Barrier;496
10.3.7;Summary: Epithelial Cell Repair Following Injury;496
10.3.8;References;496
10.4;46 Fibrogenesis;501
10.4.1;Introduction;501
10.4.2;Experimental Models of Lung Fibrosis;501
10.4.3;Fibroblastic Foci and the Fibroblast Phenotype;501
10.4.4;Sources of Fibroblasts;503
10.4.5;Mechanisms of Fibrosis;504
10.4.5.1;Oxidative Stress;504
10.4.5.2;Apoptosis;504
10.4.5.3;Transforming Growth Factor-ß;505
10.4.5.4;Viral Infection;506
10.4.5.5;Angiogenesis;506
10.4.6;Inherited Forms of Interstitial Lung Disease;507
10.4.6.1;Surfactant Protein C Mutations;507
10.4.6.2;Hermansky-Pudlak Syndrome;508
10.4.6.3;Genetic Studies of Sporadic and Familial Interstitial Lung Disease;508
10.4.7;References;508
10.5;47 Stem Cells in Nonneoplastic Lung Disorders;511
10.5.1;Introduction;511
10.5.2;Pulmonary Repopulation by Bone Marrow–Derived Adult Stem Cells;512
10.5.2.1;Epithelial Cells;512
10.5.2.2;Endothelial Cells;515
10.5.2.3;Fibrocytes;515
10.5.3;Resident Pulmonary Stem Cells;516
10.5.3.1;Large Airways;516
10.5.3.2;Small Airways;516
10.5.4;Side Population Cells;517
10.5.5;Conclusion;518
10.5.6;References;518
10.6;48 Gene Therapy in Nonneoplastic Lung Disease;521
10.6.1;Introduction;521
10.6.2;Gene Therapy in the Lung;521
10.6.2.1;Administration;521
10.6.2.2;Barriers to Gene Transfer;521
10.6.2.3;Cell Entry and Nuclear Entry;522
10.6.2.4;Physical Methods of Overcoming Gene Transfer Barriers;523
10.6.2.5;Gene Transfer Efficacy;523
10.6.3;Cystic Fibrosis;524
10.6.3.1;Stem Cells and Progenitor Cells;525
10.6.3.2;Cystic Fibrosis Transmembrane Conductance Regulator Protein Function and Safety;525
10.6.3.3;Vectors;525
10.6.3.4;Endpoint Assays;527
10.6.3.5;Future Directions;527
10.6.4;a1-Antitrypsin Deficiency ;527
10.6.5;Other Conditions;528
10.6.6;References;528
11;Section 7 Molecular Pathology of Other Nonneoplastic Pulmonary Diseases: Specific Entities;535
11.1;49 Smoking-Related Lung Diseases;536
11.1.1;Effects of Tobacco Smoke on the Respiratory Tract;536
11.1.1.1;Effects of Toxins;536
11.1.1.2;Carcinogenic Effects;537
11.1.1.3;Temperature;537
11.1.1.4;Other Factors Relevant for the Action of Toxic and Carcinogenic Substances/Particles ;538
11.1.1.5;The Repair Program and Its Impact on the Reaction of the Epithelium Toward Inhaled Toxins;538
11.1.1.6;The Defence System;538
11.1.1.6.1;Mucociliary Escalator and Clearance;538
11.1.1.6.2;The Phagocytic System;538
11.1.1.6.3;The Enzymes;538
11.1.2;Chronic Obstructive Pulmonary Disease;539
11.1.2.1;Anatomic Basis;539
11.1.2.2;Cells and Mediators;540
11.1.2.2.1;Epithelial Cells;540
11.1.2.2.2;Neutrophils;541
11.1.2.2.3;Macrophages;541
11.1.2.2.4;Eosinophils;541
11.1.2.2.5;Dendritic Cells;541
11.1.2.2.6;T Lymphocytes;541
11.1.2.3;Oxidative Stress;542
11.1.2.4;Proteases;543
11.1.3;Other Tobacco Smoking-Induced Lung Diseases;543
11.1.3.1;Pulmonary Histiocytosis X;543
11.1.3.2;Respiratory Bronchiolitis–Combined Interstitial Lung Disease;544
11.1.3.3;Combined Respiratory Bronchiolitis–Combined Interstitial Lung Disease and Histiocytosis X;545
11.1.3.4;Desquamative Interstitial Pneumonia;545
11.1.4;Conclusion;545
11.1.5;References;546
11.2;50 Heritable a1-Antitrypsin Deficiency;550
11.2.1;Introduction;550
11.2.2;Heritable a1-Antitrypsin Deficiency;550
11.2.2.1;Associated Disorders;550
11.2.2.2;Structural and Cellular Abnormalities;551
11.2.3;A Case For Disease Modifiers;551
11.2.4;Glycoprotein Biosynthetic Quality Control;551
11.2.4.1;Glycoprotein Structural Maturation;552
11.2.4.1.1;Involvement of Asparagine-Linked Oligosaccharides;552
11.2.4.1.2;The Current Model;552
11.2.4.2;Orchestration of Glycoprotein Degradation;554
11.2.4.2.1;Precision of Substrate Selection;554
11.2.4.2.2;Substrate Recruitment and Proteolysis;554
11.2.5;Potential Therapeutic Approaches;554
11.2.6;References;556
11.3;51 Asthma;558
11.3.1;Introduction;558
11.3.2;Molecular Pathogenesis of Asthma;559
11.3.2.1;Cytokines, Growth Factors, and Related Regulatory DNA;560
11.3.2.1.1;Interleukin-4 and Interleukin-13;560
11.3.2.1.2;Interleukin-4 Receptor a-Subunit;561
11.3.2.1.3;Conserved Noncoding Sequence 1;561
11.3.2.1.4;Interleukin-5 and Interleukin-9;561
11.3.2.1.5;Transforming Growth Factor-a1 ;562
11.3.2.1.6;Interleukin-1a and Interleukin-1ß;562
11.3.2.1.7;Epidermal Growth Factor;563
11.3.2.1.8;Vascular Endothelial Growth Factor;563
11.3.2.1.9;Endothelin-1;564
11.3.2.1.10;Fibroblast Growth Factors, Angiogenin, and Platelet-Derived Growth Factor;564
11.3.2.1.11;Tumor Necrosis Factor;564
11.3.2.1.12;Interleukin-12;564
11.3.2.2;Toll-Like Receptors;564
11.3.2.3;Chemokines and Their Receptors;565
11.3.2.4;Integrins;565
11.3.2.5;Transcription Factors;566
11.3.2.5.1;Signal Transducer and Activator of Transcription 1;566
11.3.2.5.2;Signal Transducer and Activator of Transcription 6;567
11.3.2.5.3;GATA3;567
11.3.2.5.4;Nuclear Factor-kB;567
11.3.2.5.5;T-Box Expressed in T Cells;567
11.3.2.6;Costimulatory Molecules;567
11.3.2.6.1;CD28 and CD134;567
11.3.2.6.2;Cytotoxic T-Lymphocyte Antigen 4;568
11.3.2.6.3;CD40;568
11.3.2.6.4;T-Cell Immunoglobulin and Mucin Domain Protein Molecules;568
11.3.2.7;Seven Transmembrane Spanning Receptors;568
11.3.2.7.1;Complements 3a and 5a;569
11.3.2.7.2;Cysteinyl Leukotrienes;569
11.3.2.7.3;Prostaglandins;569
11.3.2.7.4;Adenosine;570
11.3.2.7.5;The ß2-Adrenergic Receptor;570
11.3.2.7.6;Muscarinic Acetylcholine Receptors;571
11.3.2.7.7;Platelet-Activating Factor;571
11.3.2.7.8;Immunoglobulin E and Its Receptors;571
11.3.2.8;Endogenous and Exogenous Proteinases;571
11.3.2.8.1;Matrix Metalloproteinases;572
11.3.2.8.2;Trypsin;572
11.3.2.8.3;Tryptase;572
11.3.2.8.4;Neutrophil Elastase;572
11.3.2.8.5;Other Endogenous Proteinases;572
11.3.2.8.6;Exogenous Proteinases;572
11.3.2.9;Miscellaneous Molecules;572
11.3.2.9.1;Syndecan-1;572
11.3.2.9.2;Gob-5;573
11.3.2.9.3;Human Leukocyte Antigens;573
11.3.2.9.4;Nitric Oxide Synthase;573
11.3.2.9.5;Histamine and Its Receptors;573
11.3.2.9.6;Chitinases and Related Molecules;573
11.3.3;Conclusion;574
11.3.4;References;574
11.4;52 Cystic Fibrosis;586
11.4.1;Introduction;586
11.4.2;Genetics;586
11.4.3;Structure and Function of the Cystic Fibrosis Transmembrane Conductance Regulator;587
11.4.4;Pathophysiologic Features of Lung Disease in Cystic Fibrosis;588
11.4.5;Diagnosis;589
11.4.6;Clinical Manifestations;589
11.4.7;Function Assays;589
11.4.7.1;Sweat Test;589
11.4.7.2;Transepithelial Nasal Potential Difference;589
11.4.8;Treatment Approaches;590
11.4.9;Conclusion;590
11.4.10;References;591
11.5;53 Pulmonary Organogenesis and Developmental Abnormalities;593
11.5.1;Lung Organogenesis;593
11.5.1.1;Introduction;593
11.5.1.2;Signaling Pathways;594
11.5.1.2.1;Wingless Signaling Pathway;594
11.5.1.2.2;Sonic Hedgehog;594
11.5.1.2.3;Fibroblast Growth Factor;594
11.5.1.2.4;Notch;594
11.5.1.2.5;Epithelial Growth Factor;594
11.5.1.2.6;Transforming Growth Factor-ß/Bone Morphogenic Protein 4;594
11.5.1.3;Branching;595
11.5.1.4;Airway;595
11.5.1.5;Peripheral Airway;595
11.5.1.6;Alveoli;595
11.5.1.7;Mesenchyme;595
11.5.1.8;Vascular Factors;596
11.5.1.9;Specific Genes and Developmental Abnormalities ;596
11.5.2;Conclusion;597
11.5.3;References;597
11.6;54 Genetic Abnormalities of Surfactant Metabolism ;599
11.6.1;Introduction;599
11.6.2;Overview of Pulmonary Surfactant;599
11.6.3;Respiratory Distress Syndrome;600
11.6.4;Surfactant Protein B;600
11.6.5;Surfactant Protein C;602
11.6.6;Member A3 of the Adenosine Triphosphate Binding Cassette Family of Proteins;604
11.6.7;Lung Pathology Associatedwith Inborn Errors of Surfactant Metabolism;604
11.6.8;Genetic Testing;608
11.6.9;Other Proteins Important in Surfactant Metabolism Linked to Genetic Diseases;609
11.6.10;Pulmonary Alveolar Proteinosis;609
11.6.11;Conclusion;609
11.6.12;References;610
11.7;55 Usual Interstitial Pneumonia;616
11.7.1;Introduction;616
11.7.2;Pathogenesis;616
11.7.3;DNA Microarray Studies;617
11.7.4;Molecular Pathways Involved in Alveolar Damage and Reepithelialization;617
11.7.5;Molecular Characterization of Fibroblast Foci;619
11.7.6;Molecular Pathways Involved in Bronchiolar Reepithelialization;620
11.7.7;Molecular Characterization of Epithelial Cells in Fibroblast Foci;621
11.7.8;References;622
11.8;56 Sarcoidosis: Are There Sarcoidosis Genes?;625
11.8.1;Introduction;625
11.8.2;Morphology and Its Implications;625
11.8.3;Variants of Sarcoidosis;625
11.8.3.1;Löfgren’s Disease/Acute Sarcoidosis;625
11.8.3.2;Nodular Sarcoidosis;625
11.8.3.3;Necrotizing Sarcoid Granulomatosis;626
11.8.4;What Is the Meaning of Indistinguishable Differentials?;626
11.8.5;The Cells in Sarcoidosis;627
11.8.5.1;T Lymphocytes;627
11.8.5.2;Epithelioid Cells;627
11.8.5.3;Giant Cells (Foreign Body and Langerhans Type);628
11.8.6;Mycobacteria and Other Trigger Mechanisms—Is Sarcoidosis an Infectious Disease?;628
11.8.7;Risk Factors;628
11.8.8;The Steps of an Immune Reaction and What Might Happen in Sarcoidosis;629
11.8.9;Antigen Uptake and Processing;629
11.8.10;Antigen Presentation, Costimulatory Molecules, and Gene Polymorphisms and Where They Come Into Play;630
11.8.10.1;Human Leukocyte Antigen Class I Genes;630
11.8.10.2;Human Leukocyte Antigen Class II Genes;630
11.8.11;Effector Mechanisms, the Lymphocyte–Macrophage Network, and Gene Expression in Sarcoidosis;631
11.8.12;Disease Modifier Genes and Aspects of Organ Involvement in Sarcoidosis;632
11.8.13;References;633
11.9;57 Histiocytic Diseases of the Lung;636
11.9.1;Introduction;636
11.9.2;Pulmonary Histiocytosis X;636
11.9.2.1;Clinical Disease;636
11.9.2.2;Pathologic Features;636
11.9.2.3;Cellular and Molecular Biology;636
11.9.3;Erdheim-Chester Disease;637
11.9.3.1;Clinical Disease;637
11.9.3.2;Pathologic Features;637
11.9.3.3;Cellular and Molecular Biology;637
11.9.4;Lysosomal Storage Disorders;638
11.9.4.1;Gaucher’s Disease;638
11.9.4.1.1;Clinical Disease;638
11.9.4.1.2;Pathologic Disease;638
11.9.4.1.3;Cellular and Molecular Biology;638
11.9.4.2;Niemann-Pick Disease;638
11.9.4.2.1;Clinical Disease;638
11.9.4.2.2;Pathologic Disease;638
11.9.4.2.3;Cellular and Molecular Disease;638
11.9.4.3;Hermansky-Pudlak Syndrome;639
11.9.4.3.1;Clinical Disease;639
11.9.4.3.2;Pathologic Disease;639
11.9.4.3.3;Cellular and Molecular Biology;640
11.9.5;References;640
11.10;58 Pulmonary Arterial Hypertension;643
11.10.1;Introduction;643
11.10.2;Pathology;643
11.10.3;Genetics;646
11.10.3.1;Bone Morphogenetic Protein Receptor Gene Mutations;646
11.10.3.2;Serotonin Transporter Gene Overexpression;647
11.10.4;Pathogenesis;647
11.10.4.1;Role of Bone Morphogenic Protein and Its Receptor;647
11.10.4.2;Role of Serotonin and Serotonin Transporters;649
11.10.4.3;Role of the Endothelium;649
11.10.4.4;Extracellular Matrix Remodeling;650
11.10.4.5;The Thrombotic System;650
11.10.4.6;Inflammatory Mechanisms;650
11.10.5;Conclusion;651
11.10.6;References;651
11.11;59 Immunopathology of Pulmonary Vasculitides;653
11.11.1;Introduction;653
11.11.2;Pathologic Features;654
11.11.3;Molecular Pathology;656
11.11.3.1;Antineutrophil CytoplasmicAntibody–Associated Vasculitides;657
11.11.3.2;T Cells in Antineutrophil Cytoplasmic Antibody–Mediated Vasculitis;657
11.11.3.3;Leukocyte–Endothelial Cell Interaction;658
11.11.3.4;Cytokines in Vasculitides;658
11.11.3.5;Transforming Growth Factor-ß;659
11.11.3.6;Other Cytokines;659
11.11.3.6.1;Interferon-a;659
11.11.3.7;Chemokines;660
11.11.3.8;Adhesion Molecules;660
11.11.3.9;Apoptosis in Wegener’s Granulomatosis;660
11.11.4;References;661
11.12;60 Asbestosis and Silicosis;667
11.12.1;Introduction;667
11.12.2;Asbestosis;667
11.12.3;Silicosis;669
11.12.4;Conclusion;669
11.12.5;References;669
12;Index;672
"Section 5 Molecular Pathology of Pulmonary Infections (p. 369-370)
36 Basis of Susceptibility to Lung Infection
Frank C. Schmalstieg and Armond S. Goldman
Introduction
The myriad microbial pathogens encountered by the lung presents a daunting challenge to the human immune system. Nowhere else in the body is such a vast surface area (approximately 100 m2)1 directly exposed to airborne pathogens at about 20 times per minute. Not only is the area and exposure extreme, but the underlying blood circulation is only two cell layers, of about 0.5 µm each, removed from the alveolar surface. Furthermore, gravity and manifold branching of bronchioles and bronchi interfere with the expulsion of these organisms and tissue debris that occurs during lung infection. It is not surprising, then, that pneumonias are among the most common infectious diseases in the United States.
Understanding the susceptibility to lung infection requires a comprehension of (1) the anatomy and function of the lung, (2) environmental exposures, (3) systemic and mucosal immune functions, (4) virulence of pathogens, and (5) genetic variabilities of the host defenses. Numerous “experiments of nature” and identi- ? cation of the molecular mechanisms of pathogen entry into lung cells especially have provided unique insights into understanding immune aspects of host susceptibility. More recently, rapid, high volume methods of analyzing potential genetic determinants for host susceptibility to speci? c pathogens have shown considerable promise. These considerations and their results are explored in some detail in this chapter.
Lung Anatomy and Function
Unique Aspects of the Lung Microcirculation
Three distinct circulations supply the lung and airways with blood. They are the tracheal, bronchial, and pulmonary circulations. The tracheal arteries branch from the superior and inferior thyroid arteries and drain to the inferior thyroid venous plexus. More importantly, the bronchial arterial supply is from the thoracic aorta, and the venous drainage from this artery is largely (~70%) anastomosed to the pulmonary circulation in a precapillary location3 in the sheep. This also likely occurs in humans.
These anastomoses are signi? cant because neutrophils may be in? uenced by mediators from airway epithelium and then interact directly with the pulmonary capillaries, thus providing a connection with in? ammation in the airway and in the alveolar capillaries. In this regard, the capillary diameter in the bronchial microcirculation is about 8.5 µm but only approximately 5.5 µm in the pulmonary capillaries.4 Neutrophils have to deform during passage through the pulmonary capillaries (Figure 36.1) because of their relatively large diameter (10– 15 µm).
In contrast, erythrocytes pass through those capillaries more readily because of their smaller diameters. Delay in the passage of neutrophils results in a relative increase in neutrophil concentration in the pulmonary capillaries.5 This may be an adaptive modi? cation for better control of any organisms breaching the extensive and exposed surfaces of the alveoli.
The slowing and momentary stopping of neutrophils in the pulmonary capillaries under certain stimuli may allow selectin- and integrin-independent migration of these cells from the capillaries.6,7 The bronchial circulation is also unique in that airway injury can stimulate a ? vefold increase in bronchial blood ? ow in sheep.
Although the increased blood ? ow during injury amounts to less than 3% of the cardiac output, neutrophils activated in the bronchial microcirculation may be directly delivered to the pulmonary capillaries to produce damage. In fact, bronchial artery ligation decreases lung edema in a sheep model of smoke and burn injury.9 The anatomy of the lung then potentially allows damage in the airway to produce in? ammatory changes in the lung that may enhance lung protection or lead to further damage under some circumstances."
