Molecular Pathology of Lung Diseases

Molecular Pathology of Lung Diseases (Molecular Pathology Library)......Page 1
Front-matter......Page 2
Title Page\r......Page 4
Copyright Page\r......Page 5
Series Preface......Page 6
Preface......Page 8
Table of Contents\r......Page 9
Contributors......Page 14
Section 1            Basic Concepts of Molecular Pathology......Page 21
Nucleic Acids, Genes, and Gene Products......Page 22
Transcription Factors......Page 24
References......Page 25
Signaling Pathways......Page 30
The Cell Cycle......Page 32
DNA Damage Repair......Page 33
References......Page 34
Integrins......Page 41
Cyclooxygenase-2......Page 42
Other Integrin-Related Research......Page 43
E-Cadherin......Page 44
Cadherins and Epidermal Growth Factor Receptor......Page 45
Other Cadherin-Related Research......Page 46
Selectins......Page 48
Immunoglobulin-Like Cell Adhesion Molecules......Page 49
CD44......Page 51
References......Page 52
Necrosis......Page 59
Autophagy......Page 60
Caspases......Page 61
Extrinsic Death Pathway......Page 62
Intrinsic Death Pathway......Page 63
Adapter Proteins......Page 64
Inhibitors of Apoptosis Proteins......Page 65
Acute Lung Injury/Acute Respiratory Distress Syndrome......Page 66
Conclusion......Page 67
References......Page 68
Genetic Alterations......Page 72
Chromosomal Alterations in Lung Cancer......Page 73
Complex Chromosomal Rearrangements in Lung Cancer......Page 74
Epimutations in Lung Cancer......Page 75
Gene Mutations in Cystic Fibrosis......Page 76
References......Page 77
Section 2        \rTechniques and Experimental Systems in\rMolecular Pathology......Page 81
Transcriptomics......Page 82
References......Page 83
Nucleic Acid Extraction......Page 87
Polymerase Chain Reaction......Page 88
Signal Amplification......Page 89
Sanger Sequencing......Page 91
Chromosomal Microarrays......Page 92
Systems Biology Approaches......Page 93
References......Page 94
Introduction......Page 95
Oncogenes......Page 96
Anatomic Pathology Testing forInfectious Agents......Page 97
References......Page 98
Principles......Page 100
Annealing Step Programming and Primer Design\r......Page 103
Deoxynucleotides......Page 104
Postprocedure Analysis......Page 105
Real-Time Polymerase Chain Reaction......Page 106
Reverse Transcription......Page 109
References......Page 111
Large-Insert Clone Arrays......Page 114
Repeat-Free and NonredundantSequence Arrays......Page 116
General Platform Considerations......Page 117
Microdissection and DNA Amplification......Page 118
Reference DNA......Page 119
Data Analysis......Page 120
Identifying an Aberration......Page 121
Conclusion......Page 122
References......Page 123
Detecting Loss of Heterozygosity......Page 125
Pathogens......Page 126
Patterns of Loss of Heterozygosity in Lung Cancer\r......Page 127
Loss of Heterozygosity at 8p......Page 128
Loss of Heterozygosity on the X Chromosome......Page 129
References......Page 130
Principles of Base Pairing......Page 134
Denaturation, Renaturation, and Influencing Factors......Page 135
Chromosome Enumeration Probes......Page 136
Procedure......Page 137
Removing  Nonspecifically Bound  Probe......Page 139
Chromogenic In Situ Hybridization......Page 140
Comparative Genomic Hybridization......Page 141
Multicolor Whole-Chromosome Painting......Page 142
Tumor Typing......Page 143
Conclusion......Page 144
References......Page 145
Proteomics......Page 147
Shotgun and Protein Profiling\r......Page 148
Methodologic Obstacles of PAGE......Page 149
Enzymatic and Nonenzymatic Digestion......Page 150
Imaging Mass Spectrometry......Page 151
A “Dream Team” Mass Spectrometry System......Page 152
Sequence-Based Identification......Page 153
Validation of Protein Match......Page 154
Detection of Posttranslational Modification......Page 155
Noninfectious Inflammatory Diseases of the Lung......Page 156
Neoplastic Diseases of the Lung......Page 157
References......Page 159
Chronic Bronchitis and Emphysema......Page 161
Interstitial Lung Diseases......Page 162
Knockout Mouse Models......Page 163
References......Page 164
History of Tissue Culture......Page 167
Types of Tissue Culture......Page 168
Culture Environment......Page 169
Functional Environment......Page 170
Pulmonary Endothelial Cells......Page 171
Lung Cancer Tissue and the Development of Novel Therapeutics......Page 172
Conventional Bioreactors and Three-Dimensionality: The Origins of Three-Dimensional Culture\r......Page 173
Lung Cancer......Page 175
Rotating-Wall Vessel Normal Human Tissue Models as Disease Targets......Page 177
References......Page 179
Section 3 \rMolecular Pathology of Pulmonary and\rPleural Neoplasms: General Principles......Page 183
Oncogene Activation......Page 184
Myc Activation......Page 185
The p53 Pathway......Page 186
Other Chromosomal Deletions......Page 187
References......Page 188
Familial Lung Cancer Risk......Page 191
Xenobiotic-Metabolizing Enzymes......Page 192
Polymorphisms and DNA Adduct Levels......Page 193
Cytochrome P450 Polymorphisms and Lung Cancer Susceptibility\r......Page 194
Multiple Xenobiotic-Metabolizing Enzymes......Page 195
Nucleotide Excision Repair Pathway Polymorphisms......Page 196
References......Page 197
c-erbB2......Page 208
p53......Page 209
Epidermal Growth Factor Receptor......Page 210
Neuroendocrine Lung Cancers......Page 211
References......Page 212
The CXC Chemokines......Page 215
CXCR2 Is the Receptor for Angiogenic ELR+ CXC Chemokine-Mediated Angiogenesis......Page 216
CXCR3 Is the Major Receptor for CXC Chemokines That Inhibit Angiogenesis......Page 217
Angiogenesis and Pulmonary Hypertension......Page 218
Angiogenesis and Fibroproliferation in the Lung\r......Page 219
Non-ELR+ CXC Chemokines Attenuate Angiogenesis Associated with Tumorigenesis\r......Page 220
Molecular Mechanisms of Angiogenesis......Page 221
Possible Nonreceptor-Mediated Inhibition of Angiogenesis\r......Page 223
References......Page 224
Cancer Stem Cells......Page 228
Cancer Stem Cell Regulation......Page 229
Lung Cancer Stem Cells......Page 230
References......Page 231
Mechanism of p53 Tumor Suppressionand Rationale for p53 Gene Therapy......Page 234
Clinical Trials of p53 Gene Replacement......Page 235
Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy\r......Page 236
Systemic Gene Therapy......Page 237
References......Page 238
Predictors of Response to Traditional Therapy......Page 241
Tyrosine Kinase Inhibitors......Page 242
Antiangiogenesis Therapy......Page 243
Small Cell Lung Carcinoma......Page 244
References......Page 245
Mechanisms of Action of Environmental Carcinogens......Page 248
Properties of Asbestos......Page 249
Mechanisms of Asbestos-Induced Cell Signaling In Mitogenesis, Tumor Promotion, and Progression\r......Page 250
Mitogen-Activated Protein Kinase Signaling, Fos/Jun Proteins, and Activator Protein-1 Activation......Page 251
Conclusion......Page 252
References......Page 253
Introduction......Page 255
Mechanisms of Tumorigenesis......Page 256
Viruses in Human Tumors......Page 257
References......Page 260
Section 4     Molecular Pathology of Pulmonary and Pleural Neoplasms: Specifi c Histologic Types......Page 263
Why Is Adenocarcinoma Now the Most Common Lung Carcinoma?......Page 264
Regeneration and Its Implications......Page 265
The Role of Cancer Stem Cells......Page 266
Genomic Aberrations in Adenocarcinoma......Page 267
Specifi c Gene Loci in Adenocarcinomas......Page 268
RNA Expression in Adenocarcinoma......Page 271
Proteomics of Adenocarcinoma......Page 273
The Epidermal Growth Factor Receptor System......Page 274
The Histone Deacetylase System......Page 275
Insulin-Like Growth Factor System......Page 276
The Nuclear Factor-κB Pathway......Page 277
The Hepatocyte Growth Factor Pathway......Page 278
References......Page 279
Introduction......Page 283
Chromosomal Abnormalities:Loss of Heterozygosity......Page 284
p53 Mutations......Page 285
Telomerase Dysregulation and Upregulation......Page 286
Epidermal Growth Factor Receptorand Tyrosine Kinase Inhibitors......Page 287
Conclusion......Page 288
References......Page 289
Introduction......Page 292
Basaloid Carcinoma......Page 294
Basaloid Carcinoma......Page 295
Large Cell Carcinoma......Page 299
Large Cell Neuroendocrine Carcinoma......Page 300
Gene Expression Profiling Studies......Page 301
Proteomics......Page 302
References......Page 303
Signature of Cell Differentiation......Page 306
p53 Pathway Alterations......Page 307
Alteration of Upstream Regulators of  p53:p14ARF and MDM2......Page 308
Telomerase Expression......Page 309
Tyrosine-Kinase Growth Factor and Receptors......Page 310
References......Page 311
Histopathologic Defi nitions......Page 314
The Retinoblastoma Pathway......Page 315
Somatic Genetics: Cytogenetics and Comparative Genomic Hybridization......Page 316
Adhesion Molecule of E-Cadherin–b-Catenin Complex......Page 317
References......Page 318
Mucosa-Associated Lymphoid Tissue Lymphoma......Page 320
Case 30.1......Page 321
Pulmonary Lymphoma in Acquired Immunodeficiency Syndrome......Page 323
Case 30.2......Page 324
Lymphomatoid Granulomatosis......Page 325
References......Page 326
Classification......Page 328
Lung Transplantation and Posttransplantation Lymphoproliferative Disorder......Page 329
Virology of Epstein-Barr Virus......Page 330
In Vitro Epstein-Barr Virus Infection......Page 332
Persistence of Infection......Page 333
Cellular Signaling Pathway......Page 335
Cytotoxic Activity......Page 336
Patterns of Epstein-Barr Virus Latency and Related Diseases......Page 337
Molecular Histogenesis......Page 338
Genetic Profi le......Page 340
Diagnosis and Evaluation......Page 341
Treatment and Management......Page 342
Epstein-Barr Virus–Negative Disease......Page 343
References......Page 344
Sclerosing Hemangioma......Page 347
Solitary Fibrous Tumor......Page 348
Lipomatous Neoplasms......Page 349
Chondroma and Chondrosarcoma......Page 350
Pulmonary Artery Sarcoma......Page 351
References......Page 352
Background: Value of Immunohistochemistry......Page 354
Molecular Markers in the Differential Diagnosis of Primary Versus Metastatic Tumor to the Lung: Are We There?......Page 355
References......Page 357
Asbestos-Induced Oncogenesis......Page 360
Comparative Genomic Hybridization Studies......Page 361
Gene Profi ling and Mesothelioma......Page 362
Polymorphisms in Genes as Risk Factors for Asbestos-Related Malignant Mesothelioma......Page 363
The p53 Gene......Page 364
Simian Virus 40 and Human Mesothelioma......Page 365
Wilms’ Tumor 1 Susceptibility Gene......Page 366
References......Page 367
Pleuropulmonary Blastoma......Page 371
Relationship of Pleuropulmonary Blastoma to Congenital Cystic Adenomatoid Malformation......Page 372
Cytogenetic and Molecular Studies......Page 374
Etiologic Role of Infectious Agents......Page 375
Cytogenetic and Molecular Studies in Ewing’s Family of Tumors......Page 376
References......Page 377
Section 5     \rMolecular Pathology of Pulmonary Infections......Page 380
Unique Aspects of the Lung Microcirculation......Page 381
Complement......Page 382
Lung Epithelial Cells......Page 383
Neutrophils......Page 384
Adaptive Immunity......Page 386
T Lymphocytes......Page 387
Humoral Immunity (B Lymphocytes and Antibodies)......Page 390
References......Page 391
Introduction......Page 394
Envelope......Page 395
Viral Pathogenesis......Page 396
Classification......Page 397
Paramyxoviridae......Page 399
Coronaviruses......Page 401
Picornaviruses......Page 402
References......Page 404
Rickettsial Infections That Impact Lung Structure and Function......Page 409
Cellular and Tissue Injury......Page 410
Host Innate and Adaptive Immune Responses to Infection......Page 412
Clinical Disease and Pathophysiology......Page 413
Host Innate and Adaptive Immune Responses to Infection......Page 415
References......Page 416
Pathology......Page 419
Diagnosis......Page 420
Diagnostic Testing......Page 421
Pathogenesis......Page 422
Clinical Features......Page 423
Diagnostic Testing......Page 424
Diagnostic Testing......Page 425
Staphylococcus aureus......Page 426
Clinical Features......Page 427
References......Page 428
Primary and Secondary Tuberculosis Pathology......Page 431
Immune Response to Tuberculosis......Page 434
References......Page 437
Cellular Component of Immunity......Page 441
Dendritic Cells......Page 442
Aspergillus......Page 443
Molecular Basis of Pathogenesis......Page 444
Pathology......Page 447
Diagnosis......Page 448
Polymerase Chain Reaction......Page 449
Conclusion......Page 450
References......Page 451
Principles of Parasitic Molecular Pathogenesis......Page 454
Adaptive Immune Response......Page 455
Parasitic Proteases and Their Role in Pathogenesis......Page 456
Toxoplasmosis......Page 458
Microsporidiosis......Page 459
Cryptosporidiosis......Page 460
Strongyloidiasis......Page 461
Paragonomiasis......Page 462
Schistosomiasis......Page 463
References......Page 464
Section 6     Molecular Pathology of Other Nonneoplastic Pulmonary Diseases: General Principles......Page 469
The Inflammatory Response......Page 470
Innate Immunity: Toll-Like Receptors......Page 471
Acquired Immunity: Macrophages, Dendritic Cells and Antigen Presentation......Page 472
Granulomatous Inflammation......Page 474
Interstitial Inflammation......Page 475
Human Leukocyte Antigen–Linked Lung Disease......Page 476
References......Page 478
Reactive Oxygen Species......Page 481
Enzymatic Antioxidants......Page 482
Redox-Sensitive Transcription Factors......Page 483
Oxidative Stress-Associated Lung Disease/Injury......Page 484
References......Page 485
Steps in Injury and Repair......Page 487
Epithelial Cell Dedifferentiation......Page 489
Reestablishment of the Normal Basement Membrane......Page 490
Lung Progenitor and Lung Epithelial Stem Cells Roles......Page 491
Developmental Signaling Pathways Mediating Differentiation......Page 492
Fibroblast Growth Factor......Page 493
Molecular Correlates of Morphologic Events......Page 494
Alveolar Epithelial Cell Repair Following Acute Respiratory Distress Syndrome......Page 495
References......Page 496
Fibroblastic Foci and the Fibroblast Phenotype......Page 501
Sources of Fibroblasts......Page 503
Apoptosis......Page 504
Transforming Growth Factor-β......Page 505
Angiogenesis......Page 506
Surfactant Protein C Mutations......Page 507
References......Page 508
Introduction......Page 511
Epithelial Cells......Page 512
Fibrocytes......Page 515
Small Airways......Page 516
Side Population Cells......Page 517
References......Page 518
Barriers to Gene Transfer......Page 521
Cell Entry and Nuclear Entry......Page 522
Gene Transfer Efficacy......Page 523
Cystic Fibrosis......Page 524
Vectors......Page 525
α1-Antitrypsin Deficiency......Page 527
References......Page 528
Section 7     \rMolecular Pathology of Other Nonneoplastic\rPulmonary Diseases: Specifi c Entities......Page 535
Effects of Toxins......Page 536
Temperature......Page 537
The Enzymes......Page 538
Anatomic Basis......Page 539
Epithelial Cells......Page 540
T Lymphocytes......Page 541
Oxidative Stress......Page 542
Pulmonary Histiocytosis X......Page 543
Respiratory Bronchiolitis–Combined Interstitial Lung Disease......Page 544
Conclusion......Page 545
References......Page 546
Associated Disorders......Page 550
Glycoprotein Biosynthetic Quality Control......Page 551
The Current Model......Page 552
Potential Therapeutic Approaches......Page 554
References......Page 556
Introduction......Page 558
Molecular Pathogenesis of Asthma......Page 559
Interleukin-4 and Interleukin-13......Page 560
Interleukin-5 and Interleukin-9......Page 561
Interleukin-1α and Interleukin-1β......Page 562
Vascular Endothelial Growth Factor......Page 563
Toll-Like Receptors......Page 564
Integrins......Page 565
Signal Transducer and Activator of Transcription 1......Page 566
CD28 and CD134......Page 567
Seven Transmembrane Spanning Receptors......Page 568
Prostaglandins......Page 569
The β2-Adrenergic Receptor......Page 570
Endogenous and Exogenous Proteinases......Page 571
Syndecan-1......Page 572
Chitinases and Related Molecules......Page 573
References......Page 574
Genetics......Page 586
Structure and Function of the Cystic Fibrosis Transmembrane Conductance Regulator......Page 587
Pathophysiologic Features of Lung Disease in Cystic Fibrosis......Page 588
Transepithelial Nasal Potential Difference......Page 589
Conclusion......Page 590
References......Page 591
Introduction......Page 593
Transforming Growth Factor-β/Bone Morphogenic Protein 4......Page 594
Mesenchyme......Page 595
Specific Genes and Developmental Abnormalities......Page 596
References......Page 597
Overview of Pulmonary Surfactant......Page 599
Surfactant Protein B......Page 600
Surfactant Protein C......Page 602
Lung Pathology Associatedwith Inborn Errors of Surfactant Metabolism......Page 604
Genetic Testing......Page 608
Conclusion......Page 609
References......Page 610
Pathogenesis......Page 616
Molecular Pathways Involved in Alveolar Damage and Reepithelialization......Page 617
Molecular Characterization of Fibroblast Foci......Page 619
Molecular Pathways Involved in Bronchiolar Reepithelialization......Page 620
Molecular Characterization of Epithelial Cells in Fibroblast Foci......Page 621
References......Page 622
Nodular Sarcoidosis......Page 625
What Is the Meaning of Indistinguishable Differentials?......Page 626
Epithelioid Cells......Page 627
Risk Factors......Page 628
Antigen Uptake and Processing......Page 629
Human Leukocyte Antigen Class II Genes......Page 630
Effector Mechanisms, the Lymphocyte–Macrophage Network, and Gene Expression in Sarcoidosis......Page 631
Disease Modifier Genes and Aspects of Organ Involvement in Sarcoidosis......Page 632
References......Page 633
Cellular and Molecular Biology......Page 636
Cellular and Molecular Biology......Page 637
Cellular and Molecular Disease......Page 638
Pathologic Disease......Page 639
References......Page 640
Pathology......Page 643
Bone Morphogenetic Protein Receptor Gene Mutations......Page 646
Role of Bone Morphogenic Protein and Its Receptor......Page 647
Role of the Endothelium......Page 649
Inflammatory Mechanisms......Page 650
References......Page 651
Introduction......Page 653
Pathologic Features......Page 654
Molecular Pathology......Page 656
T Cells in Antineutrophil Cytoplasmic Antibody–Mediated Vasculitis......Page 657
Cytokines in Vasculitides......Page 658
Interferon-α......Page 659
Apoptosis in Wegener’s Granulomatosis......Page 660
References......Page 661
Asbestosis......Page 667
References......Page 669
Index......Page 672