Chronic Obstructive Pulmonary Disease: Cellular and Molecular Mechanisms (Lung Biology in Health and Disease)

emphasizing The Urgent Need To Clearly Understand The Underlying Cellular And Molecular Mechanisms Involved In Copd, This Reference Provides An Up-to-date Perspective On The Inflammatory Cells, Mediators, And Molecular Pathology Of Copd. doody Review Services reviewer: joel C Seidman, Md(william Beaumont Hospitals) description: this Book Reiterates Traditional Knowledge Regarding Epidemiology, Perturbations Of Respiratory Structure And Function, And Natural History Of Chronic Obstructive Pulmonary Disease. The Most Significant Elements Offered By Contributors, However, Emphasize How More Recent Research Might Facilitate The Evolution Of Novel Therapeutic Interventions To Favorably Affect The Outcomes Presently Seen. This Book Was Originally Edited By Thomas L. Petty In 1978 And In 1985, And Most Recently By Peter J. Barnes. purpose: in Aggregate, A Comprehensive Attempt Is Made To Adopt Observations Made Since The Last Edition In The Molecular And Cellular Biology Of Respiratory Structure And Function, Especially As Regards Immunology, Inflammation, And Repair, To Forecast What Avenues Might Be Taken To Minimize, Block, Or Reverse The Events Seen In A Macrocosm Of This Disease. It Is The Editor's Intent To Combine Independent Observations Within Microcosmic Processes Seen In The Laboratory, And By Inference, Speculate About How, In Combination And Acting In The Intact Human Organism, They Might Potentially Underlie And Result In Clinical Observations Already So Familiar. Admittedly, Such An Endeavor Would Not Permit "connection Of All The Dots," Not Just Because The Number And Origin Of Contributors Is So Eclectic, But Simply Because, By Its Nature, The More Elements In Human Molecular And Cellular Biology Become Characterized, The More Deficiencies In Knowledge Become Apparent. Nonetheless, The Science Is Far More Elaborately Explored Than Two Decades Ago. Most Significantly, The Monograph Attempts To Yoke Basic Science And Clinical Pulmonology In A Manner Uncommonly Observed Before. audience: pulmonologists And Researchers In This Field As Well As Trainees In Pulmonary Medicine Allergy And Immunology And Critical Care Are The Intended Audience. The Detailed Handling Of Basic Molecular And Cellular Respiratory Biology Makes This Text Unsuited For The Casual Reader. features: the Monograph Focuses Primarily On The Molecular And Cellular Biology Believed To Underlie The Evolution Of Chronic Obstructive Pulmonary Disease, Most Notably What Has Been Learned During The Last Two Decades About Immunology, Inflammation, And Repair -- About Cells, Their Differentiation, And Their Products, About Immunoglobulins, Mediators Of Various Types, Especially Those That Facilitate "inter-cellular" Communication, And About What "fibrosis" Means. Finally, Attention Is Paid To Historically Appreciated Comorbidities Associated With, Or Complications Of, Chronic Obstructive Pulmonary Disease (e.g., Weight Loss, "exacerbations," And Pulmonary Vaso-destructive Events), Attempting To Provide Biologic Bases For Such Observations Not Hitherto Well Explained. assessment: Front cover......Page 1 Introduction......Page 14 Preface......Page 16 Contributors......Page 18 Contents......Page 22 I. INTRODUCTION......Page 30 II. THE NATURE OF AIRWAY OBSTRUCTION IN COPD......Page 31 A. Differences from Asthma......Page 32 B. Small Airways......Page 33 C. Alveolar Destruction......Page 34 D. Mucus Hypersecretion......Page 35 C. Components of Inflammation......Page 36 IV. WHAT ARE THE AMPLIFYING MECHANISMS?......Page 38 REFERENCES......Page 40 I. INTRODUCTION......Page 46 II. PARENCHYMAL INFLAMMATION......Page 48 III. PARENCHYMAL DESTRUCTION......Page 53 REFERENCES......Page 56 I. INTRODUCTION......Page 62 II. CHRONIC BRONCHITIS AND SMALL AIRWAY OBSTRUCTION......Page 66 III. THE PATHOLOGIC FEATURES OF THE SMALL AIRWAYS IN COPD......Page 68 IV. THE INNATE AND ADAPTIVE HOST DEFENSE SYSTEM A. Innate Immunity......Page 70 B. Toll-Like Receptors......Page 71 C. Adaptive Immunity......Page 72 D. Remodeling......Page 75 REFERENCES......Page 77 I. INTRODUCTION......Page 84 II. ASTHMA WITH FIXED AIRFLOW LIMITATION......Page 85 A. COPD......Page 87 B. Asthma......Page 90 C. Asthma with Fixed Airflow Limitation......Page 91 A. COPD......Page 92 B. Asthma......Page 93 C. Smoking Asthmatics......Page 94 D. Asthmatics with Developed Fixed Airflow Limitation......Page 95 V. INFLAMMATORY MEDIATORS IN COPD AND ASTHMA A. COPD......Page 96 B. Asthma......Page 101 VI. CONCLUSIONS......Page 103 REFERENCES......Page 104 I. INTRODUCTION......Page 112 II. AIRWAY MUCUS, MUCINS, AND MUC GENES......Page 114 III. MUCUS HYPERSECRETORY PHENOTYPE IN COPD......Page 115 IV. ABNORMALITIES IN MUCOCILIARY CLEARANCE IN COPD......Page 118 V. EPIDEMIOLOGY OF MUCUS HYPERSECRETION IN COPD......Page 119 A. Conventional Pharmacotherapy......Page 120 B. Novel Pharmacotherapy......Page 126 VII. CHEST PHYSIOTHERAPY......Page 129 VIII. SUMMARY AND CONCLUSIONS......Page 130 REFERENCES......Page 131 II. INCREASED MACROPHAGE NUMBERS IN COPD......Page 142 A. Increased Recruitment......Page 143 C. Macrophage Survival......Page 144 A. Alveolar and Interstitial Macrophages......Page 145 IV. SECRETORY ROLE......Page 146 B. Chemokines......Page 147 F. Reactive Oxygen and Nitrogen Species......Page 148 B. Signal Transduction Pathways......Page 149 C. Histone Acetylation......Page 150 A. Corticosteroids......Page 151 VIII. PHAGOCYTIC FUNCTION......Page 153 REFERENCES......Page 154 I. INTRODUCTION......Page 162 III. PROMIGRATORY STIMULI......Page 164 A. Cytokines......Page 165 B. Chemoattractants......Page 166 IV. EPITHELIAL=ENDOTHELIAL CELLS AND NEUTROPHIL CHEMOTAXIS A. Neutrophil Migration into the Lung......Page 170 B. Neutrophil Capture in Inflammation......Page 171 V. MIGRATION......Page 173 A. Direction of Migration......Page 174 C. Transmigration......Page 175 D. Migration from the Pulmonary Capillary Network......Page 177 E. Migration in COPD......Page 178 VI. ACTIONS OF NEUTROPHIL PROTEASES IN VITRO AND IN VIVO A. The Actions of NE......Page 179 B. Matrix Metalloproteinases......Page 182 VII. CONCLUSIONS......Page 185 REFERENCES......Page 186 I. INTRODUCTION......Page 200 II. STRUCTURE OF THE AIRWAY EPITHELIUM A. Cell Types......Page 201 B. Epithelial Cell Junctions......Page 203 C. Basement Membrane......Page 206 III. NORMAL ACTIVITIES OF AIRWAY EPITHELIAL CELLS......Page 207 B. Metabolic Functions......Page 208 IV. INFLAMMATION AND INJURY......Page 209 A. Inflammatory Mediators......Page 210 V. WOUND REPAIR AND REMODELING A. Epithelial Repair......Page 212 B. Airway Remodeling......Page 215 REFERENCES......Page 217 I. INTRODUCTION......Page 234 II. INNATE IMMUNITY A. Innate and Adaptive Immunity......Page 235 B. Innate Immune Reaction in COPD......Page 236 C. Consequences of the Innate Immune Reaction in the Lungs—Peptides, Apoptosis, and Necrosis......Page 239 III. ADAPTIVE IMMUNITY A. Dendritic Cells......Page 241 B. Heat Shock Proteins......Page 243 C. The Adaptive Immune Reaction in COPD......Page 245 IV. SYSTEMIC T-CELLS IN COPD......Page 250 V. T-CELLS AS EFFECTOR CELLS A. T-Cell Traffic......Page 252 B. Activation of CD8þ T-Cells......Page 254 C. Effector Functions of CD8þ and CD4þ T-Cells......Page 260 VI. WHY ONLY SOME SMOKERS DEVELOP COPD: THE IMMUNOLOGICAL PARADIGM......Page 262 VII. SUMMARY AND CONCLUSIONS......Page 266 REFERENCES......Page 268 A. Prostaglandins......Page 282 B. Leukotrienes......Page 284 C. Peroxynitrite......Page 285 C. Tachykinins......Page 286 A. Interleukin-8......Page 287 B. Other CXC Chemokines......Page 288 C. CC Chemokines......Page 291 A. Tumor Necrosis Factor-a......Page 292 C. Interleukin-6......Page 293 A. Transforming Growth Factors......Page 294 D. Fibroblast Growth Factors......Page 295 REFERENCES......Page 296 I. INTRODUCTION......Page 308 II. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)......Page 309 III. CELL-DERIVED ROS......Page 310 IV. INHALED OXIDANTS AND CIGARETTE SMOKE......Page 312 V. OXIDATIVE STRESS IN THE ALVEOLAR SPACE......Page 314 VI. ALTERATIONS IN LUNG TISSUE......Page 316 VII. SYSTEMIC OXIDATIVE STRESS......Page 317 A. ROS......Page 319 B. Reactive Nitrogen Species and Carbon Monoxide......Page 321 C. Lipid Peroxidation Products......Page 322 IX. SYSTEMIC AND LOCAL DEPLETION OF ANTIOXIDANTS......Page 323 X. DEPLETION OF LUNG GLUTATHIONE......Page 325 XI. AIRSPACE EPITHELIAL INJURY=PERMEABILITY......Page 326 XII. NEUTROPHIL SEQUESTRATION AND MIGRATION IN THE LUNGS......Page 327 XIII. CONSEQUENCES OF OXIDANT=ANTIOXIDANT IMBALANCE A. Protease=Antiprotease Imbalance......Page 328 C. Remodeling of Extracellular Matrix......Page 329 D. Apoptosis......Page 330 E. Muscle Dysfunction......Page 331 XV. OXIDATIVE STRESS AND SUSCEPTIBILITY TO COPD......Page 332 XVI. OXIDATIVE STRESS, NF-kB ACTIVATION, AND GENE EXPRESSION A. NF-kB Activation......Page 333 B. Pro-Inflammatory Genes......Page 335 C. Antioxidant and Stress Response Genes......Page 336 XVII. CHROMATIN REMODELING (HISTONE ACETYLATION AND DEACETYLATION) AND GLUCOCORTICOID INEFFICACY IN RESPONSE TO SMOKING......Page 338 A. Phosphodiesterase 4 Inhibitor......Page 339 B. Spin Traps and Antioxidant Enzyme Mimetics......Page 340 D. Thiol Compounds......Page 341 E. Glutathione Peroxidase Mimic......Page 343 IX. CONCLUSIONS......Page 344 REFERENCES......Page 345 I. INTRODUCTION......Page 356 A. Serine Proteinases......Page 357 B. Matrix Metalloproteinases......Page 360 III. EVIDENCE FOR ROLE OF PROTEINASES IN EMPHYSEMA A. Human Data......Page 363 B. Animal Models......Page 364 REFERENCES......Page 368 I. INTRODUCTION......Page 372 B. Activity......Page 373 d. Non-AAT Deficient Emphysema......Page 374 e. Other Functions......Page 375 III. SECRETORY LEUKOPROTEASE INHIBITOR......Page 376 B. Antibacterial Activity......Page 378 C. Anti-inflammatory/Immunomodulatory Activities......Page 379 V. TISSUE INHIBITORS OF METALLOPROTEASES......Page 380 A. MMP Inhibition......Page 381 C. Other Functions of TIMPs......Page 382 A. Cathepsin Inhibition......Page 383 C. Other Functions of Cystatins......Page 384 VII. THERAPEUTIC APPLICATIONS OF ANTIPROTEASES IN LUNG DISEASE......Page 385 REFERENCES......Page 386 II. THE MOLECULAR BASIS OF INFLAMMATION IN CHRONIC LUNG DISEASES INCLUDING COPD......Page 396 A. Transcription Factors......Page 397 III. HOW CORTICOSTEROIDS SWITCH OFF INFLAMMATION......Page 398 V. MOLECULAR MECHANISMS UNDERLYING CORTICOSTEROID INSENSITIVITY......Page 401 A. Defects in GR Sequence and Pharmacokinetics......Page 402 B. Defects in Ligand Binding......Page 403 C. Cross-Talk with Transcription Factors......Page 404 D. Neutrophilic Inflammation......Page 405 E. Latent Viral Infection......Page 406 F. Reduced Histone Deacetylase Activity in COPD......Page 407 VI. THERAPEUTIC IMPLICATIONS......Page 409 REFERENCES......Page 411 II. GENETIC EPIDEMIOLOGY A. Family Studies......Page 420 C. Segregation Analyses......Page 421 A. Genome Screens for COPD......Page 422 B. Candidate genes for COPD......Page 425 REFERENCES......Page 440 I. INTRODUCTION......Page 454 A. Systemic Oxidative Stress......Page 455 D. Mechanisms of Systemic Inflammation in COPD......Page 456 IV. SKELETAL MUSCLE DYSFUNCTION (SMD)......Page 457 A. Sedentary Lifestyle......Page 459 D. Systemic Inflammation......Page 460 E. Oxidative Stress......Page 461 H. Genetic Susceptibility......Page 462 A. Cardiovascular Effects......Page 463 B. Nervous System Effects......Page 464 ACKNOWLEDGMENTS......Page 465 REFERENCES......Page 466 I. INTRODUCTION......Page 476 II. AIRWAY INFLAMMATION AT EXACERBATION......Page 477 III. VIRAL INFECTIONS......Page 481 IV. ROLE OF BACTERIAL INFECTIONS......Page 485 V. OTHER INFECTIVE AGENTS—CHLAMYDIA PNEUMONIAE......Page 486 VI. CONCLUSIONS......Page 487 REFERENCES......Page 488 I. INTRODUCTION......Page 492 A. Mild-to-Moderate COPD......Page 493 B. Severe COPD......Page 494 III. CHANGES IN VASCULAR CELLS A. Endothelial Cells......Page 495 B. Endothelial Dysfunction......Page 496 C. Smooth Muscle Cells......Page 498 D. Potassium Channels and Smooth Muscle Cell Function......Page 499 E. Serotonin Transporter......Page 500 IV. INFLAMMATORY CELLS......Page 501 V. GROWTH FACTORS......Page 502 A. Vascular Endothelial Growth Factor......Page 503 B. Transforming Growth Factor......Page 504 VI. PATHOGENETIC MECHANISMS A. Genetic Factors......Page 505 B. Hypoxia......Page 506 C. Inflammation......Page 508 D. Cigarette Smoking......Page 509 VII. PATHOBIOLOGY OF PULMONARY VASCULAR CHANGES IN COPD......Page 510 ACKNOWLEDGMENTS......Page 511 REFERENCES......Page 512 A. The Need for Novel Therapies......Page 522 B. The Challenge of Drug Development......Page 523 III. NEW BRONCHODILATORS......Page 525 B. Combination Inhalers......Page 526 A. Leukotriene Inhibitors......Page 527 D. Chemokine Inhibitors......Page 528 E. Tumor Necrosis Factor-a Inhibitors......Page 529 B. Nuclear Factor-kB Inhibitors......Page 530 D. Phosphoinositide 3-Kinase Inhibitors......Page 531 H. Resveratrol......Page 532 B. Fibrosis Inhibition......Page 533 C. Antiproteases......Page 534 E. Pulmonary Vascular Drugs......Page 535 IX. FUTURE DIRECTIONS......Page 536 REFERENCES......Page 537 Index......Page 546 Back cover......Page 552 Why more research into molecular and cellular mechanisms of COPD is needed Inflammation in lung parenchyma Small airways disease in COPD Asthma vs. COPD: cellular and molecular differences Airway mucus secretion Macrophages Neutrophils Epithelial cells T-Lymphocytes Inflammatory mediators Oxidative stress Proteinases in COPD Antiproteases Corticosteroid resistance in COPD Molecular genetics Mechanisms of systemic effects Mechanisms of exacerbations of chronic obstructive pulmonary disease Mechanisms of pulmonary vascular changes Therapeutic implications and future developments. COPD is a major and increasing global health problem, which is predicted to become the third commonest cause of death and the fifth commonest cause of disability in the world by 2020 (1).