Main description:

Throughout the centuries, inflammation has been considered as a disease in itself. This misconception arose from the inability to distinguish between inflammatory changes and the insults which induce them. The understanding of the distinction between the genesis of inflammation and the tissue reactions that follow is attributed to JOHN HUNTER, who, at the end of the 18th century, substantially contributed to the analysis of inflammation in objective terms. Today, however, we are still trying to find explanations for Celsus' Signs in terms of structural and functional changes occurring in the inflamed tissue. There are drugs which modulate these signs but, without a detailed knowledge of the basic physiopathological events, it is impossible to understand their mechanism of action. Notwithstanding, the effects of anti inflammatory drugs provided new knowledge of the relevance of the signs and symptoms to the sequence of biochemical and morphological changes occurring in inflammation. When we accepted the invitation to edit a Handbook on Inflammation and Anti Inflammatory Drugs, we were aware of the magnitude of the task. We knew the impossibility of covering the whole field in detail, especially taking into account the rapid accumulation of experimental knowledge which would, in all likelihood, overtake the process of publication.

Contents:

Historical Survey of Definitions and Concepts of Inflammation.- References.- The Inflammatory Reaction.- 1 A Brief History of Inflammation.- A. From the Origins to the 19th Century.- B. Earlier 20th Century.- C. Chemical Mediators: Further Development.- References.- 2 The Sequence of Early Events.- A. Introduction.- B. The Phenomena of the Initial Response to Injury.- I. Changes in Vascular Calibre and Flow.- 1. The Normal Microcirculation.- 2. The Changes Seen After Injury.- II. Increased Vascular Permeability.- 1. Normal Structure of Small Blood Vessels.- 2. Exchanges Across the Wall of Normal Small Vessels.- 3. The Effects of Histamine-Type Permeability Factors-Vascular Labelling.- 4. Increased Permeability in Other Types of Inflammation.- III. Leucocytic Emigration.- 1. Pavementing of Leucocytes.- 2. Leucocytic Emigration.- 3. Chemotaxis.- 4. Mediators of Leucocytic Emigration.- C. Subsequent Course of the Inflammatory Reaction.- I. Resolution.- 1. Inflammatory Exudate.- 2. Polymorphs.- 3. Fibrin.- 4. Dead Tissue Cells.- II. Suppuration.- References.- 3 Mononuclear Phagocytes in Inflammation.- A. Nomenclature of Mononuclear Phagocytes.- B. Approaches to the Characterisation of Mononuclear Phagocytes.- I. Morphology.- II. Cytochemical Characterisation.- III. Functional Characterisation.- IV. Culture Characteristics.- C. The Characteristics of Mononuclear Phagocytes in Relation to Those of Other Cells.- D. Functions of Mononuclear Phagocytes.- E. Origin and Kinetics of Mononuclear Phagocytes During the Normal Steady State.- F. Origin and Kinetics of Mononuclear Phagocytes During an Inflammatory Response.- I. Acute Inflammation.- II. Chronic Inflammation.- G. The Effects of Anti-Inflammatory Drugs.- I. Glucocorticosteroids.- II. Azathioprine.- H. Humoral Control of Monocytopoiesis During Inflammation.- I. The Mononuclear Phagocyte System and Disease.- References.- 4 The Adhesion, Locomotion, and Chemotaxis of Leucocytes.- A. Introduction.- B. Leucocyte Adhesion.- I. General Considerations.- II. Studies of the Adhesion of Leucocytes.- C. Leucocyte Locomotion.- I. Morphological Observations.- II. Contact Inhibition of Movement.- III. Redistribution of Membrane in Moving Cells.- D. Chemotaxis.- I. Chemotaxis and Chemokinesis.- II. Methods for Measuring Leucocyte Chemotaxis.- III. Methods by Which Cells Detect Gradients.- IV. Chemoattractants.- 1. Products of Specific Immune Reactions.- 2. Non-Specific Endogenous Factors.- 3. Exogenous Chemoattractants.- V. Possible Models of Action of Chemoattractants at the Cell Membrane.- VI. Motor Mechanisms in Leucocyte Locomotion and Chemotaxis.- VII. Other Biochemical Mechanisms.- 1. Energy Sources for Locomotion.- 2. Cyclic Nucleotides.- 3. Protein and Nucleic Acid Synthesis.- 4. Effects of Other Agents.- VIII. Migration of Individual Leucocyte Types.- 1. Neutrophils and Mononuclear Phagocytes.- 2. Eosinophils.- 3. Lymphocytes.- IX. Does Chemotaxis Occur in vivo?.- References.- Addendum.- 5 Platelet Aggregation Mechanisms and Their Implications in Haemostasis and Inflammatory Disease.- A. Introduction.- B. Relationship of Morphology to Physiological Function in the Blood Platelet.- I. The Amorphous Coat.- II. The Trilaminar Plasma Membrane.- III. The Surface-Connecting ("Open Channel" or "Cannicular") System.- IV. The Dense-Tubular System.- V. Microtubules.- VI. Microfilaments.- VII. Granules.- VIII. Organelles Concerned With Carbohydrate, Protein and Lipid Metabolism.- C. Mechanisms of Platelet Aggregation.- I. Adhesion and Spreading.- II. The Shape Change.- III. Aggregation.- IV. The Platelet Release Reaction.- V. An Outline of Methods for Studying Platelet Aggregation and Related Processes.- VI. Mechanisms of Platelet Aggregation.- 1. Semantics-First and Second Phase Aggregation.- 2. Mechanisms of Directly Induced Platelet Aggregation.- 3. The Labile Aggregation-Stimulating Substances (LASS) Derived From Arachidonic Aci.- 4. Mechanisms of Aggregation Induced Indirectly (i.e. Mediated Through Pro-Aggregatory Platelet Substances).- 5. "Special Cases" (e.g. Zymosan and Ristocetin.- D. The Role of Platelets in Haemostasis and Haemostatic Defects.- I. Events Occurring in Haemostasis.- II. Haemostatic Defects.- 1. Thrombocytopenia (Decreased Level of Circulating Platelets).- 2. Afibrinogenemia.- 3. Von Willebrand's Disease.- 4. Bernard Soulier (Giant Platelet) Syndrome.- 5. Thrombasthenia.- 6. Storage Pool Disease.- 7. Congenital Aspirin-Like Defects in Aggregation.- 8. Other Platelet Abnormalities.- E. The Role of Platelets in Inflammatory Processes.- I. The Platelet as a Source of Pro-Inflammatory Material.- 1. Mediators of Acute Inflammation Released From Platelets.- 2. Chemotactic Factors From Platelets.- 3. Cationic Proteins and Peptides Which Induce Increased Vascular Permeability.- 4. Pro-Inflammatory and Autolytic Enzymes From Platelets.- II. Evidence for Participation of Platelets in Various Inflammatory Diseases.- 1. Acute Inflammatory Responses Induced in the Rat by Non-Immunological Mechanisms.- 2. Inflammation Produced by Immunological Mechanisms.- F. Concluding Remarks.- I. Haemostasis.- II. Platelet Aggregation Mechanisms.- III. Inflammation.- References.- 6 Regeneration and Repair.- A. The Replacement of Lost Tissue.- I. Tissues Capable of Regeneration.- II. Tissues Incapable of Adequate Regeneration.- B. The Nature of the Stimulus Leading to Formation of Scar Tissue.- C. The Generation of Scar Tissue.- I. Generation of Scar Tissue in the Presence of Fibrin.- II. Generation of Scar Tissue in the Absence of Fibrin.- D. Stages in Scar Tissue Formation.- I. Formation of Capillaries.- II. The Formation of Connective Tissue.- 1. The Cells Involved.- 2. The Non-Fibrous Components of Connective Tissue.- 3. The Fibrous Components of Connective Tissue.- E. The Maturation of Scar Tissue: Contraction.- F. Abnormalities of Scar Tissue.- I. Keloids and Hypertrophic Scars.- II. Dupuytren's Contracture.- III. Scleroderma: Systemic Sclerosis.- IV. Drug-Induced Fibrosis.- G. Healing of Specialised Tissues.- Summary.- References.- 7 Immunological and Para-Immunological Aspects of Inflammation.- A. Introduction.- B. Mechanisms of Reactions in the Skin, Joints, and Body Cavities.- I. Complement-Dependent.- 1. Classical Pathway of Complement Activation.- 2. The Arthus Reaction.- 3. The Alternative Pathway of Complement Activation.- 4. Non-Specific Reactions to Endotoxin and the Local Shwartzman Phenomenon.- II. Cell-Mediated Immunity.- C. Complement-Dependent Inflammation-Classical Pathway.- I. Arthus Reaction.- 1. Experimental.- 2. Clinical.- II. Circulating Immune Complexes.- 1. Experimental.- 2. Clinical.- D. Complement-Dependent Inflammation-Alternative Pathway.- 1. Local Skin Inflammation-Local Shwartzman Reaction.- 2. The Effect of Intravenous Injection of Endotoxin-The Generalised Shwartzman Reaction.- E. Delayed Hypersensitivity.- 1. "Jones-Mote" vs. "Tuberculin-Type" Reactivity-Normal Homeostasis by Suppressor Cells.- 2. Humoral Antibody Reactions Resembling Delayed Hypersensitivity.- 3. Granuloma Formation.- F. Endogenous Antigen and Autoimmune Phenomena in Acute and Chronic Inflammation.- G. Allergic Arthritis.- 1. Experimental Models.- 2. Arthritis in Swine.- H. The Inflammatory Response in the Pleural Cavity.- 1. As an Experimental Model for Inflammation of Serosal Surface Including the Synovia.- 2. The Arthus Reaction.- 3. Cell-Mediated Immunity.- I. New Experimental Models for the Assay of Anti-Inflammatory Drugs.- References.- 8 The Release of Hydrolytic Enzymes From Phagocytic and Other Cells Participating in Acute and Chronic Inflammation.- A. Mechanism of Release of Hydrolytic Enzymes From Cells.- I. Lysis of Membranes.- II. Selective Release of Hydrolytic Enzymes Following Membrane Fusion.- B. The Selective Release of Acid Hydrolases by Polymorphonuclear Leucocytes.- I. Factors Influencing Enzyme Release.- II. Mechanism of Selective Release of Acid Hydrolases From Polymorphonuclear Leucocytes.- III. Selective Release of Lysosomal Enzymes From Polymorphonuclear Leucocytes by Factors Generated During Inflammatory Responses.- 1. Immune Complexes.- 2. Components of the Complement System.- IV. Lysis of Polymorphonuclear Leucocytes by Toxic Particles.- C. Blood Platelets.- D. Macrophages.- I. Selective Release of Acid Hydrolases by Macrophages.- 1. The Direct Interaction With Macrophages of Substances Which Cause Chronic Inflammation of a Non-Immunological Nature.- 2. The Release of Macrophage Lysosomal Enzymes by Products of Immune Reactions.- II. Secretion of Neutral Proteinases by Macrophages.- 1. Collagenase.- 2. Ekstase.- 3. Plasminogen Activator.- III. Secretion of Lysozyme by Macrophages.- E. Secretion of Lysosomal Enzymes by Cells of Soft Connective Tissue.- F. Effect of Released Enzymes on Macromolecular Natural Substrates.- I. Degradation of Connective Tissue Components.- II. Generation of Inflammatory Mediators by Hydrolytic Enzymes.- G. The Effects of Drugs on the Release of Hydrolytic Enzymes at Sites of Inflammation.- I. Steroid Anti-Inflammatory Drugs.- II. Nonsteroid Anti-Inflammatory Drugs.- References.- 9 Lysosomal Enzymes.- A. Lysosomes as Organelles.- B. Polymorphonuclear Leucocyte Lysosomes.- I. Granule Type.- II. Vacuolar Apparatus and Types of Lysosomes.- C. Lysosomes, Polymorphonuclear Leucocytes, and Inflammation.- D. Lysosomal Enzymes as Mediators of Inflammation and Tissue Injury.- I. Acid Proteinases.- II. Neutral Proteinases.- III. Other Lysosomal Enzymes.- IV. Collagenase.- E. Non-Enzymatic Mediators of Inflammation.- F. Regulation of Lysosomal Enzyme Release From Phagocytic Cells.- G. Summary.- References.- 10 Lymphokines.- A. Discovery and Definition.- B. Method of Production.- C. Biological Actions and Bioassay.- I. Lymphocyte Transformation.- II. Macrophage Activation.- III. Skin Response.- IV. Chemotaxis.- V. Other Lymphokine Actions.- D. Lymphokine Heterogeneity.- E. Modification of Lymphokine Production and Action by Drugs.- F. Relevance of Lymphokines to Inflammation.- Conclusion.- References.- Inflammatory Mediators Released From Cells.- 11 Histamine, 5-Hydroxytryptamine, SRS-A: Discussion of Type I Hypersensitivity (Anaphylaxis).- A. Immediate Hypersensitivity: General Considerations.- B. IgE and Other Antibodies Capable of Triggering Mast Cells and Basophils.- C. Mast Cells, Basophils, and Platelets.- D. Biochemistry of Release.- E. Assay of Mediators.- F. Histamine.- G. 5-Hydroxytryptamine.- H. SRS-A.- I. Summary: In vivo Significance of Mediators.- References.- 12 Prostaglandins and Related Compounds.- A. Introduction.- B. Reasons for Studying the Metabolism of Polyoxygenated Fatty Acid Derivatives.- C. A Note on Nomenclature.- I. Enzyme Nomenclature.- II. Fatty Acid Nomenclature.- III. Prostaglandin Nomenclature.- D. Nature and Origin of Fatty Acid Substrates for the Cyclo-Oxygenase.- E. Nature and Location of the Cyclo-Oxygenase.- F. Distribution of the Cyclo-Oxygenase.- G. Chemical Transformations Catalysed by the Cyclo-Oxygenase.- I. Generation of the Cyclic Endoperoxides.- II. Transformation of the Endoperoxide to HHT.- III. Transformation of the Endoperoxide to PGs.- IV. Transformation of the Endoperoxide to Thromboxane 'A' and 'B' (PHD).- V. Other Products Formed by the Cyclo-Oxygenase.- H. Enzymology of the Cyclo-Oxygenase.- I. Purification of the Enzyme.- II. Co-Factor Requirements.- III. Conditions for Optimal Activity.- IV. Turnover and Replacement of the Cyclo-Oxygenase.- V. Miscellaneous Remarks.- VI. Summary.- I. Turnover of Prostaglandins.- J. Lipoxygenase.- I. Distribution of the Enzyme.- II. Nature and Location of the Enzyme.- III. Chemical Transformations Catalysed.- IV. Formation of HPETE (Hydroperoxy Acid).- V. Formation of HETE (Hydroxy Acid).- VI. Enzymology of the Lipoxygenase.- K. Prostaglandin Inactivation.- I. Chemistry of Prostaglandin Catabolism.- II. Tissue Distribution of Catabolising Enzymes.- III. Other Metabolic Transformations.- L. Metabolism of Other Compounds.- M. Inhibition of Substrate Release From Phospholipids.- N. Inhibition of the Cyclo-Oxygenase.- O. Inhibition of Prostaglandin Inactivation.- P. Inhibition of Lipoxygenase.- Q. Summary.- References.- Inflammatory Mediators Generated by Activation of Plasma Systems.- 13 Complement.- A. Introduction.- B. Classical Activating Pathway.- C. Alternative Pathway.- I. Amplification Convertase.- II. Activation.- D. Effector Sequence.- E. Control of the Complement Reaction.- I. Cl?INH.- II. Anaphylatoxin Inactivator (AI).- F. Phylogeny.- G. Biological Activity of Complement.- I. Permeability Factors.- II. Chemotactic Factors.- III. Leucocyte Mobilizing Factor.- IV. Adherence Reactions.- H. Complement in Experimental Tissue Injury.- I. Complement in Human Disease.- I. Genetic Abnormalities.- II. Acquired Abnormalities.- K. Pharmacological Agents.- I. Activators.- II. Inhibitors.- References.- 14 Bradykinin-System.- A. Introduction.- B. Bradykinin System.- I. Kininogens.- 1. Kininogen Levels and Kininogen Depletion.- 2. Effect of Catecholamines on Kininogen Levels.- II. Kininogenases and the Release of Kinins.- 1. Plasma and Glandular Kallikreins.- 2. Plasmin.- 3. Other Proteolytic Enzymes.- 4. Generation of Kinins.- III. Kininases.- 1. Kininases in Biological Materials.- 2. Carboxypeptidase B and Chymotrypsin.- IV. Summary.- C. Involvement of Kinins in Inflammatory Reactions.- I. Effects of Kinins Related to the Signs and Symptoms of Inflammation.- 1. Vasodilation.- 2. Permeability-Increasing Action.- 3. Oedema.- 4. Production of Pain.- 5. Leucocyte Accumulation.- II. Release of Kinins by Trauma.- 1. Thermal Injury.- 2. Changes in Lymph Resulting From Burns.- 3. Chemical Injury.- 4. Electrical Stimulation and Interference of Nervous Structures.- 5. Micro-Organisms.- 6. Anaphylaxis.- D. Intervention of Cells in the Release and Destruction of Kinins.- E. Cell Proliferation and Tissue Repair.- F. Kinins and Disease.- I. Rheumatoid Arthritis.- II. Acute Gouty Arthritis.- III. Bronchial Asthma.- IV. Pancreatitis.- V. Miscellaneous.- G. Effect of Drugs on Kinin System and Consequences in Inflammatory Reactions.- I. Interference With the Actions of Kinins.- II. Interference With the Generation of Kinins.- III. Potentiating and Destroying Agents.- IV. Anti-Inflammatory Drugs and Experimental Inflammation.- H. Conclusions.- References.- 15 Endogenous Modulators of the Inflammatory Response.- A. New Look at an Old Phenomenon.- I. Terminology: By Way of Questioning What is a Modulator?.- II. Homeostatic Function and Self-Limiting Nature of Inflammation.- B. Counter-Irritation.- I. Inflammations Responsive and Non-Responsive to Counter-Irritation.- II. Components of Inflammation Susceptible and Non-Susceptible to Counter-Irritation.- III. Stimulants and Tissue Sites to Trigger Counter-Irritation.- IV. Modulating Mechanisms Triggered by Counter-Irritation.- C. Humoral Factors as Modulators.- I. Local Tissue Factors.- II. Plasma Factors.- III. Hepatic Factors.- IV. Endocrine Factors (Adrenal Steroids, Oestrogens, Insulin).- V. Mediators as Modulators: Role of the Cyclic Nucleotides.- D. Neurogenic Factors as Modulators.- I. Peripheral Nervous System: Neurotransmitters and Other Factors.- II. Central Nervous Influences.- E. Automodulation and Therapy.- I. Automodulation and Present Drugs.- II. Automodulation: A Possible Guide to New Drugs?.- References.- Contribution of the Inflammatory Mediators to the Signs and Symptoms of Inflammation.- 16 Inflammatory Mediators and Vascular Events.- A. Introduction.- B. Criteria for Implicating a Particular Mediator in the Production of Specific Effects.- I. Mediator Released in Adequate Amounts at Right Time.- II. Mediator Produces Effect When Administered in Reasonable Concentration.- III. Effect Blocked by Specific Blocking Agents.- IV. Prevention of Release Prevents Effects.- V. Prevention of Breakdown of Mediator Enhances Effect.- C. Difficulties With the Above.- I. Limitations of Methods of Detection and Identification.- II. Ubiquity of Mediators, Extraction Artefacts.- III. Possible Involvement of Potent Short-Lived Compounds.- IV. Interactions Between Mediators, Dual Mechanisms, Release One by Another.- V. Effect of Other Factors.- VI. Specificity of Different Inflammatory Models, Difficulties in Extrapolation.- VII. Species Variation, Strain, Site, etc.- VIII. Doubts on Specificity of Blockers.- D. Vascular Events Possibly Mediated by Endogenous Agents and Methods of Measuring Them.- I. Vasoconstriction, Vasodilatation, Changes in Blood Flow.- II. Pressure Changes in the Microcirculation, Filtration, Oedema, Stasis.- III. Permeability Changes.- IV. Leucocyte/Endothelium and Platelet/Endothelium Interactions.- E. Summary and Conclusions.- References.- 17 Pain and Inflammatory Mediators.- A. Introduction.- B. Measurement of Pain in Inflammation.- C. PainReceptors.- D. Chemical Stimulation of Pain Receptors.- E. Sensitization of Pain Receptors: Hyperalgesia.- F. Prostaglandin Release During Inflammation.- I. Prostaglandins and Pain.- II. Prostaglandins and Hyperalgesia.- G. Aspirin-Like Drugs and Their Mechanism of Analgesia.- References.- 18 Prostaglandins and Body Temperature.- A. An Introduction on Fever.- I. Exogenous Pyrogens.- II. Endogenous Pyrogens.- III. Pyrogen Injections Into the Liquor Space or Into Discrete Regions of the Brain.- IV. The Problem of Pyrogens Entering the CNS.- B. Temperature Responses to Prostaglandins in Different Species.- I. Temperature Responses in Cats.- II. Temperature Responses in Rabbits.- III. Temperature Responses in Monkeys.- IV. Temperature Responses in Humans.- V. Temperature Responses in Sheep.- VI. Temperature Responses in Rats.- VII. Temperature Responses in Mice.- VIII. Temperature Responses in Echidna (Tachyglossus aculeatus).- IX. Temperature Responses in Birds.- C. Temperature Effects of Prostaglandins at Different Ambient Temperatures.- D. Effect of Prostaglandins on Thermosensitivity of the Anterior Hypothalamus and on the Firing Rate of its Neurones.- E. Effects of Drugs on Prostaglandin Fever.- I. Antipyretics.- II. Prostaglandin Antagonist.- III. Drugs Which Deplete the Stores of the Monoamines or Block Their Actions.- IV. Atropine, Benztropine, Mecamylamine, and D-Tubocurarine.- V. Morphine and Chlorpromazine.- VI. Anaesthetics.- VII. Theophilline and Nicotinic Acid.- F. Prostaglandin Fever and Cyclic AMP.- G. Prostaglandin in CSF and Fever.- I. Endotoxin Fever.- II. Lipid A Fever.- III. Newcastle Disease Virus Fever.- IV. Endogenous Pyrogen Fever.- V. Variations in Increased Prostaglandin Activity During Endotoxin Fever and the Effect of Pentobarbitone Sodium Anaesthesia.- VI. An Unspecific Fever.- VII. Sodium Fever.- H. Febrile Episodes in Schizophrenia.- I. The Evidence for and Against the Prostaglandin Theory of Fever.- References.- Author Index.