Lipid Mediators

Contributors

Series Preface

Preface


1. Metabolism of Arachidonic Acid: An Overview


1. Introduction


2. Mechanisms Involved in Bioavailability of Arachidonic Acid for Eicosanoid Production


2.1 Phospholipases Az


2.2 Phospholipase C


2.3 Phospholipase D


2.4 Other Lipases


2.5 Metabolic Pools of Prostaglandin Precursors


2.6 Triglyceride and Free Acid Stores


3. Enzymic Conversion of Arachidonic Acid to Prostaglandins and Related "Prostanoids"


3.1 Prostaglandin-H Synthase


3.2 Further Transformation of Prostaglandin H2 into Biologically Active Eicosanoids


3.3 Endogenous Factors Controlling CeUular Levels of Prostaglandin-H Synthase


3.4 Metabolic Inactivation of Eicosanoids


4. Lipoxygenase Pathways


4.1 12-Lipoxygenase Products


4.2 5-Lipoxygenase Products (Including the Leukotrienes)


4.3 15-Lipoxygenase Products and their Activity


4.4 Monooxygenase Products


4.5 Other Lipoxygenase Products


5. "Crossover" Products


6. Alternative Substrates to Arachidonic Acid in the Formation of Eicosanoids


7. Mode of Action of Anti-inflammatory Drugs


7.1 Non-steroidal ("Aspirin-Type") Drugs


7.2 Steroidal Anti-inflammatory Drugs


8. Concluding Remarks


9. References


2. Measurement of Fatty Acids and Their Metabolites


1. Introduction


2. Approaches to Assays


2.1 Specificity Versus Sensitivity


2.2 Extraction


2.3 Internal and External Standards


2.4 Accuracy and Precision


3. Methodology


3.1 Bioassays


3.2 Radioimmunoassay and Related Assays


3.3 High-Performance Liquid Chromatography


3.4 Gas Chromatography


3.5 Gas Chromatography-Mass Spectrometry


3.6 High-Performance Liquid ChromatographyThermospray Mass Spectrometry


3.7 Other Mass Spectrometry Methods


4. Group Analysis


5. Concluding Remarks


6. References


3. Biological Properties of Cyclooxygenase Products


1. In the Cardiovascular System


1.1 Thromboxane A2


1.2 Prostacyclin


1.3 Prostacyclin and Thromboxane Balance


1.4 Prostacyclin and Thromboxane A2 in Disease


1.5 Antithrombotic Action of Aspirin


1.6 Conclusions


2. In Inflammation


2.1 Inflammatory Properties of Cyclooxygenase Products


2.2 Inhibition of Cyclooxygenase


2.3 Differences between Aspirin and Salicylate


2.4 Thromboxane A2 in Inflammation


3. In the Immune System


4. In the Central Nervous System


4.1 Prostaglandin D2 in Physiological Sleep


4.2 Prostaglandin E2 in Wakefulness


4.3 Conclusions


5. In Pain Perception


5.1 Prostaglandins and Hyperalgesia


5.2 Analgesia with Aspirin-Like Drugs


6. In the Gastrointestinal Tract


6.1 Gastric Antisecretory Actions


6.2 Gastric Vascular Actions


6.3 Gastric Anti-ulcer and Protective Actions


6.4 Actions of Non-steroidal Anti-inflammatory Agents


6.5 Prostanoid Actions on Intestinal Function


7. In Fever


7.1 Experimental Studies in Animals


7.2 Mechanisms of Hyperpyrexia


7.3 Conclusions


8. In the Kidney


8.1 Prostaglandin Production by the Kidney


8.2 Effects of Prostaglandins on Kidney Function


8.3 Inhibition ofCyclooxygenase in Animal Studies


8.4 Inhibition ofCyclooxygenase in Human Studies


9. In Reproduction and Parturition


9.1 Prostaglandins in Seminal Fluid


9.2 Regulation of Uterine Contractions


9.3 Luteolytic Action


10. Acknowledgements


11. References


4. Other Essential Fatty Acids, Their Metabolites and Cell-Cell Interactions


1. Introduction


2. Prostaglandin 12 Synthesis by Endothelial Cells


3. Other Sources of Prostaglandin 12


4. Conversion of Prostaglandin 12 and 6-Ketoprostaglandin Fla to 6-Ketoprostaglandin EI


5. The Lipoxygenase Pathway


6. Vessel Wall Lipoxygenase Metabolism of Linoleic Acid


7. Role of 13-Hydroxyoctadecadienoic Acid in Cell Adhesion Molecule Expression


8. 13-Hydroxyoctadecadienoic Acid and Cell---Cell Interactions in vivo


9. 13-Hydroxyoctadecadienoic Acid and the AtheroscleroticProne Watanabe Rabbit


10. Dietary Modifications of Linoleic and Arachidonic Acid Metabolism in Endothelial Cells


11. Concluding Remarks


12. Acknowledgements


13. References


5. Inhibitors ofFatty Acid-Derived Mediators


1. General Introduction


2. Inhibitors of Arachidonic Acid Release


2.1 Glucocorticoids


2.2 Lipocortins


2.3 Phospholipase A2 Inhibitors


3. Cyclooxygenase Inhibitors


3.1 Introduction


3.2 ChemicaUPharmacological Classes


3.3 Mechanism of Action


3.4 Preclinical Studies


3.5 Clinical Studies


3.6 Summary


4. Selective 5-Lipoxygenase Inhibitors


4.1 Introduction


4.2 ChemicaUPharmacological Classes


4.3 Mechanism of Action


4.4 Preclinical Studies


4.5 Clinical Studies


4.6 Summary


5. Dual Inhibitors of 5-Lipoxygenase and Cyclooxygenase


5.1 Introduction


5.2 ChemicaUPharmacological Classes


5.3 Mechanism of Action


5.4 Preclinical Studies


5.5 Clinical Studies


5.6 Summary


6. Thromboxane Synthetase Inhibitors


6.1 Introduction


6.2 ChemicaUPharmacological Classes


6.3 Mechanism of Action


6.4 Preclinical Studies


6.5 Clinical Studies


6.6 Summary


7. Receptor Antagonists - Cyclooxygenase Pathway


7.1 Introduction


7.2 Chemical/Pharmacological Classes


7.3 Summary


8. Receptor Antagonists - Lipoxygenase Pathway


8.1 Peptidoleukotriene (Leukotriene D4) Receptor Antagonists


8.2 Leukotriene B4 Receptor Antagonists


9. Potential Novel Agents/Future Directions


9.1 Introduction


10. Conclusions


11. Acknowledgements


12. References


6. Biosynthesis and Catabolism ofPlatelet-Activating Factor


1. Introduction


2. Biosynthesis of Platelet-Activating Factor


2.1 Remodelling Pathway


2.2 De novo Pathway


3. Catabolism of Platelet-Activating Factor and Related Metabolites


3.1 Platelet-Activating Factor Acetylhydrolase


3.2 l-Alkyl-2-acetyl-sn-glycerol Acetylhydrolase


3.3 Tetrahydropteridine-Dependent Alkyl Cleavage Enzyme


3.4 Phospholipases


3.5 Transacylase


4. Regulation of Platelet-Activating Factor Metabolism


5. Acknowledgements


6. References


7. Cellular Sources ofPlatelet-Activating Factor and Related Lipids


1. Introduction


2. Detection and Measurement of Platelet-Activating Factor and Related Analogues


2.1 Isolation and Separation of Platelet-Activating Factor and Acyl-Platelet-Activating Factor


2.2 Detection of Platelet-Activating Factor and Acyl-Platelet-Activating Factor


2.3 Catabolism


2.4 Lyso Analogues of Platelet-Activating Factor


2.5 Purity of Cell Populations


3. Synthesis and Release of Platelet-Activating Factor and Related Analogues


3.1 Mechanisms of Release of Platelet-Activating Factor and Related Analogues


4. Stimulation of Inflammatory Cells to Produce PlateletActivating Factor and Related Analogues


4.1 Human Cells that Synthesize Predominantly AlkylLinked Platelet-Activating Factor Species


4.2 Human Cells that Synthesize Predominantly Acyl-Platelet-Activating Factor


4.3 Human Cells for which Platelet-Activating Factor Synthesis is Attributed, but the Linkage Predominance is Unknown


5. Transcellular Biosynthesis of Platelet-Activating Factor


6. Other Cellular Sources of Platelet-Activating Factor


7. Synthesis of Platelet-Activating Factor and Related Analogues with Other Lipid Mediators


8. Conclusions


9. References


8. Biological Properties of Platelet-Activating Factor


1. Introduction


1.1 Physicochemical Properties


2. Cellular Actions


2.1 Platelets


2.2 Monocytes/Macrophages


2.3 Neutrophils


2.4 Eosinophils


2.5 Vascular Endothelium


2.6 Mesangial Cells


3. Organ Systems


3.1 Cardiovascular Actions


3.2 Bronchopulmonary Actions


3.3 The Central Nervous System


3.4 The Immune System


3.5 Renal Actions of Platelet-Activating Factor


3.6 Reproduction


3.7 Skin


4. Pathophysiology


4.1 Anticancer Ether Phospholipids


4.2 Asthma


4.3 Endotoxaemia


4.4 Gastric Ulceration and Ischaemic Bowel Disease


4.5 Hypertension and Atherosclerosis


4.6 Inflammation


4.7 Ischaemia


4.8 Renal Pathology


4.9 Transplantation


5. Perspectives


6. Acknowledgements


7. References


9. Platelet-Activating Factor: Receptors and Receptor Antagonists


1. Introduction


2. Existence of Platelet-Activating Factor Receptors


3. Platelet-Activating Factor Receptor Antagonists


3.1 Phospholipid Analogues


3.2 Lignans and Neolignans


3.3 Ginkgolide B and Other Terpenoid-Related Compounds


3.4 Calcium Channel Blockers


3.5 Triazolobenzodiazepines


3.6 Gliotoxin and Diketopiperazines


3.7 Synthetic Platelet-Activating Factor Antagonists


3.8 Dual Inhibitors


3.9 Irreversible Platelet-Activating Factor Antagonists


4. Multiple Conformational States of Platelet-Activating Factor Receptors


5. Endogenous Modulator(s) of Platelet-Activating Factor Receptors


6. Existence of Intracellular Platelet-Activating Factor Receptors


7. Possible Functions of Intracellular Platelet-Activating Factor Receptors


8. Heterogeneity of Platelet-Activating Factor Receptors


8.1 Receptor Heterogeneity for Platelet-Activating Factor in the Same Cell


8.2 Receptor Heterogeneity for Platelet-Activating Factor between Different Cell Types


9. Solubilization and Identification of Platelet-Activating Factor Receptors


10. The Cloned Platelet-Activating Factor Receptor


11. Signal Transduction Mechanisms


12. Priming Effects of Platelet-Activating Factor


13. Desensitization


14. Conclusion


15. Acknowledgements


16. References

Glossary

Key to Illustrations

Index