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Kluwer Academic Gastric Cytoprotection A ClinicianS Guide 1989 Edition by Daniel Hollander Andrzej S. Tarnawski
Gastric secretions contain hydrogen ions at a concentration that is more than one million times higher than their intracellular concentration. This phenomenal gradient as well as the demonstrated ability of gastric juice to digest tissues has motivated clinicians and investigators alike to emphasize acid secretion and acid ablation in studying the pathogenesis and therapy of peptic ulcer disease. Conse- quently over the past 150 years we have made considerable progress in under- standing the mechanisms and regulation of acid secretion by the stomach. Not surprisingly therapy for both peptic disease and mucosal injury has also been predominantly directed at either neutralizing acid or suppressing its production. During the past 10 years attention has been focused on factors other than acid in the genesis and therapy of ulcer disease. Work done worldwide demon- strated that acid hypersecretion is not a common event in peptic ulcer disease. Therefore we began realizing that factors other than acid secretion may be important in the genesis of ulcer disease or in gastroduodenal mucosal damage.In addition new physiological information has established that the gas- troduodenal mucosa is normally protected by a complex series of events includ- ing mucus and bicarbonate secretion cell renewal surface mucosal restitution and preservation of the microvasculature and mucosal proliferative zone. Table of contents : I. Cytoprotection for the Clinician.- 1 Cytoprotection: Historical Perspective.- 1. Introduction.- 2. Antiulcer Effect without Acid Inhibition.- 3. Direct Cytoprotection.- 4. Differences among Prostaglandins.- 5. Clinical Studies on Cytoprotection.- 6. Adaptive Cytoprotection.- 7. Functional Cytoprotection.- 8. Intestinal Cytoprotection.- 9. Conclusions.- Annotated Bibliography.- 2 Acid Hypersecretion: Important Factor or Innocent Bystander?.- 1. Introduction.- 2. Information Interpreted as Indicating a Connection between Gastric Juice and Duodenal Ulceration.- 2.1. Animal Studies.- 2.2. Human Studies.- 2.3. Response to Treatment.- 2.4. Relationship between Acid and Pepsin in Gastric Juice.- 3. Analysis of the Evidence for the Role of Gastric Secretion in Ulcerogenesis.- 3.1. Animal Studies.- 3.2. Human Studies.- 3.3. Response to Treatment.- 3.4. Relationship between Acid and Pepsin.- 3.5. Heterogeneity.- 3.6. Mucosal Injury.- 4. Association and Causation.- 4.1. Strength of Association.- 4.2. Consistency of Observed Association.- 4.3. Specificity of Association.- 4.4. Temporality.- 4.5. Plausibility and Coherence.- 4.6. Bias.- 4.7. Summary: Relationship between Putative Cause and Disease.- 5. Alternative Etiologic Bases for Duodenal Ulceration.- Annotated Bibliography.- 3 Pathomorphology of Gastric Mucosal Injury.- 1. Functional Morphology of the Gastric Mucosa.- 2. General Consideration of Cell Injury.- 3. Pathogenesis of Reversible and Irreversible Cell Injuries.- 3.1. Ischemia.- 3.2. FreeRadicals.- 3.3. Cellular Signaling System.- 3.4. Cytoskeleton.- 3.5. Calcium as Ultimate Cell Killer.- 4. Gastric Mucosal Injury.- 4.1. Acutelnjury.- 4.2. Chronic Mucosal Injury - Acetic Acid-Induced Ulcers.- 4.3. Stress-Induced Ulcers.- 4.4. Endogenous Prostaglandins Thromboxanes Leukotrienes and Platelet Activating Factor.- 5. Pathogenesis of Gastric Mucosal Injury.- 6. Relevance to Human Pathology.- Annotated Bibliography.- II Defensive Mechanisms of the Stomach.- 4 Mechanisms of Mucosal Protection.- 1. Introduction.- 2. Anatomical Features of Gastroprotection.- 2.1. Cell and Organelle Membrane Permeability.- 2.2. Cell Migration (Restitution) and Division (Regeneration).- 2.3. Microcirculation.- 2.4. Muscle Tone.- 3. Biochemical Processes Relevant to Protection.- 3.1. Mucus and Bicarbonate Secretion.- 3.2. Hydrophobicity of Phospholipids.- 3.3. AcidSecretion.- 3.4. Fluid Flux.- 3.5. Free Radical Scavenging.- 3.6. Release and Action of Enzymes.- 3.7. Release and Action of Vasoactive Substances.- 4. Mechanisms of Action of Major Groups of Protective Agents.- 4.1. Major Chemical Groups.- 4.2. Individual Drugs.- 5. Summary.- Annotated Bibliography.- 5 Mucus Secretion.- 1. The Nature of the Gastroduodenal Mucus Barrier.- 2. Structure of Mucus and Its Mucin Components.- 3. Mucus and Protection against the Endogenous Aggressors.- 3.1. Acid.- 3.2. Pepsin.- 4. Impairment of the Mucus Barrier in Peptic Ulcer Disease.- 5. Mucus and Protection against Exogenous Damaging Agents.- 6. Mucus Secretion Cytoprotection Prostaglandins and Other Antiulcer Agents.- Annotated Bibliography.- 6 Bicarbonate Secretion and the Alkaline Microclimate.- 1. Introduction.- 2. Bicarbonate Secretion.- 2.1. Historical Background.- 2.2. Measurement of Bicarbonate Secretion.- 2.3. Significance of Bicarbonate Secretion.- 2.4. Mechanisms of Bicarbonate Secretion.- 3. Regulation of Gastroduodenal Bicarbonate Secretion.- 4. Effects of Damaging and Protective Agents on the Alkaline Microclimate.- 4.1. Damaging Agents.- 4.2. Protective Agents.- 5. Importance of the Alkaline Microclimate in the Pathogenesis and Treatment of Peptic Ulcer Disease.- Annotated Bibliography.- 7 Epithelial Cell Renewal.- 1. Introduction.- 2. Epithelial Renewal in the Normal Gastrointestinal Tract.- 2.1. Process of Epithelial Renewal.- 2.2. Epithelial Renewal within the Esophagus Stomach and Duodenum.- 2.3. Regulation of Epithelial Renewal.- 2.4. Restitution of the Epithelium.- 3. Methods of Studying Epithelial Renewal.- 3.1. Light Microscopy.- 3.2. Radioactive Labeling of Newly Synthesized DNA with Tritiated Thymidine.- 3.3. Measurement of Substances Involved in Cell Growth.- 4. Epithelial Renewal in Disorders of the Esophagus Stomach and Duodenum.- 4.1. Esophagus.- 4.2. Stomach and Duodenum.- 5. Relevance of Abnormalities in Epithelial Renewal to Carcinogenesis.- 6. Conclusions: Relevance of Abnormalities in Epithelial Cell Renewal to Cytoprotection.- Annotated Bibliography.- 8 Gastric Blood Flow and Mucosal Defense.- 1. Introduction.- 2. The Gastric Vasculature.- 2.1. General Anatomical Design.- 2.2. Functional Implications.- 3. Physiological Regulation of Mucosal Blood Flow.- 3.1. Basal Flow.- 3.2. Stimulated Flow.- 4. Blood Flow and the Gastric Mucosal Barrier.- 4.1. The Mucosal Barrier.- 4.2. Nonvascular Barrier Components.- 4.3. Role of Blood Flow in Barrier Function.- 4.4. Mucosal Mast Cells.- 5. Blood Flow in Mucosal Pathophysiology.- 5.1. Acid-Dependent Lesions and Blood Flow.- 5.2. Acid-Independent Mucosal Lesions.- 5.3. The Mucosal Homeostat System: A Unifying Hypothesis.- 6. Summary and Conclusions.- Annotated Bibliography.- III. Cytoprotective Therapy.- 9 Cytoprotective Therapy: Prostaglandins.- 1. Introduction.- 2. Evidence for a Role of Prostaglandin in Cytoprotection.- 2.1. Experimental Models.- 2.2. Effects of Modifiers of Arachidonic Acid Metabolism on Mucosal Integrity.- 2.3. Effects of Exogenous Prostaglandins on Mucosal Defense Mechanisms.- 2.4. Postulated Prostaglandin-Related Defects in Duodenal Ulcer Disease.- 3. Therapeutic Effects of Prostaglandins on Acute and Chronic Mucosal Injury in Humans.- 3.1. Aspirin and NSAID-Related Injury.- 3.2. Ethanol-Related Injury.- 3.3. Peptic Ulcer Disease.- 4. Summary.- 5. Future Directions.- Annotated Bibliography.- 10 The Role of Nutrient Essential Fatty Acids in Gastric Mucosal Protection.- 1. Introduction.- 2. Dietary Precursors of Prostanoid Synthesis.- 3. Protective Activity of Dietary Essential Fatty Acids against Acute Injury.- 4. Advantages of Dietary Essential Fatty Acids over Synthetic Prostaglandins.- 5. Mucosal Protective Effect of Chronic Feeding of Dietary Essential Fatty Acids.- 6. Effect of Dietary Essential Fatty Acids on Human Gastric Mucosa.- 7. Dietary Essential Fatty Acids and the Epidemiology of Peptic Ulcer Disease.- 8. Conclusions and Future Directions.- Annotated Bibliography.- 11 Gastroprotection by Nonprostaglandin Substances.- 1. Introduction.- 2. Gastroprotection by Suppression of Release or Action of PAF Tx or LT in the Gastric Mucosa.- 3. Endogenous Nonprostaglandin Gastroprotective Substances: Sulfhydryls EGF Gastrin Somatostatin.- 4. Antiulcer Drugs with Gastroprotective Activity: Antacids Carbenoxolone Solon Sucralfate and Colloidal Bismuth.- 5. Other Nonprostaglandin Gastroprotective Substances: Sulfhydryls Meciadanol Certain Inorganic Compounds Papavarine.- 6. Concluding Remarks.- Annotated Bibliography.