Immunopharmacology of the Gastrointestinal System (eBook)

John L. Wallace (Herausgeber)

eBook Download: PDF | EPUB

1993 | 1. Auflage
198 Seiten
Elsevier Science (Verlag)
978-1-4832-8933-5 (ISBN)

Infos

Diseases of the digestive system have a higher morbidity rate than any other group of disorder. There is a growing body of evidence that the immune system participates in the pathogenesis of a wide range of these diseases, including peptic ulcer disease and the gastropathy induced by nonsteroidal anti-inflammatory drugs (NSAIDS). For these reasons, efforts to develop novel therapies for digestive diseases are increasingly focused on the immune system. This volume reviews the immunopharmacology of the gastrointestinal tract at four distinct levels: Immunomodulation at a cellular level Cellular targers for immunomodulating drugs Specific classes of inflammatory mediators Utility and mechanisms of action of glucocorticoids in the treatment of diseases of the gastrointestinal tract.

Inhalt

Front Cover 1
Immunopharmacology of the Gastrointestinal System 4
Copyright Page 5
Table of Contents 6
Contributors 10
Series Preface 12
Preface 14
Chapter 1. Neuromodulation of Gastrointestinal Immune and Inflammatory Responses 16
1. Introduction 16
2. The Intestinal Immune System 18
3. Innervation of the Gastrointestinal Tract 21
4. Inflammation and Gastrointestinal Neuroplasticity 22
5. Neuroregulation of Cells of the Mucosal Immune System 23
6. Integration of Intestinal Neuroimmunology 26
7. References 27
Chapter 2. Immunomodultion of the Gas Gastrointestinal Epithelium 30
1. Introduction 30
2. Epithelial Form and Function 31
3. Antigen in Sensitized Hosts 32
4. Immunocompetent Cells 36
5. Fibroblasts 44
6. Goblet Cells 45
7. Neuronal Amplification and Inhibition of GI Epithelium 45
8. Negative Feedback "Off" Mechanisms 46
9. Pharmacological Modification of Epithelial Function 47
10. Conclusions 47
11. Acknowledgements 48
12. References 49
Chapter 3. The Immune Modulation of Intestinal Motor Function 56
1. Overview 56
2. Evidence of Altered Motor Function in vivo in the Inflamed Gut 56
3. Structural Abnormalities in the Motor System in Inflamed Gut 58
4. Altered Contractility of Muscle in the Inflamed Gut 59
5. Changes in Enteric Nerve Function in the Inflamed Gut 61
6. Conclusions 62
7. Acknowledgements 62
8. References 62
Chapter 4. Modulation of Neutrophil Function as a Mode of Therapy for Gastrointestinal Inflammation 66
1. Introduction 66
2. Neutrophil-derived Reactive Oxygen Metabolism 67
3. Antioxidants and Free Radical Scavengers 72
4. Role of Neutrophils and Oxidants in Gastrointestinal Inflammation: Mechanistic and Pharmacologic Approaches 74
5. Neutrophil-derived Proteases 77
6. Role of Neutrophil-derived Proteases in Gastrointestinal Inflammation: Mechanistic and Pharmacologic Approaches 78
7. Cationic Proteins 78
8. Summary 79
9. References 79
Chapter 5. The Vascular Endothelium in Gastrointestinal Inflammation 84
1. Introduction 84
2. Structure of Vascular Endothelium 85
3. Neutrophil–Endothelial Cell Interactions 85
4. Microvascular Exchange of Fluid and Protein 91
5. Ischemia/ Reperfusion-induced Inflammation 95
6. Ethanol-induced Inflammation 100
7. Inflammation Induced by Non-steroidal Anti-inflammatory Drugs 104
8. Summary 105
9. Acknowledgements 105
10. References 105
Chapter 6. Modulation of Mast Cell Function in the Gastrointestinal Tract 110
1. Introduction 110
2. Heterogeneity of Mast Cells 111
3. Mast Cell Mediators 111
4. Mast Cell Activation 112
5. Modulation of Mast Cell Functions 113
6. Conclusions 115
7. References 116
Chapter 7. Immunopathophysiolop/y of the Gastrointestinal Tract: Role of Platelet Activating Factor 120
1. Introduction 120
2. Historical Overview 120
3. Platelet Activating Factor and Blood Flow 121
4. Platelet Activating Factor-induced Vasoconstriction: Role of Secondary Mediators 122
5. Platelet Activating Factor and Polymorphonuclear Leukocytes 124
6. Microvascular Dysfunction 125
7. Mucosal Dysfunction 128
8. Platelet Activating Factor and Gastrointestinal Disease 129
9. Sources of Platelet Activating Factor 132
10. Summary 134
11. Acknowledgements 134
12. References 134
Chapter 8. Cytokines 138
1. Oveview 138
2. Cytokines in Gastrointestinal Diseases 144
3. Summary 147
4. References 147
Chapter 9. Immunopharmacology of Eicosanoids in the Gastrointestinal Tract 152
1. Overview 152
2. Eicosanoids in the Gastrointestinal Tract: Actions, Sources and Receptors 154
3. Role of Eicosanoids in Gastrointestinal Disease 156
4. Conclusions 164
5. References 164
Chapter 10. Nitric Oxide and the Gastrointestinal Tract 170
1. Introduction 170
2. Nitric Oxide Synthase 171
3. Role of Nitric Oxide in Gastrointestinal Motility 173
4. Nitric Oxide and the Gastric Microcirculation 173
5. Role of Nitric Oxide in Modulating Gastric Integrity 174
6. Nitric Oxide and the Intestinal Vasculature 175
7. Nitric Oxide and Intestinal Vascular Integrity 175
8. Cellular Interactions in Vascular Damage 176
9. Role of Nitric Oxide in Immunologically Activated Processes 177
10. Further Implications of the Nitric Oxide System 177
11. References 178
Chapter 11. Glucocorticoids and Gastrointestinal Inflammation 184
1. Introduction 184
2. Glucocorticoid Use and Association with Gastrointestinal Disease: Clinical and Experimental Evidence 185
3. Mechanisms of the Anti-inflammatory Action of Glucocorticoids 185
4. Conclusions 192
5. References 192
Glossary 200
Key to Illustrations 204
Index 210

Textauszug

2

Immunomodulation of the Gastrointestinal Epithelium

Mary H. Perdue and Derek M. Mckay

Publisher Summary

This chapter discusses intestinal immunophysiology and presents evidence showing the modulation of epithelial function by immunocompetent cells and their contents. Immune cells are a significant component of the gastrointestinal (GI) tract both in terms of number and in terms of function; it has been estimated that GALT constitutes approximately 40% of the body’s immune effector cells. The chapter also discusses the impact of immunological reactions on GI epithelial physiology, using intestinal ion transport as the main indicator of epithelial function. The small intestine is lined by a continuous one-cell thick sheet of epithelial cells consisting primarily of columnar polarized cells. Interspersed among these cells are mucus-producing goblet cells, endocrine cells, and intraepithelial leucocytes. Stem cells at cell-position four in the crypt give rise to the enterocytes that migrate upwards toward the lumen of the intestine and are eventually sloughed from the tips of the villi.

1. Introduction

2. Epithelial Form and Function

3. Antigen in Sensitized Hosts

3.1. Parasite/Rat Model

3.1.1. Nippostrongylus Brasiliensis

3.1.2. Trichinella Spiralis

3.2. Egg Albumin/Rodent Model

3.2.1. Prolonged Antigen Exposure

3.3. β -Lactoglobulin/Guinea Pig Model

4. Immunocompetent Cells

4.1. Mast cells

4.1.1. Histamine

4.1.2. Serotonin

4.1.3. Adenosine

4.1.4. Eicosanoids

4.1.4.1. Leukotrienes

4.1.4.2. Prostaglandins

4.1.5. Platelet-activating Factor

4.1.6. Cytokines

4.2. Phagocytes

4.2.1. Reactive Oxygen Metabolites

4.2.2. Bacterial Peptides

4.3. Lymphocytes

4.3.1. Antibody Production

4.3.2. Cytokines

4.4. Intraepithelial Leucocytes

5. Fibroblasts

6. Goblet Cells

7. Neuronal Amplification and Inhibition of GI Epithelium

8. Negative Feedback “Off” Mechanisms

9. Pharmacological Modification of Epithelial Function

10. Conclusions

11. Acknowledgements

12. References

The mucosa of the gastrointestinal tract contains large numbers of immunocompetent cells, many of which are in close proximity to the epithelium. In biological systems, spatial associations often infer functional relationships, therefore, immunocytes have the potential to regulate the transport and barrier properties of the intestinal epithelium. It is this premise that is the basis of the study of intestinal immunophysiology and there is now a substantial body of evidence showing modulation of epithelial function by immunocompetent cells and their contents.

1 Introduction

Immune cells are a significant component of the GI tract both in terms of number and function; it has been estimated that GALT constitutes approximately 40% of the body’s immune effector cells (O’Dorisio, 1986). For the purposes of this chapter granulated leucocytes (eosinophils, neutrophils and mast cells) and macrophages are included in the category of immune cells, along with cells of the T and B cell linages, as these cells react to antigen and are clearly involved in immunological processes. Immune cells have been localized in all compartments of the intestine, including the epithelial layer, throughout the lamina propria and mucosal layers and even in the smooth muscle and ganglionic plexuses. For a detailed discussion of the intestinal immune system see Enders (1987), Doe (1989) and Brandtzaeg et al. (1989). Over the past decade it has become increasingly apparent that immune cells have the ability to synthesize and secrete a plethora of molecules, including biogenic amines, lipid metabolites (i.e. eicosanoids), enzymes and cytokines. Activation of immunocompetent cells elicits mediator release which, by virtue of their close proximity to the epithelial basement membrane, may affect GI epithelial function directly, or indirectly via an intermediatory cell type. For example, immunohistochemical studies have revealed that under the inflammatory conditions induced by infection of the intestinal nematode, Nippostrongylus brasiliensis, in rats, mast cell hyperplasia occurs and approximately 65% of these cells are juxtaposed to a nerve fibre (Stead et al., 1987). This association would appear indicative of a functional unit allowing bidirectional transfer of information between the immune and nervous systems. Arizono and coworkers (1990) have extended these observations to include spatial associations between eosinophils and other lymphocytes with mucosal nerve fibres, and as we shall see, there is increasing evidence illustrating neuroimmune interaction and the control of epithelial function. When the intestine is presented with an antigenic stimulus these cell populations may interact to eradicate successfully the noxious stimulus, that is the gut has the ability to adapt or respond to environmental conditions or cues. When this homeostatic control mechanism fails or is evaded by the pathogen (i.e. maladaption) the result can be manifest as chronic inflammation, pathophysiology and disease.

The intestinal lumen can be considered as the external environment composed of a panoply of microhabitats, the physicochemical character of which is largely unappreciated, and it is the enterocyte that serves as the interface between this outside world and the interstitial environment. Consequently the barrier function of the epithelial cell layer is vital in preventing the entry of antigenic material. When this barrier becomes „leaky” or is breached, a cascade of events is initiated in an attempt to remove or inactivate the antigen. Chronic inflammation can result if this process goes unchecked or is inappropriately exaggerated and, as we discuss below, the immunocompetent cell is one of the focal cell types in this phenomenon. The other major role of the intestine is the degradation of food materials, the subsequent absorption of nutrients, ions and water and the secretion of ions, electrolytes and water. The intestinal epithelial cell layer has the plasticity to alternate between a net absorptive and a net secretory organ (Mitchell, 1979). These two processes are inextricably linked, as secretion is necessary for the solubilization of nutrients, the propulsion of luminal contents and the provision of the ions required for cotransport absorption. Furthermore, it has been suggested that there may be bulk flow of luminal macromolecules across the epithelium in association with fluid transport linked to glucose absorption (Pappenheimer and Reiss, 1987). Thus, immunogenic material may be continually introduced into the submucosa. This would imply an intimate relationship between the intestine’s absorptive function and constant activity of the immune system in the immobilization of antigen.

Thus, under pathophysiological and disease conditions the phenotype of the epithelial and immune cells may be significantly altered towards secretion. Here we review the impact of immunological reactions on GI epithelial physiology, using intestinal ion transport as the main indicator of epithelial function (the reader is also referred to the review by Powell (1991) on the control of intestinal secretion). However, where appropriate, changes in intestinal permeability, absorption and ultrastructure are also considered. A more comprehensive knowledge of immune-enterocyte interaction may lead to improved treatment strategies for patients suffering from many intestinal disorders, including inflammatory bowel disease.

2 Epithelial Form and Function

The small intestine is lined by a continuous one-cell thick sheet of epithelial cells consisting primarily of columnar polarized cells. Interspersed among these cells are mucus-producing goblet cells, endocrine cells and intraepithelial leucocytes. Stem cells at cell-position four in the crypt give rise to the enterocytes which migrate upwards toward the lumen of the intestine and are eventually sloughed from the tips of the villi. During this migration the enterocyte becomes differentiated into a functional secretory cell in the crypt and then alters its phenotype to become a predominantly absorptive cell on the villus. The lifespan of the differentiated enterocyte...

Produkt-Details

• Erscheint lt. Verlag: 1.3.1993
• Mitarbeit: Herausgeber (Serie): Clive Page
• Sprache: englisch
• Themenwelt: Geisteswissenschaften ► Psychologie ► Klinische Psychologie
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Gastroenterologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Psychiatrie / Psychotherapie
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• ISBN-10: 1-4832-8933-8 / 1483289338
• ISBN-13: 978-1-4832-8933-5 / 9781483289335