MEDIATORS OF INFLAMMATION

CONTRIBUTORS Ira M. Goldstein Department of Medicine, Division of Rheumatology,

New York University School of Medicine, New York, New York

Peter M. Henson Department of Experimental Pathology, Scripps Clinic and Research Foundation, La Jolla, California

David A. Levy Johns Hopkins Medical Institutions, Baltimore, Maryland

Shaun Ruddy Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

Jocelyn Spragg Department of Medicine, Harvard Medical School, and Department of Medicine, Robert B. Brigham Hospital, Boston, Massachusetts

Daniel J. Stechschulte Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas

Gerald Weissmann Department of Medicine, Division of Rheumatology, New York University School of Medicine, New York, New York

Robert B. Zurier Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut

MEDIATORS OF INFLAMMATION

Edited by

Gerald Weissmann Department of Medicine Division of Rheumatology School of Medicine New York University Medical Center New York, New York

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Weissmann, Gerald. Mediators of inflammation.

Includes bibliographies and index. 1. Inflammation. I. Title. [DNLM: 1. Inflammation. QZ150 W433m]

RB131.W44 616'.047 74-20786

ISBN-13: 978-1-4684-0747-1 e-ISBN-13: 978-1-4684-0745-7 DOl: 10.1007/978-1-4684-0745-7

@ 1974 Plenum Press, New York

Softcover reprint of the hardcover 1st edition 1974

A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011

United Kingdom edition published by Plenum Press, London A Division of Plenum Publishing Company, Ltd. 4a Lower John Street, London WIR 3PD, England

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

PREFACE

Lewis Thomas has suggested that "Perhaps the inflammatory reaction should be regarded as a defense of an individual against all the rest of nature, symbolizing his individuality and announcing his existence as an entity." Provision of these symbols and announcements is the task of various mediators of inflammation and this volume has been designed to present our current understanding of their biochemistry, cellular origins, pharmacology, and role in pathology. Unlike other volumes of collected papers, this book did not result from a specific conference or symposium at which each contributor presented his own, narrowly framed research experience. Rather, each of the chapters represents, in the form of a general review, a summary of our knowledge of the mediators and the mecha­nisms by which they are released to launch the inflammatory response. Much effort has been taken to insure that the often conflicting terminology in this field is defmed in detail: many synonyms (e.g., of the properdin system or the alternate pathway of complement activation) have been repeatedly presented, in order to avoid confusion. Although each of the contributors is actively engaged in the field of inflammation, few text figures or tables of ongoing research have been included; the overall aim was to provide a volume readily accessible to workers in other areas as well as to the general reader.

It can now be appreciated that the study of inflammation and its mediators has passed from the purely descriptive to the soundly quantitative level of analYSis, and it is hoped that this compact volume will conveniently bring the results of this effort to the attention of biolOgists, biochemists, immunolOgists, pathologists, and clinicians. Scrutiny of the chapters will indicate that they represent views of inflammation currently held in New York, Boston, Hartford, Kansas City, Baltimore, Richmond, and La Jolla; the editor would especially like to thank Drs. Charles G. Cochrane and K. Frank Austen for suggestions as to their contents.

This volume was prepared during tenure by the editor of a Guggenheim

v

vi PREFACE

Fellowship at the Centre de Physiologie et d'Imrnunologie Cellulaires at the Hospital St. Antoine in Paris and thanks also are due to Dr. Roger Robineaux for his hospitality. Ms. Sarah Cohen prepared the index, Dr. Sylvia Hoffstein provided the cover figure, and Mrs. Harriet Funt contributed her invaluable secretarial help.

New York G.W.

CONTENTS

INTRODUCTION ............................................. 1

Gerald Weissmann

1. The Mediators of Inflammation .............................. 2 2. Mechanisms Common to Several Mediator Systems ............... 3

2.1. Cellular Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 2.2. Fluid-Phase Activation ................................. 3 2.3. Bypass Mechanisms .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4 2.4. Extracellular Control Loops ............................. 4 2.5. Intracellular Controls .................................. 4

3. Centrality ofPhagocytes ................................... 5 4. References .............................................. 7

Chapter 1

MECHANISMS OF MEDIATOR RELEASE FROM INFLAMMATORY CELLS

Peter M. Henson

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 9 2. General Characteristics of Mediator Release from Cells ............ 11

2.1.Mediators ........................................... 11 2.2. Morphology of the Noncytotoxic Release Process ............. 11 2.3. Stimuli for Noncytotoxic Release ......................... 12 2.4. Mechanisms of Noncytotoxic Release ...................... 12 2.5. Cytotoxic Reactions ................................... 17 2.6. Release In Vivo ....................................... 17

3. Platelets ................................................ 17 3.1. Platelet Mediators ..................................... 19 3.2. Morphology ofthe Release Reaction ....................... 19

vii

viii CONTENTS

3.3. Stimuli Inducing the Noncytotoxic Platelet Release Reactions.. 19 3.4. Mechanisms of Noncytotoxic Release from Platelets. . . . . . . . .. 22 3.5. Cytotoxic Reactions of Platelets .. . . . . . . . . . . . . . . . . . . . . . .. 23 3.6. In Vivo Release from Platelets. . . . . • . . . . . . . . . . . . . . . . . . . .. 25

4. Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 26 4.1. Mast Cell Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 26 4.2. Morphology of the Release from Mast Cells ................ 26 4.3. Stimuli Inducing Release from Mast Cells .................. 26 4.4. Mechanisms of Release from Mast Cells. . . . . . . . . . . . . . . . . . .. 28 4.5. Cytotoxic Reactions of Mast Cells . . . . . . . . . . . . . . . . . . . . . . .. 30 4.6.In Vivo Release from Mast Cells. . . . . . . . . . . . . . . . . . . . . . . . .. 30

5. Basophils .........•.................................... 31 5.1. Basophil Mediators ................................... 31 5.2. Morphology of the Release ............................. 31 5.3. Stimuli Inducing Basophil Release. . . . . . . . . . . . . . . . . . . . . . .. 31 5.4. Mechanisms of Release from Basophils .................... 33

6. Neutrophils ............................................ 33 6.1. Neutrophil Mediators ................................. 34 6.2. Morphology of Release from Neutrophils .................. 34 6.3. Stimuli Inducing Neutrophil Release. . . . . . . . . . . . . . . . . . . . .. 35 6.4. Mechanisms of Release from Neutrophils .................. 37 6.5. Cytotoxic Reactions of Neutrophils ...................... 40 6.6. Release from Neutrophils In Vivo . . . . . . . . . . . . . . . . . . . . . . .. 41

7. Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 41 8. Mediator Release as a Secretory Phenomenon .................. 43 9. References ............................................. 44

Chapter 2

LYSOSOMAL HYDRO LASES AND INFLAMMATORY MATERIALS

Ira M Goldstein

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. S 1 2. Polymorphonuclear Leukocyte Lysosomes .................... 52

2.1. Types ............................................. 52 2.2. Phagosomes, Secondary Lysosomes, pH ...... . .. . . . .. . . . .. S3

3. Polymorphonuclear Leukocytes, Lysosomes, and Inflammation .... 55 4. Lysosomal Enzymes as Inflammatory Mediators ................ 57

4.1. Acid Proteases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57 4.2. Neutral Proteases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 58 4.3. Human Leukocyte Elastase-like Esterase . . . . . . . . . . . . . . . . . .. 59 4.4. Human Leukocyte Collagenase .......................... 60

CONTENTS

4.5. Neutral Proteases and Human Disease .. . . . . . . . . . . . . . . . . . .. 61 5. Nonenzymatic Inflammatory Mediators. . . . . . . . . . . . . . . . . . . . . .. 62

5.1. Cationic Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 62 5.2. Histamine .......................................... 64 5.3. Leukocyte Pyrogen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 65 5.4. Leukocytic Endogenous Mediator. . . . ... . . . . . . . . . . . . . . . . .. 66

6. Leukocyte-Derived Substances and Inflammatory Mediator Systems. 67 6.1. Complement and Mediators of Chemotaxis. . . . . . . . . . . . . . . .. 67 6.2. Coagulation and Fibrinolytic Systems . . . . . . . . . . . . . . . . . . . .. 69 6.3. Leukokinins ........................................ 71

7. Antibacterial Substances .................................. 73 8. Conclusions ............................................ 74 9. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 74

Chapter 3

THE PLASMA KININ-FORMING SYSTEM

Jocelyn Spragg

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 85 2. Biological Activities of Components and Their Inhibition ......... 86

2.1. The Several forms of Hageman Factor; PF/dil . . . . . . . . . . . . . .. 86 2.2. Plasminogen Activator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 88 2.3. Plasmin ............................................ 88 2.4. Kallikrein .......................................... 89 2.5. Bradykinin ......................................... 89 2.6. Inhibitors of Enzymes in the Kinin-Forming System. . . . . . . . .. 90

3. Preparation and Physicochemical Characterization of Components .. 92 3.1. Precursor and Active Hageman Factor. .. ... ... . ... ........ 92 3.2. Hageman Factor Fragments. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 94 3.3. Plasminogen Pro activator and Activator ................... 95 3.4. PlaSminogen and Plasmin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 95 3.5. Prekallikrein and Kallikrein. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 95 3.6. Kininogen. . . . . . . . . . . .. ... .. .. ... . . .. . . . . .. .. . . .. ... 96 3.7. Kininases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 98

4. Methods of Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 99 4.1. Functional Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 99 4.2. ImmunolOgical Methods for Measuring Certain Components

of the Kinin-Forming System ........................... 99 5. Components of the Kinin System in White Blood Cells ........... 101

5.1. Kinin-Forming Enzymes and Leukokinins . . . . . . . . . . . . . . . . .. 101 5.2. Kininases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102

x CONTENTS

6. Role ofthe Kinin-Forming System in Inflammation ............. 102 6.1. Activation of Hageman Factor .......................... 103 6.2. Interaction with Other Plasma Systems .................... 104

7. References ............................................. 104

Chapter 4

THE COMPLEMENT AND PROPERDIN SYSTEMS

ShaunRuddy

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 113 2. Nomenclature ........................................... 114 3. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 116

3.1. Complement System .................................. 116 3.2. Properdin System .................................... 118 3.3. Control Proteins ..................................... 119

4. Reaction Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120 4.1. General Principles .................................... 120 4.2. Classic Complement Activation .......................... 121 4.3. The Properdin System: Activation and Amplification ......... 122 4.4. The Terminal Sequence ................................ 124 4.5. Control Mechanisms .................................. 125

5. Biological Activities ...................................... 126 5.1. Permeability Factors .................................. 126 5.2. Chemotactic Factors .................................. 128 5.3. Adherence Phenomena ................................ 129 5.4. Membrane Damage ................................... 132

6. References ............................................. 134

Chapter 5

mST AMINE AND SEROTONIN

David A. Levy

1. Histamine .............................................. 141 1.1. Introduction ........................................ 141 1.2. Chemical Properties ................................... 142 1.3. Assay Methods ...................................... 143 1.4. Distribution ......................................... 145 1.5. Metabolism ....................................... ~. 146 1.6. Pharmacological and Physiological Effects ................. 147 1.7. Effect at a Cellular and a Molecular Level .................. 149

CONTENTS xi

1.8. Role in Inflammation ................................. 150 2. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 157 3. References ............................................. 159

Chapter 6

PROSTAGLANDINS

Robert B. Zurier

1. Introduction ............................................ 163 2. Chemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 163 3. Physiological Actions ..................................... 164

3.1. Induction ofInflammation ............................. 166 3.2. Release During Inflammation ........................... 167 3.3. Effects of Anti-inflammatory Drugs ...................... 169

4. Prostaglandins as Possible Modulators of Inflammation ........... 170 5. Summary .............................................. 174 6. References ............................................. 175

Chapter 7

SLOW REACTING SUBSTANCES

Daniel J. Stechschulte

1. Introduction ............................................ 181 2. Slow Reacting Substance (SRS) ............................. 182 3. Slow Reacting Substance of Anaphylaxis (SRS-A) . . . . . . . . . . . . . .. 183

3.1. Pharmacological Properties ............................. 184 3.2. Physicochemical Properties ............................. 186 3.3. In Vitro Production ................................... 188 3.4.In Vivo Production ................................... 191

4. Concluding Comments ..........•......................... 193 5. References ............................................. 193

IN'DEX .................................................... 199

MEDIATORS OF INFLAMMATION