Inflammation: A Review of the Process

Library of Congress Cataloging-in-Publication

Trowbridge, Henry O.

Inflammation : a review of the process / Henry O. Trowbridge,

Robert C. Emiling. – – 5th ed.

p. cm.

Includes bibliographical references and index.

ISBN 0-86715-310-5 | eISBN 978-0-86715-895-3

1. Inflammation. I. Emling, Robert C. II. Title.

[DNLM: 1. Inflammation. QZ 150 T863i 1997]

RB131.T76 1997

616’.0473 – – dc21

DNLM/DLC

Fifth Edition

© 1997 by Quintessence Publishing Co, Inc

Quintessence Publishing Co, Inc

551 North Kimberly Drive

Carol Stream, IL 60188

All right reserved. This book or any part thereof may not be reproduced, stored in a retieval system, or transmitted in any form or by any means, electronics, mechanical, photocopying, or otherwise, without prior written permission of the publisher.

Fourth edition copyrighted 1993

Editor: Betsy Solaro

Production: Eric S. Przyblyski

Cover design: Jennifer A. Sabella

Printed in the United States of America

Contents

Preface

Introduction

Abbreviations

Part I

Acute Inflammatory Process

1Vascular Response to Injury

Quick review

The vascular events

Exudation, transudation, and edema

The lymphatic system

Postscript

2Chemical Mediators of the Vascular Response

Histamine

Serotonin

Plasma proteases

The kinin system

The fibrinolytic system

Advice from some old friends

The complement system

Eicosanoids

Platelet activation factor

Nitric oxide

Neuropeptides

Other mediators

3The Blood Leukoctyes

The cells involved

The individual leukocytes

The mononuclear-phagocytic system

4Systemic Manifestations of Inflammation

Part II

Immunity

5The Immune System

The opponents

The defenders

Antigen-presenting cells

The system

Immunoglobulins

General battle plan

Duration of antibody repsonses

6Hypersensitivity Reactions

Type I—Immediate-type hypersensitivity

Type II—Immune cytotoic reactions

Type III—Immune complex hypersensitivity

Type IV—Delayed-type hypersensitivity

Immunologic tolerance

Immunodeficiency

7Chronic Inflammatory Processes

General considerations

Causes of chronic inflammation

Factors contributing to chronicity

Maintenance of chronicity

Other cells involved

Tissue damage

Chemical mediators

Essential elements

Granulomatous inflammation

Control of inflammation

Part III

Repair of Host Tissues

8Healing

Resolution vs repair

Regeneration

Fibrous repair

Cell-matrix interaction

Cell-cell interaction

The role cells play in wound healing

What is organization?

Epithelialization

Strength of healing wounds

Remodeling wounds

Local and systemic factors influencing healing

Part IV

Application of Basic Principles

9Clinical Connections

Inflammation of the tooth pulp (pulpitis)

Inflammatory lesions of the periapical tissues

Acute pyogenic osteomyelitis of the jaws

Chronic osteomyelitis of the jaws

Cellulitis

Periodontal disease

Acquired immunodeficiency syndrome

Answers to Self-Test and Charts

Index

Preface

Over the past few years, we have witnessed an explosion of information concerning the processes of inflammation and immunity and how they protect, and in some instances, harm the host. In revising the fourth edition of this book, we have drawn extensively from the most upto-date journals and textb.ooks. We do not attempt a comprehensive treatment of these processes, complete with references and background material. Full detail would merely mean another book of esoteric language and of necessity would be hundreds of pages long. The amount of detail has therefore been purposefully kept at an essential level with the needs of the practicing professional always in mind.

The book is designed on the premise that the reader possesses a background understanding of the basic sciences.

Each chapter builds on that background and introduces new concepts in a careful and studied manner. Two chapters have been added in the fifth edition, one concerning the systemic manifestations of inflammation, and the other applying what has been covered in the preceding chapters to specific clinical conditions.

With our combined backgrounds in pathology and education, we have creijted a self-study book that will bring readers up to date b_n the fundamentals of inflammation and immunology at)a;, further, will help them understand related materials they \/Viii come across in journals and at meetings. It will also be useful for graduate students in specialty pro grams when pieparing for specialty board examinations.

This book is also designed with a teaching methodology. Based on research and experience in higher education, and especially in continuing education, this methodology involves modes of quick comprehension and strategically placed review mechanisms. This structure enables you to read, study, and comprehend, while moving through the material. In other words, this is a workbook of sorts. Take time to understand each chapter before moving on to the next. In this way, as the material builds, you will be able to follow the development and fully understand the referrals back to earli er passages.

The book is divided into four sections. The first covers the various components of inflammation, both local and systemic; the second provides a review of immunology and immunopathology; and the third explains healing, the final stage of inflammation. The fourth section is new in this edition. It consists of familiar clinical conditions. We hope that by applying what you have learned in the first three sections, you will gain new insights into these disease processes and that as a result, your therapeutic decisions will have a strong scientific basis. As you proceed through the book, you will be amazed at how effective our host defensive system is. At times these defenses may harm the host, but for most of us, they provide a long and healthy life.

The wide acceptance of this book since its first appearance in 1978 has been most gratifying. A special thanks goes to Professor Masaki Shimono, Department of Pathology, Tokyo Dental College, for the use of some illustrations. We acknowledge with heartfelt gratitude our benefactor, Dr J.B. Bender, foremost among those to whom we are indebted. Without his impelling influence this book never would have been launched.

Introduction

Inflammation is a defense reaction of higher animals to the presence of any injurious stimulus. An irritant can be physical in nature, such as heat, or it can be chemical, or bacterial. One can look upon inflammation as an immunologic mechanism of definite significance in bodily economy.

To inflame means to set afire, which conjures up the color red, a sense of heat, and often pain. The word comes to us by way of Middle English (enflamme), from the Middle French (enflamm), and from Latin (enflammare). The word inflammation is particularly appropriate as a descriptive term for the physiological response of the body to injury.

The inflammatory reaction tends to be stereotyped. Regardless of the nature of the stimulus, a sequence of events occurs whereby the deleterious agent tends to be localized and ultimately destroyed. To avoid confusion, a distinction should be made between acute and chronic inflammation. Acute refers to a response that is abrupt in onset and of short duration. Thus, acute inflammation may become chronic (in the temporal sense) if the injurious agent is persistent.

Chronic inflammation is characterized by a proliferation of fibroblasts and .small blood vessels, as well as an influx of chronic inflamq:iatory cells (lymphocytes, plasma cells, macrophages). At times, chronic inflammation is primary and is not preceded by an acute inflammatory response. This is the case in certain immunologic conditions. Chronic inflam mation also differs from acute inflammation in that it is orchestrated almost entirely by cells of the immune system.

We must hasten to add that there is a great deal of overlap between acute inflammation, chronic inflammation, and healing, but for the sake of simplicity we often consider them separately. Although frequently regarded as a separate process, healing commences soon after injury, while acute inflammation is still in full swing. Chronic inflammation is very similar to repair; in fact, it is often referred to as frustrated repair because healing is held in abeyance until the injurious agent has been completely eliminated. Do keep this overlap in mind as you proceed through the book.

Abbreviations

Ab antibody

ACTH adrenocorticotropic hormone

ADCC antibody-dependent cell-mediated cytotoxicity

ADP adenosine diphosphate

Ag antigen

AIDS acquired immunodeficiency syndrome

AMP adenosine monophosphate

APC antigen-presenting cell

APR acute phase reaction

BMP bone morphogenetic protein

CD cluster designation

CD4 surface marker on T-effector/helper lymphocyte surface

CD8 marker on T-cytotoxic/suppressor lymphocyte

CGRP ca/citonin gene-related peptide

CMI cell-mediated immunity

CMV cytomegalovirus

CRP C-reactive protein

CSF colony-stimulating factors

CTL cytotoxic T lymphocyte

DTH delayed-type hypersensitivity

EBV Epstejn-Barr virus

ECM extritcellu/ar matrix

EGF epitdermal growth factor

ELAM endothelial leukocyte adhesion molecule

ESR erythrocyte sedimentation rate

Fc portion of immunoglobulin molecule

FDC follicular dendritic cell

FGF fibroblast growth factor

GALT gut-associated lymphoid tissue

GF growth factor

GM-CSF granulocyte-macrophage colony-stimulating factor

GMP guanosine monophosphate

Hhistamine

5-HPETE 5-hydroperoxyeicosatetraenoic acid

5-HT 5-hydroxytryptamine (serotonin)

H2O2 hydrogen peroxide

HLA human lymphocyte antigen

HMP hexosemonophosphate

HOCI hypochlorous acid

ICAM intracellular adhesion molecule

Ig immunoglobulin

IGF insulin-like growth factor

IL interleukin

INF interferon

JP juvenile periodontitis

LAK lymphokine-activated killer (NK cell)

LPS lipopolysaccharide (endotoxin)

LT leukotriene

MAC membrane attack complex

MHC major histocompatibility complex

MIF macrophage inhibition factor

NADPH nicotinamide adenine dinucleotide phosphate (reduced form)

NGF nerve growth factor

NK natural killer (cell)

NO nitic oxide

PAF platelet activating factor

PBL peripheral blood lymphacyte

PDGF platelet-derived growth factor

PDL periodontal ligament

PG prostoglandin

PMN polymorphonuclear neutrophil

RD reparative dentin

SC secretory component (of IgA)

SP substance P

SRS-A slow-reacting substance of anaphylaxis

TCR T-cell receptor

TGF transforming growth factor

Th1 T-helper cell subset

Th2 T-helper cell subset

TNF tumor necrosis factor

VEGF vascular endothelial growth factor

I

Acute Inflammatory Process

1Vascular Response to Injury

The vascular response to injury is a reactionary process that sets up the delivery system of inflammation. What is needed at the site of an injury is a way to deliver supplies and materials for defense. By initially opening up the vascular delivery system, more supplies and materials are shipped into an area than would normally pass that way. Without something else, however, the supplies would rapidly pass right on by. Therefore, the system builds in a slowing-down process once the supplies are on location. Finally, the system must get the supplies unloaded from the delivery system and across the country to the injury site.

Injury to an organ or tissue results in progressive changes in the damaged area. The main signs of such a response are redness, heat, and swelling. These signs are the result of vascular alterations in the area of injury. The redness and heat result from an increase in blood flow, which in turn is the result of vasodilatation, first involving arterioles, and then capillaries and venules. Swelling is the result of alterations in vascular permeability leading to exudation of fluid, plasma proteins, and white blood cells.

Quick review

Certain blood vessels are involved in the response to injury. These vessels constitute the microvasculature. Since numerous references will be made to these vessels in the first section of this book, a quick review is in order (Fig 1-1).

Arteriole: Smaller than an artery, it consists of an inner layer of endothelial cells, a middle layer in which there is at least one layer of smooth muscle, and an outer layer of adventitia.

Fig 1–1 Microvasculature. (A) Adventitia; (SM) smooth muscle; (E) endothelium; (PS) precapillary sphincter; (1) arteriole; (2) metarteriole; (3) capillary; (4) venule.

Metarterioles: Branches of arterioles that are similar to capillaries except for the presence of muscle fibers that encircle the lining of endothelial cells. The muscle fibers do not form a continuous layer but tend to occur in groups.

Precapillary: May arise from either an arteriole or a metarteriole and is distinguished by the presence of a few muscle fibers that form a sphincter around the underlying endothe lial cells.

Capillary: The structural unit of the circulatory system. Except for the capillaries, the blood is normally contained within relatively heavy-walled, impervious tubes. Even in the capillary network the plasma and cells of the blood are separated from the tissues they serve by a thin sheet of endothelial cells that form the capillary wall. Fluid and metabolites are transported through the walls of the capillaries and reach the tissues by diffusion. Capillaries are surrounded by a basement membrane.

Fig 1–2 Fluid exchange across walls of small blood vessels.

Venules: Blood is drained from the capillaries by these vessels. They possess a basement membrane and an adventitia but lack smooth muscle fibers.

Starling’s law

The movement of fluid in and out of arterioles, capillaries, and venules is regulated by the balance between intravascular hydrostatic pressure, which tends to force fluid out of the vessels, and the opposing effects of osmotic pressure exerted by the plasma proteins, which tend to retain fluid within the vessels (Fig 1-2). This is often referred to as Starling’s law.

Edema fluid

During the acute inflammatory response, swelling results from (1) an increase in the hydrostatic pressure in the micro-circulation (this forces more fluid out of the vessels), and (2) the passage of fluid from small vessels (principally venules), which become more permeable to plasma proteins. When these proteins leave the vessels and enter the extravascular space, they increase the osmotic pressure in the tissue. This draws more fluid out of the blood vessels and into the tissues. The fluid that accumulates in the tissues is termed edema fluid.

Response to injury

The immediate responses to injury produced by physical, chemical, or microbial agents are quite similar, suggesting that injurious agents mediate their effects through common pathways. Thus, the acute inflammatory response is determined more by the severity of the injury than the actual cause.

The vascular response to injury is variable and may be reversible. The amount of variability and reversibility depends more upon the severity of injury than the kind of injury.

The vascular events

Vasodilation

Following a very brief period of vasoconstriction, the arterioles dilate (vasodilation, Fig 1-3) and the microvasculature at the site of injury becomes filled with blood (congestion). Thus, the process of increased delivery is set in motion. This process is known as active hyperemia.

Fig 1–3 Vasodilation.

Fig 1–4 Increase in blood flow associated with inflammation. (A) Arteriole; (V) venule.

Vasodilation results from a relaxation of the smooth muscle layer of arterioles and the sphincter of precapillaries. This opens previously inactive capillaries and may result in as much as a tenfold increase in blood flow in the injured area (Fig 1-4). Postcapillary venules dilate as more blood flows in through the capillaries.

Increased vascular permeability

From the thousands of letters we have received about vascular permeability it is clear that you want to know why a vessel becomes leaky. Your long wait is over. . . .

Vessels become leaky for a couple of reasons (more detailed discussion later). For now, you should know that first the vessel dilates. The cells of the endothelium, which make up the inner layer, then contract. (This happens only in small postcapillary venules.) When the endothelial cells contract and draw away from each other, gaps form between the cells through which fluid and plasma proteins can move (Fig 1-5).

Another mechanism by which vessels may become more leaky is through an injury that causes destruction of endothelial cells but does not damage the basement membrane that surrounds the vessel. (If the basement membrane remains intact there is no hemorrhage.) Now this is more of the useful information we promised to deliver. Next time you see a bruise on your squash partner’s leg, you can comment with assurance, Oh . . . I see your basement membrane was not intact! As he tries to figure you out, you can probably nail down a couple more squash points. This destruction of endothelial cells can occur in capillaries and arterioles, as well as in venules.

Fig 1–5 Intercellular gaps.

1. In mild injury it is principally the postcapillary venules that become more permeable.

2. In moderate injury the capillaries as well as the small venules become more permeable.

3. In very severe injury the capillaries, venules, and arterioles may all become leaky.

Now you can see why the pattern of vascular permeability is known to be related more to the intensity of the injury than to the nature of the injury.

Vascular stasis — sequence of events

At first there is an escape of fluid (but not red or white blood cells) from the microvasculature due to (1) an increase in hydrostatic pressure inside the blood vessels, (2) increased vascular permeability, and (3) increased osmotic pressure in the extravascular tissue fluid (remember Starling’s law!).

Because fluid is lost from the vessels while blood cells are retained, there is an increase in the viscosity of the blood (hemoconcentration), and this tends to slow the flow of blood right at the site, where it is needed to deliver supplies.

Leukocytes (white blood cells) commence to stick to the endothelium of the venules (leukocyte margination or pavementing) producing an increase in resistance to blood flow, which in turn increases the hydrostatic pressure in the venules and capillaries.

As the blood flow continues to decrease there may