Ch09.pdf

CHAPTER

Inﬂammation, Tissue

Repair, and Fever

The Inﬂammatory Response

Acute Inﬂammation

Cardinal Signs

The Vascular Response

The Cellular Stage

Inﬂammatory Mediators

Chronic Inﬂammation

Nonspeciﬁc Chronic Inﬂammation

Granulomatous Inﬂammation

Local Manifestations of Inﬂammation

Systemic Manifestations of Inﬂammation

Acute-Phase Response

White Blood Cell Response (Leukocytosis and

Leukopenia)

Lymphadenitis

Tissue Repair and Wound Healing

Regeneration

Connective Tissue Repair

Inﬂammatory Phase

Proliferative Phase

Remodeling Phase

Factors That Affect Wound Healing

Malnutrition

Blood Flow and Oxygen Delivery

Impaired Inﬂammatory and Immune Responses

Infection, Wound Separation, and Foreign Bodies

Temperature Regulation and Fever

Body Temperature Regulation

Mechanisms of Heat Production

Mechanisms of Heat Loss

Fever

Patterns

Manifestations

Diagnosis and Treatment

Fever in Children

Fever in the Elderly

microbial agents, and repair damaged tissue is dependent

upon the inﬂammatory reaction, the immune system re-

sponse, and tissue repair and wound healing. Although the ef-

fects of inﬂammation are often viewed as undesirable because

they are unpleasant and cause discomfort, the process is essen-

tially a beneﬁcial one that allows a person to live with the ef-

fects of everyday stress. Without the inﬂammatory response,

wounds would not heal, and minor infections would become

overwhelming. Inﬂammation also produces undesirable ef-

fects. For example, the crippling effects of rheumatoid arthritis

result from chronic inﬂammation.

This chapter focuses on the manifestations of acute and

chronic inﬂammation, tissue repair and wound healing, and

temperature regulation and fever. The immune response is dis-

cussed in Chapter 8.

THE INFLAMMATORY RESPONSE

Inﬂammation is the reaction of vascularized tissue to local in-

jury. The causes of inﬂammation are many and varied. Inﬂam-

mation commonly results because of an immune response to

infectious microorganisms. Other causes of inﬂammation are

trauma, surgery, caustic chemicals, extremes of heat and cold,

and ischemic damage to body tissues.

Inflammatory conditions are named by adding the suffix

-itis to the affected organ or system. For example, appendicitis

refers to inflammation of the appendix, pericarditis to inflam-

mation of the pericardium, and neuritis to inflammation of a

nerve. More descriptive expressions of the inflammatory pro-

cess might indicate whether the process was acute or chronic

and what type of exudate was formed ( e.g., acute fibrinous

pericarditis).

Acute Inﬂammation

Acute inﬂammation is the early (almost immediate) response

to injury. It is nonspeciﬁc and may be evoked by any injury

short of one that is immediately fatal. It is usually of short du-

ration and typically occurs before the immune response be-

comes established and is aimed primarily at removing the in-

jurious agent and limiting the extent of tissue damage.

150

T he ability of the body to sustain injury, resist attack by

Chapter 9: Inﬂammation, Tissue Repair, and Fever

151

Cardinal Signs

The classic description of acute inﬂammation has been handed

down through the ages. In the ﬁrst century AD , the Roman

physician Celsus described the local reaction of injury in terms

that have come to be known as the cardinal signs of inﬂamma-

tion. These signs are rubor (redness), tumor (swelling), calor

(heat), and dolor (pain). In the second century AD , the Greek

physician Galen added a ﬁfth cardinal sign, functio laesa, or loss

of function. These signs and symptoms, which are apparent

when inﬂammation occurs on the surface of body, may not be

present when internal organs are involved. For example, in-

ﬂammation of the lung does not usually cause pain unless the

pleura, where pain receptors are located, is affected. In addi-

tion, an increase in heat is uncommon in inﬂammation in-

volving internal organs, where tissues are normally maintained

at core temperature.

In addition to the cardinal signs that appear at the site of in-

jury, systemic manifestations ( e.g., fever) may occur as chemi-

cal mediators produced at the site of inﬂammation gain en-

trance to the circulatory system. The constellation of systemic

manifestations that may occur during an acute inﬂammatory

response is known as the acute-phase response (to be discussed).

The manifestation of acute inﬂammation can be divided

into two categories: vascular and cellular responses. 1,2,3 At the

biochemical level, many of the responses that occur during

acute inﬂammation are associated with the release of chemical

mediators.

redness (erythema) and warmth associated with acute inﬂam-

mation. Accompanying this hyperemic vascular response is an

increase in capillary permeability, which causes ﬂuid to move

into the tissues and cause swelling, pain, and impaired func-

tion. The exudation or movement of the ﬂuid out of the capil-

laries and into the tissue spaces dilutes the offending agent. As

ﬂuid moves out of the capillaries, stagnation of ﬂow and clot-

ting of blood in the small capillaries occurs at the site of injury.

This aids in localizing the spread of infectious microorganisms.

Depending on the severity of injury, the vascular changes

that occur with inﬂammation follow one of three patterns of

response. 3 The ﬁrst is an immediate transient response, which

occurs with minor injury. The second is an immediate sus-

tained response, which occurs with more serious injury and

continues for several days and damages the vessels in the area.

The third type of response is a delayed hemodynamic response,

which involves an increase in capillary permeability that occurs

4 to 24 hours after injury. A delayed response often accompa-

nies radiation types of injuries, such as sunburn.

The Cellular Stage

The cellular stage of acute inﬂammation is marked by move-

ment of phagocytic white blood cells (leukocytes) into the

area of injury. Two types of leukocytes participate in the acute

inﬂammatory response—the granulocytes and monocytes.

Granulocytes. Granulocytes are identiﬁable because of their

characteristic cytoplasmic granules. These white blood cells

have distinctive multilobed nuclei. The granulocytes are divided

into three types ( i.e., neutrophils, eosinophils, and basophils)

according to the staining properties of the granules (Fig. 9-2).

The neutrophil is the primary phagocyte that arrives early at

the site of inflammation, usually within 90 minutes of injury.

The neutrophils’ cytoplasmic granules contain enzymes and

other antibacterial substances that are used in destroying and

degrading the engulfed particles. They also have oxygen-

dependent metabolic pathways that generate toxic oxygen

( e.g., hydrogen peroxide) and nitrogen ( e.g., nitric oxide)

products. Because these white blood cells have nuclei that are

divided into three to five lobes, they often are called polymor-

phonuclear neutrophils (PMNs) or segmented neutrophils (segs).

The neutrophil count in the blood often increases greatly dur-

ing the inflammatory process, especially with bacterial infec-

tions. After being released from the bone marrow, circulating

neutrophils have a life span of only approximately 10 hours

and therefore must be constantly replaced if their numbers

are to remain adequate. This requires an increase in circulat-

ing white blood cells, a condition called leukocytosis. With ex-

cessive demand for phagocytes, immature forms of neutro-

phils are released from the bone marrow. These immature

cells often are called bands because of the horseshoe shape of

their nuclei.

The cytoplasmic granules of the eosinophils stain red with the

acid dye eosin. These granulocytes increase in the blood dur-

ing allergic reactions and parasitic infections. The granules of

eosinophils contain a protein that is highly toxic to large para-

sitic worms that cannot be phagocytized. They also regulate in-

ﬂammation and allergic reactions by controlling the release of

speciﬁc chemical mediators during these processes.

The granules of the basophils stain blue with a basic dye. The

granules of these granulocytes contain histamine and other

The Vascular Response

The vascular, or hemodynamic, changes that occur with in-

ﬂammation begin almost immediately after injury and are

initiated by a momentary constriction of small blood vessels

in the area. This vasoconstriction is followed rapidly by va-

sodilation of the arterioles and venules that supply the area

(Fig. 9-1). As a result, the area becomes congested, causing the

KEY CONCEPTS

THE INFLAMMATORY RESPONSE

■

Inﬂammation represents the response of body tissue

to immune reactions, injury, or ischemic damage.

■

The classic response to inﬂammation includes red-

ness, swelling, heat, pain or discomfort, and loss

of function.

■

The manifestations of an acute inﬂammatory re-

sponse can be attributed to the immediate vascular

changes that occur (vasodilation and increased capil-

lary permeability), the inﬂux of inﬂammatory cells

such as neutrophils, and, in some cases, the wide-

spread effects of inﬂammatory mediators, which pro-

duce fever and other systemic signs and symptoms.

■

The manifestations of chronic inﬂammation are due

to inﬁltration with macrophages, lymphocytes, and

ﬁbroblasts, leading to persistent inﬂammation, ﬁbro-

blast proliferation, and scar formation.

152

Unit Two: Alterations in Body Defenses

Exudate

Arteriole

Venule

Arteriole

dilation

Normal

Extracellular

expansion

Venule

dilation

Acute inflammation

■ FIGURE 9-1 ■ Vascular phase of acute inﬂammation. ( A ) Normal capillary bed. ( B ) Acute inﬂamma-

tion with vascular dilation causing increased redness (erythema) and heat (calor), movement of ﬂuid into

the interstitial spaces (swelling), extravasation of plasma proteins into the extracellular spaces (exudate),

and emigration of leukocytes.

bioactive mediators of inﬂammation. The basophils are in-

volved in producing the symptoms associated with inﬂamma-

tion and allergic reactions. The mast cell, which is widely dis-

tributed in connective tissues throughout the body, is very

similar in many of its properties to the basophil. It can partici-

pate in acute and chronic inﬂammatory responses. 2 Sensitized

mast cells, which are “armed” with IgE, play a central role in

allergic and hypersensitivity responses (see Chapter 10). They

also may play a role in parasitic infections. Mast cells can also

elaborate tumor necrosis factor (TNF), thereby participating in

chronic inﬂammatory responses.

Mononuclear Phagocytes. The monocytes are the largest of the

white blood cells and constitute 3% to 8% of the total blood

leukocytes. The circulating life span of the monocyte is three to

four times longer than that of the granulocytes, and these cells

survive for a longer time in the tissues. These longer-lived

phagocytes help to destroy the causative agent, aid in the sig-

naling processes of speciﬁc immunity, and serve to resolve the

inﬂammatory process.

The monocytes, which migrate in increased numbers into

the tissues in response to inﬂammatory stimuli, mature into

macrophages. Within 24 hours, mononuclear cells arrive at the

inﬂammatory site, and by 48 hours, monocytes and macro-

phages are the predominant cell types. The macrophages engulf

larger and greater quantities of foreign material than do the

neutrophils. They also migrate to the local lymph nodes to

prime speciﬁc immunity. These leukocytes play an important

role in chronic inﬂammation, where they can surround and

wall off foreign material that cannot be digested.

Band cell

Basophil

Neutrophil

Cellular Response. The sequence of events in the cellular

response to inflammation includes: (1) pavementing, (2) em-

igration, (3) chemotaxis, and (4) phagocytosis (Fig. 9-3).

During the early stages of the inﬂammatory response, ﬂuid

leaves the capillaries, causing blood viscosity to increase. The

release of chemical mediators ( i.e., histamine, leukotrienes,

and kinins) and cytokines affects the endothelial cells of the

capillaries and causes the leukocytes to increase their expres-

sion of adhesion molecules. As this occurs, the leukocytes slow

their migration and begin to marginate, or move to and along

the periphery of the blood vessels.

Emigration is a mechanism by which the leukocytes extend

pseudopodia, pass through the capillary walls by ameboid

movement, and migrate into the tissue spaces. The emigra-

tion of leukocytes also may be accompanied by an escape

of red blood cells. Once they have exited the capillary, the

leukocytes wander through the tissue guided by secreted

cytokines (chemokines; interleukin [IL]-8), bacterial and

cellular debris, and complement fragments (C3a, C5a). The

process by which leukocytes migrate in response to a chemi-

cal signal is called chemotaxis. The positive movement up the

Lymphocyte

Monocyte

Eosinophil

■ FIGURE 9-2 ■ White blood cells.

Chapter 9: Inﬂammation, Tissue Repair, and Fever

153

Blood vessel

Neutrophil

complement, its adherence is increased because of binding

to complement. This process of enhanced binding of an anti-

gen caused by antibody or complement is called opsonization

(Chapter 8). Engulfment follows the recognition of the agent

as foreign. Cytoplasmic extensions (pseudopods) surround

and enclose the particle in a membrane-bounded phagocytic

vesicle or phagosome. In the cell cytoplasm, the phagosome

merges with a lysosome containing antibacterial molecules and

enzymes that can digest the microbe.

Intracellular killing of pathogens is accomplished through

several mechanisms, including enzymes, defensins, and toxic

oxygen and nitrogen products produced by oxygen-dependent

metabolic pathways. The metabolic burst pathways that gen-

erate toxic oxygen and nitrogen products ( i.e., nitric oxide,

peroxyonitrites, hydrogen peroxide, and hypochlorous acid)

require oxygen and metabolic enzymes such as myeloperoxi-

dase, NADPH oxidase, and nitric oxide synthetase. Individuals

born with genetic defects in some of these enzymes have

immunodeﬁciency conditions that make them susceptible to

repeated bacterial infection.

Pavementing

Emigration

Bacteria

Chemotaxis

Inﬂammatory Mediators

Although inflammation is precipitated by injury, its signs and

symptoms are produced by chemical mediators. Mediators can

be classiﬁed by function: those with vasoactive and smooth

muscle-constricting properties such as histamine, prostaglan-

dins, leukotrienes, and platelet-activating factor; chemotactic

factors such as complement fragments and cytokines; plasma

proteases that can activate complement and components of

the clotting system; and reactive molecules and cytokines lib-

erated from leukocytes, which when released into the extra-

cellular environment can damage the surrounding tissue.

Table 9-1 describes some chemical mediators and their major

impact on inflammation.

Phagocytosis

■ FIGURE 9-3 ■ Cellular phase of acute inﬂammation. Neutrophil

margination, pavementing, chemotaxis, and phagocytosis.

concentration gradient of chemical mediators to the site of

injury increases the probability of a sufficiently localized cel-

lular response.

During the next and ﬁnal stage of the cellular response, the

neutrophils and macrophages engulf and degrade the bacteria

and cellular debris in a process called phagocytosis. Phagocytosis

involves three distinct steps: (1) adherence plus opsonization,

(2) engulfment, and (3) intracellular killing (see Fig. 9-4).

Contact of the bacteria or antigen with the phagocyte cell mem-

brane is essential for trapping the agent and triggering the ﬁnal

steps of phagocytosis. If the antigen is coated with antibody or

Histamine. Histamine is widely distributed throughout the

body. It is found in high concentration in platelets, basophils,

and mast cells. Histamine causes dilation and increased per-

meability of capillaries. It is one of the ﬁrst mediators of an in-

ﬂammatory response. Antihistamine drugs inhibit this imme-

diate, transient response.

Opsonins

Plasma Proteases. The plasma proteases consist of the ki-

nins, activated complement proteins, and clotting factors.

One kinin, bradykinin, causes increased capillary permeabil-

ity and pain. The clotting system (see Chapter 12) contributes

to the vascular phase of inﬂammation, mainly through ﬁbrino-

peptides that are formed during the ﬁnal steps of the clotting

process.

Engulfment

Bacterium

Attachment

Phagolysosome

formation and

degranulation

Opsonin

receptors

Prostaglandins. The prostaglandins are ubiquitous, lipid-

soluble molecules derived from arachidonic acid, a fatty acid

liberated from cell membrane phospholipids. Several prosta-

glandins are synthesized from arachidonic acid through the

cyclooxygenase metabolic pathway (Fig. 9-5). Prostaglandins

contribute to vasodilation, capillary permeability, and the pain

and fever that accompany inﬂammation. The stable prosta-

glandins (PGE 1 and PGE 2 ) induce inflammation and poten-

tiate the effects of histamine and other inflammatory media-

tors. The prostaglandin thromboxane A 2 promotes platelet

aggregation and vasoconstriction. Aspirin and the nonsteroidal

Intracellular

killing

■ FIGURE 9-4 ■ Phagocytosis of a particle ( e.g., bacterium): op-

sonization, attachment, engulfment, and intracellular killing.

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Unit Two: Alterations in Body Defenses

TABLE 9-1

Signs of Inflammation and Corresponding Chemical Mediator

Inﬂammatory Response

Chemical Mediator

Swelling, redness, and tissue warmth

(vasodilation and increased capillary permeability)

Tissue damage

Histamine, prostaglandins, leukotrienes, bradykinin, platelet-activating factor

Lysosomal enzymes and products released from neutrophils, macrophages,

and other inﬂammatory cells

Complement fragments

Prostaglandins

Bradykinin

Interleukin-1 and interleukin-6

Tumor necrosis factor and interleukin-8

Chemotaxis

Pain

Fever

Leukocytosis

anti-inﬂammatory drugs (NSAIDs) reduce inﬂammation by

inactivating the ﬁrst enzyme in the cyclooxygenase pathway for

prostaglandin synthesis.

wheal-and-ﬂare reaction and the leukocyte inﬁltrate character-

istic of immediate hypersensitivity reactions. When inhaled,

PAF causes bronchospasm, eosinophil inﬁltration, and non-

speciﬁc bronchial hyperreactivity.

Leukotrienes. Like the prostaglandins, the leukotrienes are

formed from arachidonic acid, but through the lipoxygenase

pathway (see Fig. 9-5). Histamine and leukotrienes are com-

plementary in action in that they have similar functions.

Histamine is produced rapidly and transiently while the more

potent leukotrienes are being synthesized. Leukotrienes C4 and

D4 are recognized as the primary components of the slow-

reacting substance of anaphylaxis (SRS-A) that causes slow and

sustained constriction of the bronchioles and is an important

inﬂammatory mediator in bronchial asthma and anaphylaxis.

The leukotrienes also have been reported to affect the perme-

ability of the postcapillary venules, the adhesion properties of

endothelial cells, and the chemotaxis and extravascularization

of neutrophils, eosinophils, and monocytes.

Chronic Inﬂammation

Acute infections usually are self-limiting and rapidly controlled

by the host defenses. In contrast, chronic inﬂammation is self-

perpetuating and may last for weeks, months, or even years. It

may develop during a recurrent or progressive acute inﬂam-

matory process or from low-grade, smoldering responses that

fail to evoke an acute response.

Characteristic of chronic inﬂammation is an inﬁltration by

mononuclear cells (macrophages) and lymphocytes, instead of

the inﬂux of neutrophils commonly seen in acute inﬂamma-

tion. Chronic inﬂammation also involves the proliferation of

ﬁbroblasts instead of exudates. As a result, the risk of scarring

and deformity usually is considered greater than in acute in-

ﬂammation. Agents that evoke chronic inﬂammation typically

are low-grade, persistent irritants that are unable to penetrate

deeply or spread rapidly. Among the causes of chronic inﬂam-

mation are foreign bodies such as talc, silica, asbestos, and

surgical suture materials. Many viruses provoke chronic in-

flammatory responses, as do certain bacteria, fungi, and larger

parasites of moderate to low virulence. Examples are the

tubercle bacillus, the treponema of syphilis, and the actino-

myces. The presence of injured tissue such as that surrounding

a healing fracture also may incite chronic inflammation.

Immunologic mechanisms are thought to play an important

role in chronic inflammation. The two patterns of chronic

inflammation are a nonspecific chronic inflammation and

granulomatous inﬂammation.

Nonspeciﬁc Chronic Inﬂammation

Nonspeciﬁc chronic inﬂammation involves a diffuse accumu-

lation of macrophages and lymphocytes at the site of injury.

Ongoing chemotaxis causes macrophages to inﬁltrate the in-

ﬂamed site, where they accumulate because of prolonged sur-

vival and immobilization. These mechanisms lead to ﬁbroblast

proliferation, with subsequent scar formation that in many

cases replaces the normal connective tissue or the functional

parenchymal tissues of the involved structures. For example,

scar tissue resulting from chronic inﬂammation of the bowel

causes narrowing of the bowel lumen.

Platelet-Activating Factor. Platelet-activating factor (PAF),

which is generated from a complex lipid stored in cell mem-

branes, affects a variety of cell types and induces platelet aggre-

gation. It activates neutrophils and is a potent eosinophil

chemoattractant. When injected into the skin, PAF causes a

Disturbance in cell membrane

Membrane phospholipids

Arachidonic acid

Lipoxygenase

pathway

Cyclooxygenase

pathway

Leukotrienes

Prostaglandins

■ FIGURE 9-5 ■ The cyclooxygenase and lipoxygenase pathways.

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