Ch02.pdf

CHAPTER

Tissue Adaptation

and Injury

Cellular Adaptation

Atrophy

Hypertrophy

Hyperplasia

Metaplasia

Dysplasia

Intracellular Accumulations

Cell Injury and Death

Causes of Cell Injury

Injury From Physical Agents

Radiation Injury

Chemical Injury

Injury From Biologic Agents

Injury From Nutritional Imbalances

Mechanisms of Cell Injury

Free Radical Injury

Hypoxic Cell Injury

Impaired Calcium Homeostasis

Reversible Cell Injury and Cell Death

Reversible Cell Injury

Cell Death

lead to atrophy, hypertrophy, hyperplasia, metaplasia, and dys-

plasia (Fig. 2-1). Adaptive cellular responses also include in-

tracellular accumulations and storage of products in abnormal

amounts. 1,2

There are numerous molecular mechanisms mediating cel-

lular adaptation, including factors produced by other cells or

by the cells themselves. These mechanisms depend largely on

signals transmitted by chemical messengers that exert their ef-

fects by altering gene function. In general, the genes expressed

in all cells fall into two categories: “housekeeping” genes that

are necessary for normal function of a cell, and genes that de-

termine the differentiating characteristics of a particular cell

type. In many adaptive cellular responses, the expression of the

differentiation genes is altered, whereas that of the housekeep-

ing genes remains unaffected. 1 Thus, a cell is able to change size

or form without compromising its housekeeping function.

Once the stimulus for adaptation is removed, the effect on ex-

pression of the differentiating genes is removed and the cell re-

sumes its previous state of specialized function. Whether adap-

tive cellular changes are normal or abnormal depends on

whether the response was mediated by an appropriate stimu-

lus. Normal adaptive responses occur in response to need and

an appropriate stimulus. After the need has been removed, the

adaptive response ceases.

W hen confronted with stresses that endanger its normal

Atrophy

When confronted with a decrease in work demands or adverse

environmental conditions, most cells are able to revert to a

smaller size and a lower and more efﬁcient level of functioning

that is compatible with survival. This decrease in cell size is

called atrophy. Cell size, particularly in muscle tissue, is related

to workload. As the workload of a cell diminishes, oxygen con-

sumption and protein synthesis decrease. Cells that are atro-

phied reduce their oxygen consumption and other cellular

functions by decreasing the number and size of their organelles

and other structures. There are fewer mitochondria, myoﬁla-

ments, and endoplasmic reticulum structures. When a sufﬁ-

cient number of cells are involved, the entire tissue or muscle

atrophies.

The general causes of atrophy can be grouped into ﬁve cat-

egories: (1) disuse, (2) denervation, (3) loss of endocrine

stimulation, (4) inadequate nutrition, and (5) ischemia or a

CELLULAR ADAPTATION

Cells adapt to changes in the internal environment, just as the

total organism adapts to changes in the external environment.

Cells may adapt by undergoing changes in size, number, and

type. These changes, occurring singly or in combination, may

structure and function, the cell undergoes adaptive

changes that permit survival and maintenance of

function. It is only when the stress is overwhelming or adapta-

tion is ineffective that cell injury and death occur.

Chapter 2: Tissue Adaptation and Injury

Change in cell

size or number

Normal

Change in

cell type

Hypertrophy

Hypertrophy represents an increase in cell size and with it an in-

crease in the amount of functioning tissue mass. It results from

an increased workload imposed on an organ or body part and

is commonly seen in cardiac and skeletal muscle tissue, which

cannot adapt to an increase in workload through mitotic divi-

sion and formation of more cells. Hypertrophy involves an in-

crease in the functional components of the cell that allows it to

achieve equilibrium between demand and functional capacity.

For example, as muscle cells hypertrophy, additional actin and

myosin ﬁlaments, cell enzymes, and adenosine triphosphate

(ATP) are synthesized.

Hypertrophy may occur as the result of normal physiologic

or abnormal pathologic conditions. The increase in muscle

mass associated with exercise is an example of physiologic

hypertrophy. Pathologic hypertrophy occurs as the result of

disease conditions and may be adaptive or compensatory. Ex-

amples of adaptive hypertrophy are the thickening of the uri-

nary bladder from long-continued obstruction of urinary out-

ﬂow and the myocardial hypertrophy that results from valvular

heart disease or hypertension. Compensatory hypertrophy is

the enlargement of a remaining organ or tissue after a portion

has been surgically removed or rendered inactive. For instance,

if one kidney is removed, the remaining kidney enlarges to

compensate for the loss.

The precise signal for hypertrophy is unknown. It may be re-

lated to ATP depletion, mechanical forces such as stretching of

the muscle ﬁbers, activation of cell degradation products, or

hormonal factors. 1 Whatever the mechanism, a limit is eventu-

ally reached beyond which further enlargement of the tissue

mass is no longer able to compensate for the increased work

demands. The limiting factors for continued hypertrophy

might be related to limitations in blood ﬂow. For example, in

hypertension the increased workload required to pump blood

against an elevated arterial pressure results in a progressive in-

crease in left ventricular muscle mass (Fig. 2-2).

There has been recent interest in the signaling pathways that

control the arrangement of contractile elements in myocardial

hypertrophy. Research suggests that certain signal molecules

Metaplasia

Hyperplasia

Dysplasia

Hypertrophy

Atrophy

■ FIGURE 2-1 ■ Adaptive tissue cell responses (large circles) in-

volving a change in number (hyperplasia), cell size (hypertrophy

and atrophy), cell type (metaplasia), or size, shape, and organi-

zation (dysplasia).

decrease in blood ﬂow. Disuse atrophy occurs when there is a

reduction in skeletal muscle use. An extreme example of disuse

atrophy is seen in the muscles of extremities that have been en-

cased in plaster casts. Because atrophy is adaptive and rever-

sible, muscle size is restored after the cast is removed and mus-

cle use is resumed. Denervation atrophy is a form of disuse

atrophy that occurs in the muscles of paralyzed limbs. Lack of

endocrine stimulation produces a form of disuse atrophy. In

women, the loss of estrogen stimulation during menopause re-

sults in atrophic changes in the reproductive organs. With mal-

nutrition and decreased blood ﬂow, cells decrease their size

and energy requirements as a means of survival.

KEY CONCEPTS

CELLULAR ADAPTATIONS

■

Cells are able to adapt to changes in work demands

or threats to survival by changing their size (atrophy

and hypertrophy), number (hyperplasia), and form

(metaplasia).

■

Normal cellular adaptation occurs in response to an

appropriate stimulus and ceases once the need for

adaptation has ceased.

■ FIGURE 2-2 ■ Myocardial hypertrophy. Cross-section of the

heart in a patient with long-standing hypertension. (From Rubin

E., Farber J.L. [1999]. Pathology [3rd ed., p. 9]. Philadelphia:

Lippincott Williams & Wilkins)

Unit One: Mechanisms of Disease

can alter gene expression controlling the size and assembly of

the contractile proteins in hypertrophied myocardial cells. For

example, the hypertrophied myocardial cells of well-trained

athletes have proportional increases in width and length. This

is in contrast to the hypertrophy that develops in dilated car-

diomyopathy, in which the hypertrophied cells have a rela-

tively greater increase in length than width. In pressure over-

load, as occurs with hypertension, the hypertrophied cells have

greater width than length. 3 It is anticipated that further eluci-

dation of the signal pathways that determine the adaptive and

nonadaptive features of cardiac hypertrophy will lead to new

targets for treatment.

Metaplasia usually occurs in response to chronic irritation

and inﬂammation and allows for substitution of cells that are

better able to survive under circumstances in which a more

fragile cell type might succumb. However, the conversion of

cell types never oversteps the boundaries of the primary groups

of tissue ( e.g., one type of epithelial cell may be converted to

another type of epithelial cell, but not to a connective tissue

cell). An example of metaplasia is the adaptive substitution of

stratiﬁed squamous epithelial cells for the ciliated columnar

epithelial cells in the trachea and large airways of a habitual

cigarette smoker. A vitamin A deﬁciency also induces squa-

mous metaplasia of the respiratory tract. Although the squa-

mous epithelium is better able to survive in these situations,

the protective function that the ciliated epithelium provides

for the respiratory tract is lost. In addition, continued exposure

to the inﬂuences that cause metaplasia may predispose to can-

cerous transformation of the metaplastic epithelium.

Hyperplasia

Hyperplasia refers to an increase in the number of cells in an

organ or tissue. It occurs in tissues with cells that are capable of

mitotic division, such as the epidermis, intestinal epithelium,

and glandular tissue. Nerve cells and skeletal and cardiac mus-

cle do not divide and therefore have no capacity for hyper-

plastic growth. There is evidence that hyperplasia involves ac-

tivation of genes controlling cell proliferation and the presence

of intracellular messengers that control cell replication and

growth. As with other normal adaptive cellular responses,

hyperplasia is a controlled process that occurs in response to

an appropriate stimulus and ceases after the stimulus has been

removed.

The stimuli that induce hyperplasia may be physiologic or

nonphysiologic. Physiologic hyperplasia can occur as the result

of hormonal stimulation, increased functional demands, or as

a compensatory mechanism. Breast and uterine enlargement

during pregnancy are examples of a physiologic hyperplasia

that results from estrogen stimulation. An increased demand

for parathyroid hormone, as occurs in chronic renal failure, re-

sults in hyperplasia of the parathyroid gland. The regeneration

of the liver that occurs after partial hepatectomy ( i.e., partial re-

moval of the liver) is an example of compensatory hyperplasia.

Hyperplasia is also an important response of connective tissue

in wound healing, during which proliferating ﬁbroblasts and

blood vessels contribute to wound repair. Although hyper-

trophy and hyperplasia are two distinct processes, they may

occur together and are often triggered by the same mechanism. 1

For example, the pregnant uterus undergoes both hypertrophy

and hyperplasia as the result of estrogen stimulation.

Most forms of nonphysiologic hyperplasia are due to exces-

sive hormonal stimulation or the effects of growth factors on

target tissues. 2 Excessive estrogen production can cause endo-

metrial hyperplasia and abnormal menstrual bleeding (see

Chapter 34). Benign prostatic hyperplasia, which is a common

disorder of men older than 50 years of age, is thought to be re-

lated to the synergistic action of estrogen and androgens (see

Chapter 33). Skin warts are an example of hyperplasia caused

by growth factors produced by the human papillomaviruses.

Dysplasia

Dysplasia is characterized by deranged cell growth of a speciﬁc

tissue that results in cells that vary in size, shape, and appear-

ance. Minor degrees of dysplasia are associated with chronic

irritation or inﬂammation. The pattern is most frequently en-

countered in metaplastic squamous epithelium of the respira-

tory tract and uterine cervix. Although dysplasia is abnormal, it

is adaptive in that it is potentially reversible after the irritating

cause has been removed. Dysplasia is strongly implicated as a

precursor of cancer. In cancers of the respiratory tract and the

uterine cervix, dysplastic changes have been found adjacent to

the foci of cancerous transformation. Through the use of the

Papanicolaou (Pap) smear, it has been documented that can-

cer of the uterine cervix develops in a series of incremental ep-

ithelial changes ranging from severe dysplasia to invasive can-

cer. However, dysplasia is an adaptive process and as such does

not necessarily lead to cancer. In many cases, the dysplastic

cells revert to their former structure and function.

Intracellular Accumulations

Intracellular accumulations represent buildup of substances

that cells cannot immediately use or dispose of. The substances

may accumulate in the cytoplasm (frequently in the lyso-

somes) or in the nucleus. In some cases the accumulation may

be an abnormal substance that the cell has produced, and in

other cases the cell may be storing exogenous materials or

products of pathologic processes occurring elsewhere in the

body. These substances can be grouped into three categories:

(1) normal body substances, such as lipids, proteins, carbohy-

drates, melanin, and bilirubin, that are present in abnormally

large amounts; (2) abnormal endogenous products, such as

those resulting from inborn errors of metabolism; and (3) ex-

ogenous products, such as environmental agents and pigments

that cannot be broken down by the cell. 2 These substances may

accumulate transiently or permanently, and they may be harm-

less or, in some cases, may be toxic.

The accumulation of normal cellular constituents occurs

when a substance is produced at a rate that exceeds its metab-

olism or removal. An example of this type of process is fatty

changes in the liver caused by intracellular accumulation of

triglycerides. Liver cells normally contain some fat, which is

Metaplasia

Metaplasia represents a reversible change in which one adult

cell type (epithelial or mesenchymal) is replaced by another

adult cell type. Metaplasia is thought to involve the repro-

gramming of undifferentiated stem cells that are present in the

tissue undergoing the metaplastic changes.

Chapter 2: Tissue Adaptation and Injury

either oxidized and used for energy or converted to triglyc-

erides. This fat is derived from free fatty acids released from adi-

pose tissue. Abnormal accumulation occurs when the delivery

of free fatty acids to the liver is increased, as in starvation and

diabetes mellitus, or when the intrahepatic metabolism of lipids

is disturbed, as in alcoholism.

Intracellular accumulation can result from genetic disorders

that disrupt the metabolism of selected substances. A normal

enzyme may be replaced with an abnormal one, resulting in

the formation of a substance that cannot be used or eliminated

from the cell, or an enzyme may be missing, so that an inter-

mediate product accumulates in the cell. For example, there are

at least 10 genetic disorders that affect glycogen metabolism,

most of which lead to the accumulation of intracellular glyco-

gen stores. In the most common form of this disorder, von

Gierke’s disease, large amounts of glycogen accumulate in

the liver and kidneys because of a deficiency of the enzyme

glucose-6-phosphatase. Without this enzyme, glycogen cannot

be broken down to form glucose. The disorder leads not only

to an accumulation of glycogen but to a reduction in blood

glucose levels. In Tay-Sachs disease, another genetic disorder,

abnormal glycolipids accumulate in the brain and other tissues,

causing motor and mental deterioration beginning at approxi-

mately 6 months of age, followed by death at 2 to 3 years of

age. In a similar manner, other enzyme defects lead to the

accumulation of other substances.

Pigments are colored substances that may accumulate in

cells. They can be endogenous ( i.e., arising from within the

body) or exogenous ( i.e., arising from outside the body).

Icterus, also called jaundice, is a yellow discoloration of tissue

caused by the retention of bilirubin, an endogenous bile pig-

ment. This condition may result from increased bilirubin pro-

duction from red blood cell destruction, obstruction of bile

passage into the intestine, or toxic diseases that affect the liver’s

ability to remove bilirubin from the blood. Lipofuscin is a

yellow-brown pigment that results from the accumulation of

the indigestible residues produced during normal turnover of

cell structures (Fig. 2-3). The accumulation of lipofuscin increases

with age and is sometimes referred to as the wear-and-tear pig-

ment. It is more common in heart, nerve, and liver cells than

other tissues and is seen most often in conditions associated

with atrophy of an organ.

One of the most common exogenous pigments is carbon in

the form of coal dust. In coal miners or persons exposed to

heavily polluted environments, the accumulation of carbon

dust blackens the lung tissue and may cause serious lung dis-

ease. The formation of a blue lead line along the margins of

the gum is one of the diagnostic features of lead poisoning.

Tattoos are the result of insoluble pigments introduced into

the skin, where they are engulfed by macrophages and persist

for a lifetime.

The signiﬁcance of intracellular accumulations depends on

the cause and severity of the condition. Many accumulations,

such as lipofuscin and mild fatty change, have no effect on cell

function. Some conditions, such as the hyperbilirubinemia

that causes jaundice, are reversible. Other disorders, such as

glycogen storage diseases, produce accumulations that result

in organ dysfunction and other alterations in physiologic

function.

In summary, cells adapt to changes in their environment

and in their work demands by changing their size, number,

and characteristics. These adaptive changes are consistent

with the needs of the cell and occur in response to an appro-

priate stimulus. The changes are usually reversed after the

stimulus has been withdrawn.

When confronted with a decrease in work demands or ad-

verse environmental conditions, cells atrophy or reduce their

size and revert to a lower and more efﬁcient level of function-

ing. Hypertrophy results from an increase in work demands

and is characterized by an increase in tissue size brought

about by an increase in cell size and functional components in

the cell. An increase in the number of cells in an organ or tis-

sue that is still capable of mitotic division is called hyperplasia .

Metaplasia occurs in response to chronic irritation and repre-

sents the substitution of cells of a type that are better able to

survive under circumstances in which a more fragile cell type

might succumb. Dysplasia is characterized by deranged cell

growth of a speciﬁc tissue that results in cells that vary in size,

shape, and appearance. It is a precursor of cancer.

Under some circumstances, cells may accumulate abnor-

mal amounts of various substances. If the accumulation re-

ﬂects a correctable systemic disorder, such as the hyperbiliru-

binemia that causes jaundice, the accumulation is reversible. If

the disorder cannot be corrected, as often occurs in many

inborn errors of metabolism, the cells become overloaded,

causing cell injury and death.

CELL INJURY AND DEATH

■ FIGURE 2-3 ■ Accumulation of intracellular lipofuscin. A photo-

micrograph of the liver of an 80-year-old man shows golden cyto-

plasmic granules, which represent lysosomal storage of lipofuscin.

(From Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 13].

Philadelphia: Lippincott Williams & Wilkins)

Cells can be injured in many ways. The extent to which any in-

jurious agent can cause cell injury and death depends in large

measure on the intensity and duration of the injury and the

type of cell that is involved. Cell injury is usually reversible to

a certain point, after which irreversible cell injury and death

occur. Whether a speciﬁc stress causes irreversible or reversible

cell injury depends on the severity of the insult and on vari-

Unit One: Mechanisms of Disease

KEY CONCEPTS

CELL INJURY

action on blood vessels and through reﬂex activity of the sym-

pathetic nervous system. The resultant decrease in blood ﬂow

may lead to hypoxic tissue injury, depending on the degree and

duration of cold exposure. Injury from freezing probably re-

sults from a combination of ice crystal formation and vaso-

constriction. The decreased blood ﬂow leads to capillary stasis

and arteriolar and capillary thrombosis.

■

Cells can be damaged in a number of ways, includ-

ing physical trauma, extremes of temperature, elec-

trical injury, exposure to damaging chemicals, radia-

tion damage, injury from biologic agents, and

nutritional factors.

Electrical Injuries. Electrical injuries can affect the body through

extensive tissue injury and disruption of neural and cardiac im-

pulses. The effect of electricity on the body is mainly deter-

mined by its voltage, the type of current ( i.e., direct or alternat-

ing), its amperage, the resistance of the intervening tissue, the

pathway of the current, and the duration of exposure. 2,4

Lightning and high-voltage wires that carry several thousand

volts produce the most severe damage. 2 Alternating current

(AC) is usually more dangerous than direct current (DC) be-

cause it causes violent muscle contractions, preventing the per-

son from releasing the electrical source and sometimes result-

ing in fractures and dislocations. In electrical injuries, the body

acts as a conductor of the electrical current. The current enters

the body from an electrical source, such as an exposed wire,

and passes through the body and exits to another conductor,

such as the moisture on the ground or a piece of metal the per-

son is holding. The pathway that a current takes is critical be-

cause the electrical energy disrupts impulses in excitable tis-

sues. Current ﬂow through the brain may interrupt impulses

from respiratory centers in the brain stem, and current ﬂow

through the chest may cause fatal cardiac arrhythmias.

The resistance to the flow of current in electrical circuits

transforms electrical energy into heat. This is why the ele-

ments in electrical heating devices are made of highly resistive

metals. Much of the tissue damage produced by electrical in-

juries is caused by heat production in tissues that have the

highest electrical resistance. Resistance to electrical current

varies from the greatest to the least in bone, fat, tendons, skin,

muscles, blood, and nerves. The most severe tissue injury usu-

ally occurs at the skin sites where the current enters and leaves

the body. After electricity has penetrated the skin, it passes

rapidly through the body along the lines of least resistance—

through body fluids and nerves. Degeneration of vessel walls

may occur, and thrombi may form as current flows along the

blood vessels. This can cause extensive muscle and deep tissue

injury. Thick, dry skin is more resistant to the flow of electric-

ity than thin, wet skin. It is generally believed that the greater

the skin resistance, the greater is the amount of local skin

burn, and the less the resistance, the greater are the deep and

systemic effects.

■

Most injurious agents exert their damaging effects

through uncontrolled free radical production, im-

paired oxygen delivery or utilization, or the destruc-

tive effects of uncontrolled intracellular calcium

release.

■

Cell injury can be reversible, allowing the cell to re-

cover, or it can be irreversible, causing cell death

and necrosis.

■

In contrast to necrosis, which results from tissue

injury, apoptosis is a normal physiologic process

designed to remove injured or worn-out cells.

ables such as blood supply, nutritional status, and regenerative

capacity. Cell injury and death are ongoing processes, and in

the healthy state, they are balanced by cell renewal.

Causes of Cell Injury

Cell damage can occur in many ways. For purposes of discus-

sion, the ways by which cells are injured have been grouped

into ﬁve categories: (1) injury from physical agents, (2) ra-

diation injury, (3) chemical injury, (4) injury from biologic

agents, and (5) injury from nutritional imbalances.

Injury From Physical Agents

Physical agents responsible for cell and tissue injury include

mechanical forces, extremes of temperature, and electrical

forces. They are common causes of injuries due to environ-

mental exposure, occupational and transportation accidents,

and physical violence and assault.

Mechanical Forces. Injury or trauma caused by mechanical

forces occurs as the result of body impact with another object.

The body or the object can be in motion or, as sometimes hap-

pens, both can be in motion at the time of impact. These types

of injuries split and tear tissue, fracture bones, injure blood ves-

sels, and disrupt blood ﬂow.

Radiation Injury

Electromagnetic radiation comprises a wide spectrum of wave-

propagated energy, ranging from ionizing gamma rays to radio-

frequency waves. A photon is a particle of radiation energy.

Radiation energy above the ultraviolet (UV) range is called

ionizing radiation because the photons have enough energy to

knock electrons off atoms and molecules. Nonionizing radiation

refers to radiation energy at frequencies below that of visible

light. UV radiation represents the portion of the spectrum of

electromagnetic radiation just above the visible range. It con-

tains increasingly energetic rays that are powerful enough to

disrupt intracellular bonds and cause sunburn.

C), such as occurs

with partial-thickness burns and severe heat stroke, causes cell

injury by inducing vascular injury, accelerating cell metabo-

lism, inactivating temperature-sensitive enzymes, and disrupt-

ing the cell membrane. With more intense heat, coagulation of

blood vessels and tissue proteins occurs. Exposure to cold in-

creases blood viscosity and induces vasoconstriction by direct

to 46

Extremes of Temperature. Extremes of heat and cold cause

damage to the cell, its organelles, and its enzyme systems.

Exposure to low-intensity heat (43

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