chapter1 cellular response and adaptation Flashcards

Question

The process in which pyknotic nucleus undergoes fragmentation.

Answer 1

Karyorrhexis

Answer 2

Liquefactive necrosis

Answer 3

Caseous ('cheeselike') Necrosis

Answer 4

Fibrinoid necrosis

Answer 5

Ischemic and Hypoxic Injury

Answer 6

Ischemic and Hypoxic Injury

Answer 7

its cause (etiology),
the mechanisms of its development (pathogenesis),
the biochemical and structural alterations induced in the cells and organs of the body (molecular and morphologic changes) ,
and the functional consequences of these changes (clinical manifestations

Answer 8

Adaptations are reversible functional and
structural responses to more severe physiologic stresses and some pathologic stimuli, during
which new but altered steady states are achieved, allowing the cell to survive and continue to
function ( Fig. 1-1 and Table 1-1 ).

Answer 9

increase in the size of cells (hypertrophy) and functional activity,
an increase in their number (hyperplasia),
a decrease in the size and metabolic activity of cells (atrophy),
or a change in the phenotype of cells (metaplasia).

Answer 10

CELLULAR ADAPTATIONS

• Hyperplasia, hypertrophy
• Atrophy
• Metaplasia

Answer 11

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• Acute reversible injury
Cellular swelling fatty change
• Irreversible injury ➙ cell death
Necrosis
Apoptosis

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Answer 12

INTRACELLULAR ACCUMULATIONS;
CALCIFICATION

Answer 13

CELLULAR AGING

Answer 14

If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or
stress, deprived of essential nutrients, or become compromised by mutations that affect
essential cellular constituents, a sequence of events follows that is termed cell injury

Answer 15

Adaptation,
reversible injury,
and cell death

For instance, in response to increased hemodynamic loads, the heart muscle becomes enlarged, a form of adaptation, and can even undergo injury. If the blood supply to the myocardium is compromised or inadequate, the muscle first suffers reversible injury, manifested by certain cytoplasmic changes (described later). Eventually, the cells suffer

irreversible injury and die

Answer 16

Cell death, the end result of progressive cell injury, is one of the most crucial events in the
evolution of disease in any tissue or organ.

It results from diverse causes, including ischemia
(reduced blood flow), infection, and toxins.

Cell death is also a normal and essential process in
embryogenesis, the development of organs, and the maintenance of homeostasis.

Answer 17

necrosis
and apoptosis

Answer 18

changes in cells and tissues other than typical adaptations, cell injury, and death (see Table 1-1 ).
Metabolic derangements in cells and sublethal, chronic injury may be associated with intracellular accumulations of a number of substances, including proteins, lipids, and carbohydrates.
Calcium is often deposited at sites of cell death, resulting in pathologic calcification.
Finally, the normal process of aging itself is accompanied by characteristic morphologic and functional changes in cells.

Answer 19

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HYPERTROPHY
HYPERPLASIA
ATROPHY
METAPLASIA

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Answer 20

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the
organ.

The hypertrophied organ has no new cells, just larger cells.

Answer 21

The increased size of the
cells is due to the synthesis of more structural components of the cells.

Cells capable of division
may respond to stress by undergoing both hyperplasia (described below) and hypertrophy,
whereas in nondividing cells (e.g., myocardial fibers) increased tissue mass is due to
hypertrophy. In many organs hypertrophy and hyperplasia may coexist and contribute to
increased size.

Answer 22

increased functional demand or
by stimulation by hormones and growth factors

Answer 23

hypertrophy.

Answer 24

increased workload

For example, the bulging muscles of bodybuilders engaged in
“pumping iron” result from an increase in size of the individual muscle fibers in response to
increased demand.

In the heart, the stimulus for hypertrophy is usually chronic hemodynamic
overload, resulting from either hypertension or faulty valves (see Fig. 1-2 ).

In both tissue types
the muscle cells synthesize more proteins and the number of myofilaments increases. This
increases the amount of force each myocyte can generate, and thus increases the strength
and work capacity of the muscle as a whole.

Answer 25

hypertrophy

Answer 26

Hypertrophy is the result of increased production of cellular proteins .

Much of our
understanding of hypertrophy is based on studies of the heart.

Answer 27

Hypertrophy can be induced by
the linked actions of :

mechanical sensors (that are triggered by increased work load),
growth factors (including TGF-β, insulin-like growth factor-1 [IGF-1], fibroblast growth factor), and
vasoactive agents (such as α-adrenergic agonists, endothelin-1, and angiotensin II).

Answer 28

phosphoinositide 3-kinase/Akt pathway (postulated to be most important in physiologic, e.g., exercise-induced, hypertrophy)
and signaling downstream of G protein-coupled receptors (induced by many growth factors and vasoactive agents, and thought to be more important in pathologic hypertrophy).

Answer 29

phosphoinositide 3-kinase/Akt pathway (postulated to be most
important in physiologic, e.g., exercise-induced, hypertrophy)

Answer 30

signaling downstream of G
protein-coupled receptors (induced by many growth factors and vasoactive agents, and thought
to be more important in pathologic hypertrophy).

Answer 31

atrial natriuretic
factor (ANF)

Cardiac hypertrophy, however, is associated with reinduction of ANF
gene expression. ANF is a peptide hormone that causes salt secretion by the kidney, decreases
blood volume and pressure, and therefore serves to reduce hemodynamic load.

Answer 32

Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in
increased mass of the organ or tissue.

Although hyperplasia and hypertrophy are distinct
processes, frequently they occur together, and they may be triggered by the same external
stimulus.

Answer 33

(1) hormonal hyperplasia, which increases the
functional capacity of a tissue when needed,

and (2) compensatory hyperplasia, which
increases tissue mass after damage or partial resection.

Answer 34

proliferation of the glandular epithelium of the female breast at puberty and during
pregnancy, usually accompanied by enlargement (hypertrophy) of the glandular epithelial cells.

Answer 35

capacity of the liver to regenerate.

As
punishment for having stolen the secret of fire from the gods, Prometheus was chained to a
mountain, and his liver was devoured daily by an eagle, only to regenerate anew every
night. [1] In individuals who donate one lobe of the liver for transplantation, the remaining cells
proliferate so that the organ soon grows back to its original size. Experimental models of partial
hepatectomy have been very useful for defining the mechanisms that stimulate regeneration of
the liver

Answer 36

excesses of hormones or growth factors
acting on target cells.

Endometrial hyperplasia is an example of abnormal hormone-induced
hyperplasia. Normally, after a menstrual period there is a rapid burst of proliferative activity in
the epithelium that is stimulated by pituitary hormones and ovarian estrogen. It is brought to a

Answer 37

Hyperplasia

Answer 38

Mechanisms of Hyperplasia
Hyperplasia is the result of growth factor–driven proliferation of mature cells and, in some
cases, by increased output of new cells from tissue stem cells.

For instance, after partial
hepatectomy growth factors are produced in the liver that engage receptors on the surviving
cells and activate signaling pathways that stimulate cell proliferation. But if the proliferative
capacity of the liver cells is compromised, as in some forms of hepatitis causing cell injury,
hepatocytes can instead regenerate from intrahepatic stem cells.

Answer 39

Atrophy is reduced size of an organ or tissue resulting from a decrease in cell size and
number .

Atrophy can be physiologic or pathologic.

Answer 40

normal development.

Some embryonic structures, such as the notochord and thyroglossal duct,
undergo atrophy during fetal development.

The uterus decreases in size shortly after
parturition, and this is a form of physiologic atrophy.

Answer 41

Decreased workload (atrophy of disuse)
Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation

The fundamental cellular changes associated with atrophy are identical in all of these settings.

Answer 42

The initial response is a decrease in cell size and organelles, which may reduce the metabolic
needs of the cell sufficiently to permit its survival.

In atrophic muscle, the cells contain fewer
mitochondria and myofilaments and a reduced amount of rough ER.

By bringing into balance
the cell's metabolic demand and the lower levels of blood supply, nutrition, or trophic
stimulation, a new equilibrium is achieved. Early in the process atrophic cells may have
diminished function, but they are not dead.

However, atrophy caused by gradually reduced
blood supply may progress to the point at which cells are irreversibly injured and die, often by apoptosis. Cell death by apoptosis also contributes to the atrophy of endocrine organs after
hormone withdrawal.

Answer 43

Atrophy results from decreased protein synthesis and increased protein degradation in cells .

Protein synthesis decreases because of reduced metabolic activity.

The degradation of cellular
proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse
may activate ubiquitin ligases, which attach the small peptide ubiquitin to cellular proteins and
target these proteins for degradation in proteasomes. [3,] [9,] [10] This pathway is also thought
to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions,
including cancer cachexia

Answer 44

autophagy,

Answer 45

Autophagy (“self eating”) is the process in
which the starved cell eats its own components in an attempt to find nutrients and survive.
Autophagic vacuoles are membrane-bound vacuoles that contain fragments of cell
components.

The vacuoles ultimately fuse with lysosomes, and their contents are digested by
lysosomal enzymes.

Some of the cell debris within the autophagic vacuoles may resist digestion
and persist as membrane-bound residual bodies that may remain as a sarcophagus in the
cytoplasm.

An example of such residual bodies is the lipofuscin granules, discussed later in the
chapter. When present in sufficient amounts, they impart a brown discoloration to the tissue
(brown atrophy). Autophagy is associated with various types of cell injury, and we will discuss it
in more detail later.

Answer 46

Metaplasia is a reversible change in which one differentiated cell type (epithelial or
mesenchymal) is replaced by another cell type.

It may represent an adaptive substitution of
cells that are sensitive to stress by cell types better able to withstand the adverse environment

Answer 47

The most common epithelial metaplasia is columnar to squamous ( Fig. 1-6 ), as occurs in the
respiratory tract in response to chronic irritation.

In the habitual cigarette smoker, the normal
ciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratified
squamous epithelial cells.

Stones in the excretory ducts of the salivary glands, pancreas, or bile
ducts may also cause replacement of the normal secretory columnar epithelium by stratified
squamous epithelium.

A deficiency of vitamin A (retinoic acid) induces squamous metaplasia in
the respiratory epithelium ( Chapter 9 ).

In all these instances the more rugged stratified
squamous epithelium is able to survive under circumstances in which the more fragile
specialized columnar epithelium might have succumbed. However, the change to metaplastic
squamous cells comes with a price. In the respiratory tract, for example, although the epithelial
lining becomes tough, important mechanisms of protection against infection—mucus secretion
and the ciliary action of the columnar epithelium—are lost. Thus, epithelial metaplasia is a
double-edged sword and, in most circumstances, represents an undesirable change. Moreover,
the influences that predispose to metaplasia, if persistent, may initiate malignant transformation
in metaplastic epithelium. Thus, a common form of cancer in the respiratory tract is composed
of squamous cells, which arise in areas of metaplasia of the normal columnar epithelium into
squamous epithelium

Answer 48

Barrett esophagus

Answer 49

Connective tissue is the formation of cartilage, bone, or adipose tissue

(mesenchymal tissues) in tissues that normally do not contain these elements.

For example,
bone formation in muscle, designated myositis ossificans, occasionally occurs after
intramuscular hemorrhage. This type of metaplasia is less clearly seen as an adaptive
response, and may be a result of cell or tissue injury.

Answer 50

Metaplasia does not result from a change in the phenotype of an already differentiated cell
type; instead it is the result of a reprogramming of stem cells that are known to exist in normal
tissues, or of undifferentiated mesenchymal cells present in connective tissue.

In a metaplastic
change, these precursor cells differentiate along a new pathway.

The differentiation of stem
cells to a particular lineage is brought about by signals generated by cytokines, growth factors,
and extracellular matrix components in the cells' environment. [11,] [12]

These external stimuli
promote the expression of genes that drive cells toward a specific differentiation pathway.

In the
case of vitamin A deficiency or excess, it is known that retinoic acid regulates gene transcription
directly through nuclear retinoid receptors ( Chapter 9 ), which can influence the differentiation
of progenitors derived from tissue stem cells. How other external stimuli cause metaplasia is
unknown, but it is clear that they too somehow alter the activity of transcription factors that
regulate differentiation.

Answer 51

reduced oxidative phosphorylation with resultant depletion of
energy stores in the form of adenosine triphosphate (ATP), and cellular swelling caused
by changes in ion concentrations and water influx.

Answer 52

necrosis and
apoptosis

Answer 53

autophagy.

Answer 54

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Oxygen Deprivation.
Physical Agents.
Chemical Agents and Drugs.
Infectious Agents.
Immunologic Reactions.
Genetic Derangements.
Nutritional Imbalances.

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Answer 55

Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative
respiration.

Hypoxia is an extremely important and common cause of cell injury and cell death.

Answer 56

reduced blood flow (celled ischemia),
inadequate oxygenation of the blood due to cardiorespiratory failure,
and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxide poisoning (producing a stable carbon monoxyhemoglobin that
blocks oxygen carriage) or after severe blood loss.

Depending on the severity of the hypoxic

state, cells may adapt, undergo injury, or die. For example, if an artery is narrowed, the tissue

supplied by that vessel may initially shrink in size (atrophy), whereas more severe or sudden

hypoxia induces injury and cell death.

Answer 57

Reversible injury is characterized by:

generalized swelling of the cell and its
organelles;
blebbing of the plasma membrane;
detachment of ribosomes from the ER;
and clumping of nuclear chromatin.

Answer 58

decreased generation of ATP,
loss of cell membrane integrity,
defects in protein synthesis,
cytoskeletal damage,
and DNA damage.

Within limits, the cell can repair these derangements and, if the

injurious stimulus abates, will return to normalcy.

Answer 59

necrosis

Necrosis is the principal outcome in many

commonly encountered injuries, such as those following ischemia, exposure to toxins, various

infections, and trauma.

Answer 60

Cell size Enlarged (swelling)
Nucleus: Pyknosis ➙ karyorrhexis
➙ karyolysis
Cellular contents: Enzymatic digestion; may
leak out of cell
Adjacent inflammation :Frequent
Physiologic or pathologic role :Invariably pathologic
(culmination of irreversible cell injury)

FIPES

Answer 61

Cell size --Reduced (shrinkage)
Nucleus -- Fragmentation into nucleosome-size fragments
Plasma membrane - Intact; altered structure, especially orientation of lipids
Cellular contents -Intact; may be released in apoptotic bodies
Adjacent inflammation - No
Physiologic or pathologic role - Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury,
especially DNA damage

FINS

Answer 62

cellular
swelling and fatty change

Answer 63

Cellular swelling

Answer 64

Fatty change

Answer 65

__________

Answer 66

1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli
2. Mitochondrial changes, including swelling and the appearance of small amorphous densities
3. Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures
may be present (see later)
4. Nuclear alterations, with disaggregation of granular and fibrillar elements.

Answer 67

denaturation of intracellular proteins
and enzymatic digestion of the lethally injured cell (cells placed immediately in fixative are dead
but not necrotic).

Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue.

The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are called in as part of the inflammatory reaction.
Digestion of cellular contents and the host response may take hours to develop, and so there
would be no detectable changes in cells if, for example, a myocardial infarct caused sudden
death. The only circumstantial evidence might be occlusion of a coronary artery. The earliest histologic evidence of myocardial necrosis does not become apparent until 4 to 12 hours later.
However, because of the loss of plasma membrane integrity, cardiac-specific enzymes and
proteins are rapidly released from necrotic muscle and can be detected in the blood as early as

2 hours after myocardial cell necrosis.

Answer 68

Necrotic cells show increased eosinophilia in hematoxylin and eosin (H & E)
stains, attributable in part to the loss of cytoplasmic RNA (which binds the blue dye,
hematoxylin) and in part to denatured cytoplasmic proteins (which bind the red dye, eosin).
The necrotic cell may have a more glassy homogeneous appearance than do normal cells, mainly as a result of the loss of glycogen particles ( Fig. 1-9C ).

When enzymes have
digested the cytoplasmic organelles, the cytoplasm becomes vacuolated and appears motheaten.
Dead cells may be replaced by large, whorled phospholipid masses called myelin
figures that are derived from damaged cell membranes.

These phospholipid precipitates
are then either phagocytosed by other cells or further degraded into fatty acids; calcification
of such fatty acid residues results in the generation of calcium soaps.

Thus, the dead cells
may ultimately become calcified.

By electron microscopy, necrotic cells are characterized by
discontinuities in plasma and organelle membranes, marked dilation of mitochondria with the
appearance of large amorphous densities, intracytoplasmic myelin figures, amorphous
debris, and aggregates of fluffy material probably representing denatured protein (see Fig.
1-10C ).

Answer 69

The basophilia of the chromatin may fade (karyolysis), a change that
presumably reflects loss of DNA because of enzymatic degradation by endonucleases.

Answer 70

A
second pattern (which is also seen in apoptotic cell death) is pyknosis, characterized by
nuclear shrinkage and increased basophilia.

Here the chromatin condenses into a solid,
shrunken basophilic mass.

Answer 71

In the third pattern, known as karyorrhexis, the pyknotic nucleus
undergoes fragmentation.

With the passage of time (a day or two), the nucleus in the
necrotic cell totally disappears.

Answer 72

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Coagulative
Liquefactive
Gangenous
Casseous
Fatty
Fibrinoid

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Answer 73

Coagulative necrosis is a form of necrosis in which the architecture of dead
tissues is preserved for a span of at least some days ( Fig. 1-11 ). The affected tissues exhibit
a firm texture.

Presumably, the injury denatures not only structural proteins but also enzymes
and so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. Ultimately the necrotic cells are removed by phagocytosis of the
cellular debris by infiltrating leukocytes and by digestion of the dead cells by the action of
lysosomal enzymes of the leukocytes.

Ischemia caused by obstruction in a vessel may lead to
coagulative necrosis of the supplied tissue in all organs except the brain.

Answer 74

A localized area of
| coagulative necrosis is called an infarct.

Answer 75

Liquefactive necrosis, in contrast to coagulative necrosis, is characterized by digestion of
the dead cells, resulting in transformation of the tissue into a liquid viscous mass.

It is seen in
focal bacterial or, occasionally, fungal infections, because microbes stimulate the
accumulation of leukocytes and the liberation of enzymes from these cells.

Answer 76

The necrotic
material is frequently creamy yellow because of the presence of dead leukocytes and is called
pus.

For unknown reasons, hypoxic death of cells within the central nervous system often
manifests as liquefactive necrosis

Answer 77

Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly used
in clinical practice.

It is usually applied to a limb, generally the lower leg, that has lost its blood
supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue
planes.

When bacterial infection is superimposed there is more liquefactive necrosis because
of the actions of degradative enzymes in the bacteria and the attracted leukocytes (giving rise
to so-called wet gangrene).

Answer 78

Caseous necrosis is encountered most often in foci of tuberculous infection ( Chapter 8 ).
The term “caseous” (cheeselike) is derived from the friable white appearance of the area of
necrosis ( Fig. 1-13 ).

Answer 79

On microscopic examination, the necrotic area appears as a collection
of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive
inflammatory border; this appearance is characteristic of a focus of inflammation known as a
granuloma ( Chapter 2 ).

Answer 80

On microscopic examination, the necrotic area appears as a collection
of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive
inflammatory border; this appearance is characteristic of a focus of inflammation known as a
granuloma ( Chapter 2 ).

Answer 81

is a term that is well fixed in medical parlance but does not in reality denote a
specific pattern of necrosis.

Rather, it refers to focal areas of fat destruction, typically
resulting from release of activated pancreatic lipases into the substance of the pancreas and
the peritoneal cavity.

This occurs in the calamitous abdominal emergency known as acute pancreatitis ( Chapter 19 ).

In this disorder pancreatic enzymes leak out of acinar cells and
liquefy the membranes of fat cells in the peritoneum. The released lipases split the
triglyceride esters contained within fat cells.

Answer 82

The fatty acids, so derived, combine with calcium
to produce grossly visible chalky-white areas (fat saponification), which enable the surgeon
and the pathologist to identify the lesions ( Fig. 1-14 ).

Answer 83

On histologic examination the necrosis
takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium
deposits, surrounded by an inflammatory reaction.

Answer 84

Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involving
blood vessels.

This pattern of necrosis typically occurs when complexes of antigens and
antibodies are deposited in the walls of arteries.

Deposits of these “immune complexes,”
together with fibrin that has leaked out of vessels, result in a bright pink and amorphous
appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists ( Fig. 1-15 ). The
immunologically mediated vasculitis syndromes in which this type of necrosis is seen are
described in Chapter 6 .

Answer 85

Ultimately, in the living patient most necrotic cells and their contents disappear by phagocytosis
of the debris and enzymatic digestion by leukocytes. If necrotic cells and cellular debris are not
promptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals and
to become calcified. This phenomenon, called dystrophic calcification, is considered later in the
chapter.

Answer 86

If necrotic cells and cellular debris are not
promptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals and
to become calcified. This phenomenon, called dystrophic calcification, is considered later in the
chapter.

Answer 87

The cellular response to injurious stimuli depends on the nature of the injury, its
duration, and its severity.
The consequences of cell injury depend on the type, state, and adaptability of the
injured cell.
Cell injury results from different biochemical mechanisms acting on several essential
cellular components
Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms
that damage cells.

Answer 88

DEPLETION OF ATP
MITOCHONDRIAL DAMAGE
INFLUX OF CALCIUM AND LOSS OF CALCIUM HOMEOSTASIS
ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)
DEFECTS IN MEMBRANE PERMEABILITY
DAMAGE TO DNA AND PROTEINS

Answer 89

reduced supply of oxygen and nutrients,
mitochondrial damage, and the actions of sometoxins (e.g., cyanide).

Tissues with a greater glycolytic capacity (e.g., the liver) are able to
survive loss of oxygen and decreased oxidative phosphorylation better than are tissues with
limited capacity for glycolysis (e.g., the brain).

Answer 90

oxidative phosphorylation of adenosine diphosphate, in a reaction that results in reduction of oxygen by the electron transfer system of mitochondria.
The second is the glycolytic pathway, which can generate ATP in the absence of oxygen using glucose derived either from body fluids or from the hydrolysis of glycogen

Answer 91

The activity of the plasma membrane energy-dependent sodium pump (ouabainsensitive
Na + , K + -ATPase) is reduced.
Cellular energy metabolism is altered
Failure of the Ca 2+ pump leads to influx of Ca 2+ , with damaging effects on numerous
cellular components, described below.
With prolonged or worsening depletion of ATP, structural disruption of the protein synthetic apparatus occurs, manifested as detachment of ribosomes from the rough ER and dissociation of polysomes, with a consequent reduction in protein synthesis.
In cells deprived of oxygen or glucose, proteins may become misfolded, and misfolded
proteins trigger a cellular reaction called the unfolded protein response that may
culminate in cell injury and even death.
Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.

Answer 92

Failure of this active transport system causes
sodium to enter and accumulate inside cells and potassium to diffuse out. The net gain
of solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation of
the ER.

Answer 93

If the supply of oxygen to cells is reduced, as in
ischemia, oxidative phosphorylation ceases, resulting in a decrease in cellular ATP and
associated increase in adenosine monophosphate. These changes stimulate
phosphofructokinase and phosphorylase activities, leading to an increased rate of
anaerobic glycolysis, which is designed to maintain the cell's energy sources by
generating ATP through metabolism of glucose derived from glycogen.

As a
consequence glycogen stores are rapidly depleted . Anaerobic glycolysis results in the
accumulation of lactic acid and inorganic phosphates from the hydrolysis of phosphate
esters.

This reduces the intracellular pH, resulting in decreased activity of many cellular
enzymes

Answer 94

unfolded protein

Answer 95

increases of cytosolic Ca 2+ ,
reactive oxygen species (discussed below),
and oxygen deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins.
In addition, mutations in mitochondrial genes are the cause of some inherited diseases

Answer 96

Mitochondrial damage often results in the formation of a high-conductance channel in
the mitochondrial membrane, called the mitochondrial permeability transition pore
The mitochondria also sequester between their outer and inner membranes several
proteins that are capable of activating apoptotic pathways; these include cytochrome c
and proteins that indirectly activate apoptosisinducing enzymes called caspases.

Answer 97

necrosis of the cell

Note: One of the structural components of
the mitochondrial permeability transition pore is the protein cyclophilin D, which is a
target of the immunosuppressive drug cyclosporine (used to prevent graft rejection). In
some experimental models of ischemia, cyclosporine reduces injury by preventing
opening of the mitochondrial permeability transition pore—an interesting example of
molecularly targeted therapy for cell injury (although its clinical value is not established).

Answer 98

cytochrome c and proteins that indirectly activate apoptosisinducing enzymes called caspases.
Increased permeability of the outer mitochondrial membrane may result in leakage of
these proteins into the cytosol, and death by apoptosis

Answer 99

release of Ca 2+ from intracellular stores

Answer 100

The accumulation of Ca 2+ in mitochondria results in opening of the mitochondrial
permeability transition pore and, as described above, failure of ATP generation.
Increased cytosolic Ca 2+ activates a number of enzymes, with potentially deleterious
cellular effects. These enzymes include phospholipases (which cause membrane
damage), proteases (which break down both membrane and cytoskeletal proteins),
endonucleases (which are responsible for DNA and chromatin fragmentation), and
ATPases (thereby hastening ATP depletion).
Increased intracellular Ca 2+ levels also result in the induction of apoptosis, by direct
activation of caspases and by increasing mitochondrial permeability. [

Answer 101

chemical and radiation injury,
ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellular aging,
and microbial killing by phagocytes.

Answer 102

Free radicals are chemical species that have a
single unpaired electron in an outer orbit. Energy created by this unstable configuration is
released through reactions with adjacent molecules, such as inorganic or organic chemicals
—proteins, lipids, carbohydrates, nucleic acids—many of which are key components of cell
membranes and nuclei.

Moreover, free radicals initiate autocatalytic reactions, whereby
molecules with which they react are themselves converted into free radicals, thus propagating
the chain of damage.

Answer 103

are a type of oxygen-derived free radical
whose role in cell injury is well established.

ROS are produced normally in cells during
mitochondrial respiration and energy generation, but they are degraded and removed by
cellular defense systems.

Thus, cells are able to maintain a steady state in which free radicals may be present transiently at low concentrations but do not cause damage.

Answer 104

When the
production of ROS increases or the scavenging systems are ineffective, the result is an excess
of these free radicals, leading to a condition called oxidative stress.

Oxidative stress has been
implicated in a wide variety of pathologic processes, including cell injury, cancer, aging, and some degenerative diseases such as Alzheimer disease.

ROS are also produced in large
amounts by leukocytes, particularly neutrophils and macrophages, as mediators for destroying
microbes, dead tissue, and other unwanted substances. Therefore, injury caused by these
reactive compounds often accompanies inflammatory reactions, during which leukocytes are
recruited and activated

Answer 105

The reduction-oxidation reactions that occur during normal metabolic processes
Absorption of radiant energy
Rapid bursts of ROS are produced in activated leukocytes during inflammation
Enzymatic metabolism of exogenous chemicals or drugs can generate free radicals that are not ROS but have similar effects
Transition metals such as iron and copper donate or accept free electrons during
intracellular reactions and catalyze free radical formation, as in the Fenton reaction
(H2O2 + Fe 2+ ➙ Fe 3+ + OH + OH-).
are not ROS but have similar effects

Answer 106

superoxide anion
hydrogen peroxide
hydroxyl ions

Answer 107

Antioxidants
iron and copper can catalyze the formation of ROS
enzymes acts as free radical–scavenging systems and breaks down H2O2 These enzymes are lo-cated near the sites of generation of the oxidants

Answer 108

```

Catalase,
Superoxide dismutases (SODs)
Glutathione peroxidase

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Answer 109

, present in peroxisomes, decomposes H2O2 (2H2O2 ➙ O2 + 2H2O).

Answer 110

are found in many cell types and convert O2 to H2O2 (2 + 2H ➙ H2O2 + O2).

This
group includes both manganese–SOD, which is localized in mitochondria, andcopper-zinc–SOD, which is found in the cytosol.

Answer 111

also protects against injury by catalyzing free radical
breakdown (H2O2 + 2GSH ➙ GSSG [glutathione homodimer] + 2H2O, or 2OH +
2GSH ➙ GSSG + 2H2O). The intracellular ratio of oxidized glutathione (GSSG)
to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and
is an important indicator of the cell's ability to detoxify ROS.

Answer 112

Lipid peroxidation in membranes
Oxidative modification of proteins
Lesions in DNA

Answer 113

Reactive oxygen species
Decreased phospholipid synthesis
Increased phospholipid breakdown
Cytoskeletal abnormalities

Answer 114

. Oxygen free radicals cause injury to cell membranes by lipid
peroxidation, discussed earlier

Answer 115

The production of phospholipids in cells may be
reduced as a consequence of defective mitochondrial function or hypoxia, both of which
decrease the production of ATP and thus affect energy-dependent enzymatic activities.
The decreased phospholipid synthesis may affect all cellular membranes, including the
mitochondria themselves.

Answer 116

Severe cell injury is associated with increased degradation of membrane phospholipids, probably due to activation of endogenous phospholipases by increased levels of cytosolic and mitochondrial Ca 2+ . [19]
Phospholipid breakdown leads to the accumulation of lipid breakdown products,
including unesterified free fatty acids, acyl carnitine, and lysophospholipids, which have
a detergent effect on membranes. They may also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes in
permeability and electrophysiologic alterations.

Answer 117

Cytoskeletal abnormalities.

Cytoskeletal filaments serve as anchors connecting the
plasma membrane to the cell interior. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton. In the presence of cell
swelling, this damage results, particularly in myocardial cells, in detachment of the cell membrane from the cytoskeleton, rendering it susceptible to stretching and rupture.

Answer 118

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Mitochondrial membrane damage.
Plasma membrane damage
Injury to lysosomal membranes

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Answer 119

mitochondrial membrane,
the plasma membrane,
and membranes of lysosomes.

Answer 120

As discussed above, damage to mitochondrial
membranes results in opening of the mitochondrial permeability transition pore leading
to decreased ATP, and release of proteins that trigger apoptotic death.

Answer 121

Plasma membrane damage results in loss of osmotic
balance and influx of fluids and ions, as well as loss of cellular contents. The cells may
also leak metabolites that are vital for the reconstitution of ATP, thus further depleting
energy stores.

Answer 122

results in leakage of their enzymes into the cytoplasm
and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g.,
ischemic) cell. Lysosomes contain RNases, DNases, proteases, phosphatases,
glucosidases, and cathepsins. Activation of these enzymes leads to enzymatic digestion
of proteins, RNA, DNA, and glycogen, and the cells die by necrosis

Answer 123

the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury,
and profound disturbances in membrane function.

Answer 124

SCHEMIC AND HYPOXIC INJURY

Answer 125

As the oxygen tension within the cell decreases, there is loss of oxidative phosphorylation and decreased generation of ATP.
The depletion of ATP results in failure of the sodium pump, with loss of potassium, influx of sodium and water, and cell swelling.
There is also influx of Ca 2+ , with its many deleterious effects.
There is progressive loss of glycogen and decreased protein synthesis. The functional consequences may be severe at this stage. For instance, heart muscle ceases to contract within 60 seconds of coronary occlusion. Note, however, that loss of contractility does not mean
cell death. If hypoxia continues, worsening ATP depletion causes further deterioration.
The cytoskeleton disperses, resulting in the loss of ultrastructural features such as microvilli and the
formation of “blebs” at the cell surface (see Figs. 1-9 and 1-10 )
. “Myelin figures,” derived from degenerating cellular membranes, may be seen within the cytoplasm (in autophagic vacuoles) or extracellularly. They are thought to result from unmasking of phosphatide groups, promoting the uptake and intercalation of water between the lamellar stacks of membranes.
At this time the mitochondria are usually swollen, as a result of loss of volume control in these organelles; the
ER remains dilated; and the entire cell is markedly swollen, with increased concentrations of
water, sodium, and chloride and a decreased concentration of potassium.
If oxygen is restored, all of these disturbances are reversible.

Answer 126

“Myelin figures,” derived from degenerating cellular membranes, may be seen within the cytoplasm (in autophagic vacuoles) or extracellularly. They are thought to result from unmasking of phosphatide groups, promoting the uptake and intercalation of water between the lamellar stacks of membranes.

Answer 127

severe swelling of mitochondria,
extensive damage to plasma membranes (giving rise to myelin figures) and swelling of lysosomes (see Fig. 1-10C ).
Large, flocculent, amorphous densities develop in the mitochondrial matrix. In the myocardium, these are
indications of irreversible injury and can be seen as early as 30 to 40 minutes after ischemia.
Massive influx of calcium into the cell then occurs, particularly if the ischemic zone is reperfused. Death is mainly by necrosis, but apoptosis also contributes; the apoptotic pathway is probably activated by release of pro-apoptotic molecules from leaky mitochondria.
The cell's components are progressively degraded, and there is widespread leakage of cellular enzymes into the extracellular space and, conversely, entry of extracellular macromolecules from the interstitial space into the dying cells. Finally, the dead cells may become replaced by large masses composed of phospholipids in the form of myelin figures.
These are then either phagocytosed by leukocytes or degraded further into fatty acids. Calcification of such fatty acid residues may occur, with the formation of calcium soaps.

Answer 128

hypoxia-inducible factor-1,

Answer 129

The
strategy that is perhaps the most useful in ischemic (and traumatic) brain and spinal cord injury is the transient induction of hypothermia (reducing the core body temperature to 92°F).

This treatment reduces the metabolic demands of the stressed cells, decreases cell swelling, suppresses the formation of free radicals, and inhibits the host inflammatory response. All of
these may contribute to decreased cell and tissue injury

Answer 130

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly
injured.

However, under certain circumstances, when blood flow is restored to cells that have been ischemic but have not died, injury is paradoxically exacerbated and proceeds at an
accelerated pace.

As a consequence, reperfused tissues may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia. This process, called ischemiareperfusion injury, is clinically important because it contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow ( Chapters 12

and 28 .

Answer 131

New damage may be initiated during reoxygenation by increased generation of reactive
oxygen and nitrogen species from parenchymal and endothelial cells and from
infiltrating leukocytes. [
Ischemic injury is associated with inflammation as a result of the production of cytokines
and increased expression of adhesion molecules by hypoxic parenchymal and
endothelial cells, which recruit circulating neutrophils to reperfused tissue
Activation of the complement system may contribute to ischemia-reperfusion injury. [

Answer 132

Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes that degrade the cells' own nuclear DNA and
nuclear and cytoplasmic proteins.

Answer 133

Apoptotic cells break up into fragments, called apoptotic
bodies, which contain portions of the cytoplasm and nucleus. The plasma membrane of the
apoptotic cell and bodies remains intact, but its structure is altered in such a way that these
become “tasty” targets for phagocytes.

The dead cell and its fragments are rapidly devoured,
before the contents have leaked out, and therefore cell death by this pathway does not elicit an
inflammatory reaction in the host.

The process was recognized in 1972 by the distinctive
morphologic appearance of membrane-bound fragments derived from cells, and named after
the Greek designation for “falling off.” [37]

Answer 134

development and throughout adulthood,

Answer 135

The programmed destruction of cells during embryogenesis , including implantation,
organogenesis, developmental involution, and metamorphosis.
Involution of hormone-dependent tissues upon hormone withdrawal , such as
endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in
menopause, the regression of the lactating breast after weaning, and prostatic atrophy
after castration.
Cell loss in proliferating cell populations , such as immature lymphocytes in the bone
marrow and thymus that fail to express useful antigen receptors ( Chapter 6 ), B lymphocytes in germinal centers, and epithelial cells in intestinal crypts, so as to maintain a constant number (homeostasis).
Elimination of potentially harmful self-reactive lymphocytes , either before or after they have completed their maturation, so as to prevent reactions against one's own tissues
Death of host cells that have served their useful purpose, such as neutrophils in an
acute inflammatory response, and lymphocytes at the end of an immune response

Answer 136

DNA damage
Accumulation of misfolded proteins
Cell death in certain infections, particularly viral infections
Pathologic atrophy in parenchymal organs after duct obstruction , such as occurs in the
pancreas, parotid gland, and kidney

Answer 137

Cell shrinkage
Chromatin condensation
Formation of cytoplasmic blebs and apoptotic bodies
Phagocytosis of apoptotic cells or cell bodies, usually by macrophages

Plasma membranes are thought to remain intact during apoptosis, until the last stages, when they become permeable to normally retained solutes. This classical description is accurate with respect to apoptosis during physiologic conditions such as embryogenesis and deletion pathway when there is advanced ATP depletion and membrane damage.
of immune cells. However, forms of cell death with features of necrosis as well as of apoptosis are not uncommon after many injurious stimuli. [39]

Under such conditions the severity rather than the nature of the stimulus determines the pathway of cell death, necrosis being the majorpathway when there is advanced ATP depletion and membrane damage.

Answer 138

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On histologic examination, in tissues stained with hematoxylin and eosin, the apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with fragments of dense
nuclear chromatin ( Fig. 1-22A ).

```

Because the cell shrinkage and formation of apoptotic
bodies are rapid and the pieces are quickly phagocytosed, considerable apoptosis may occur in tissues before it becomes apparent in histologic sections.

In addition, apoptosis—in contrast to necrosis—does not elicit inflammation, making it more difficult to detect
histologically.

Answer 139

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Activation of Caspases
DNA and Protein Breakdown.
Membrane Alterations and Recognition by Phagocytes.

```

Answer 140

A specific feature of apoptosis is the activation of several members of a family of cysteine proteases named caspases. [40]

The term caspase is based on two properties of this family of
enzymes: the “c” refers to a cysteine protease (i.e., an enzyme with cysteine in its active site), and “aspase” refers to the unique ability of these enzymes to cleave after aspartic acid residues.

Answer 141

initiator and executioner

Answer 142

caspase-8 and caspase-9

Answer 143

caspase-3 and caspase-6

Answer 144

the movement of some phospholipids
(notably phosphatidylserine) from the inner leaflet to the outer leaflet of the membrane, where
they are recognized by a number of receptors on phagocytes. These lipids are also detectable by binding of a protein called annexin V; thus, annexin V staining is commonly used to identify
apoptotic cells. The clearance of apoptotic cells by phagocytes is described later.

Answer 145

The Intrinsic (Mitochondrial) Pathway of Apoptosis
The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis
The Execution Phase of Apoptosis
Removal of Dead Cells

Answer 146

initiation phase, during which some caspases become catalytically active,
and an execution phase, during which other caspases trigger the degradation of critical cellular components

Answer 147

the intrinsic, or mitochondrial, pathway,
and the extrinsic, or death receptor–initiated, pathway

Answer 148

The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells, and its role in a variety of physiologic and pathologic processes is well established.
This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm ( Fig. 1-25 ). [42]
Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but
some of the same proteins, when released into the cytoplasm (an indication that the cell is not
healthy), initiate the suicide program of apoptosis.

Answer 149

There are more than
20 members of the Bcl family, and most of them function to regulate apoptosis.

The release of these mitochondrial proteins
is controlled by a finely orchestrated balance between pro- and anti-apoptotic members of the
Bcl family of proteins. [43] This family is named after Bcl-2, which was identified as an oncogene
in a B-cell lymphoma and is homologous to the C. elegans protein Ced-9. There are more than
20 members of the Bcl family, and most of them function to regulate apoptosis.

Growth factors
and other survival signals stimulate production of anti-apoptotic proteins, the main ones being
Bcl-2, Bcl-x, and Mcl-1.

These proteins normally reside in the cytoplasm and in mitochondrial
membranes, where they control mitochondrial permeability and prevent leakage of
mitochondrial proteins that have the ability to trigger cell death

Answer 150

Bim, Bid, and Bad

Answer 151

Bax and Bak,

Answer 152

The net result of Bax-Bak activation coupled with loss
of the protective functions of the anti-apoptotic Bcl family members is the release into the cytoplasm of several mitochondrial proteins that can activate the caspase cascade (

Fig. 1-25B
). One of these proteins is cytochrome c, well known for its role in mitochondrial respiration.

Once released into the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosisactivating factor-1, homologous to Ced-4 in C.elegans), which forms a wheel-like hexamer that has been called the apoptosome. [44]

This complex is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process.

Answer 153

the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process.

Answer 154

| arcane names like Smac/DIABLO

Answer 155

T

Apoptosis may be initiated by caspase activation upstream of
mitochondria, and the subsequent increase in mitochondrial permeability and release of proapoptotic
molecules serve to amplify the death signal. However, mechanisms of apoptosis
involving mitochondria-independent initiation are not well defined.

Answer 156

This pathway is initiated by engagement of plasma membrane death receptors on a variety of
cells. [48] [49] [50]

Answer 157

TNF receptor family

Some TNF receptor family members do

not contain cytoplasmic death domains; their function is to activate inflammatory cascades [
Chapter 2 ], and their role in triggering apoptosis is much less established.)

Answer 158

type 1 TNF receptor (TNFR1)
Fas (CD95)

Answer 159

The ligand for Fas is called Fas ligand (FasL).

FasL is expressed on T cells that recognize self
antigens (and functions to eliminate self-reactive lymphocytes), and on some cytotoxic T lymphocytes (which kill virus-infected and tumor cells)

Answer 160

This pathway of apoptosis can be inhibited by a protein called
FLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because it
lacks a protease domain. [51] Some viruses and normal cells produce FLIP and use this inhibitor to protect themselves from Fas-mediated apoptosis.

Answer 161

When FasL binds to Fas, three or more
molecules of Fas are brought together, and their cytoplasmic death domains form a binding site
for an adapter protein that also contains a death domain and is called FADD (Fas-associated
death domain).

FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain.

Answer 162

The two initiating pathways converge to a cascade of caspase activation, which mediates the
final phase of apoptosis. As we have seen, the mitochondrial pathway leads to activation of the
initiator caspase-9, and the death receptor pathway to the initiators caspase-8 and -10. After an
initiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases. Executioner caspases,
such as caspase-3 and -6, act on many cellular components. For instance, these caspases,
once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNase
enzymatically active; this enzyme induces the characteristic cleavage of DNA into nucleosomesized
pieces, described earlier. Caspases also degrade structural components of the nuclear
matrix, and thus promote fragmentation of nuclei. Some of the steps in apoptosis are not fully
defined. For instance, we do not know how the structure of the plasma membrane is changed in
apoptotic cells, or how membrane blebs and apoptotic bodies are formed.

Answer 163

mitochondrial pathway leads to activation of the
initiator caspase-9

Answer 164

caspase-8 and -10

Answer 165

caspase-3 and -6

Answer 166

The formation of apoptotic bodies breaks cells up into “bite-sized” fragments that are edible for
phagocytes.

Apoptotic cells and their fragments also undergo several changes in their membranes that actively promote their phagocytosis so they are cleared before they undergo
secondary necrosis and release their cellular contents (which can result in injurious inflammation).

In healthy cells phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid “flips” out and is expressed on the outer
layer of the membrane, where it is recognized by several macrophage receptors.

Cells that are
dying by apoptosis secrete soluble factors that recruit phagocytes. [52]

Some apoptotic bodies
express thrombospondin, an adhesive glycoprotein that is recognized by phagocytes, and macrophages themselves may produce proteins that bind to apoptotic cells (but not to live cells) and thus target the dead cells for engulfment

. Apoptotic bodies may also become coated with
natural antibodies and proteins of the complement system, notably C1q, which are recognized by phagocytes. [53] Thus, numerous receptors on phagocytes and ligands induced on
apoptotic cells are involved in the binding and engulfment of these cells.

This process of
phagocytosis of apoptotic cells is so efficient that dead cells disappear, often within minutes,
without leaving a trace, and inflammation is absent even in the face of extensive apoptosis.

Answer 167

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Growth Factor Deprivation.
DNA Damage.
Protein Misfolding.
Apoptosis Induced By the TNF Receptor Family.
Cytotoxic T Lymphocyte–Mediated Apoptosis.

```

Answer 168

Hormone-sensitive cells deprived of the relevant hormone,
lymphocytes that are not stimulated by antigens and cytokines,
and neurons deprived of nerve growth factor die by apoptosis.

In all these situations, apoptosis is triggered by the intrinsic (mitochondrial) pathway and is attributable to decreased synthesis of Bcl-2 and Bcl-x and activation of Bim and other proapoptotic members of the Bcl family.

Answer 169

tumor-suppressor gene
p53.

p53 protein accumulates in cells when DNA is damaged, and it arrests the cell cycle (at the G1 phase) to allow time for repair ( Chapter 7 ).

However, if the damage is too great to be repaired successfully, p53 triggers apoptosis.

When p53 is mutated or absent (as it is in certain cancers), it is incapable of inducing apoptosis, so that cells with damaged DNA are allowed to survive. In such cells the DNA damage may result in mutations or translocations that lead to neoplastic transformation ( Chapter 7 ).

Thus, p53 serves as a critical “life or death” switch following genotoxic stress. The mechanism by which p53 triggers the distal death effector machinery—the caspases—is complex but seems to involve its function in transcriptional activation. Among the proteins whose production is stimulated by p53 are several pro-apoptotic members of the Bcl family, notably Bax, Bak, and some BH3-only proteins, mentioned earlier.

Answer 170

Chaperones in the ER control the proper folding of newly synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for proteolysis in proteasomes

. If, however,
unfolded or misfolded proteins accumulate in the ER, because of inherited mutations or stresses, they trigger a number of cellular responses, collectively called the unfolded protein
response. [56,] [57]

This unfolded protein response activates signaling pathways that increase
the production of chaperones, enhance proteasomal degradation of abnormal proteins, and
slow protein translation, thus reducing the load of misfolded proteins in the cell ( Fig. 1-27 ).

Answer 171

However, if this cytoprotective response is unable to cope with the accumulation of misfolded proteins, the cell activates caspases and induces apoptosis. [58] [59] [60]

This process is called ER stress.

Intracellular accumulation of abnormally folded proteins, caused by genetic utations, aging, or unknown environmental factors, is now recognized as a feature of a umber of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson
diseases ( Chapter 28 ), and possibly type 2 diabetes. [61] Deprivation of glucose and oxygen,
and stress such as heat, also result in protein misfolding, culminating in cell injury and death.

Answer 172

Chaperones, such as heat shock proteins (Hsp), protect unfolded or partially folded proteins from degradation and guide proteins into organelles. B

Answer 173

TNF

(The name “tumor necrosis factor” arose not because the cytokine kills tumor cells directly but because it induces thrombosis of tumor blood vessels, resulting in

ischemic death of the tumor.)

Answer 174

Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface of infected host cells ( Chapter 6 ). Upon activation, CTLs secrete perforin, a transmembrane
pore-forming molecule, which promotes entry of the CTL granule serine proteases called granzymes. Granzymes have the ability to cleave proteins at aspartate residues and thus
activate a variety of cellular caspases. [63] In this way the CTL kills target cells by directly
inducing the effector phase of apoptosis. CTLs also express FasL on their surface and may kill
target cells by ligation of Fas receptors.

Answer 175

Disorders associated with defective apoptosis and increased cell survival .
- mutations in p53 are subjected to DNA damage, the cells not only fail to die but are susceptible to the accumulation of mutations because of defective DNA repair, and these abnormalities can give rise to cancer
- autoimmune disorders
Disorders associated with increased apoptosis and excessive cell death

Answer 176

(1) neurodegenerative diseases, manifested by loss of specific sets of neurons, in which apoptosis is caused
by mutations and misfolded proteins ( Chapter 28 );

(2) ischemic injury, as in myocardial
infarction ( Chapter 12 ) and stroke ( Chapter 28 ); and (3) death of virus-infected cells ,
in many viral infections ( Chapter 8 ).

Answer 177

Autophagy is a process in which a cell eats its own contents

It is a survival mechanism in times
of nutrient deprivation, when the starved cell lives by cannibalizing itself and recycling the
digested contents.

Answer 178

In this process intracellular organelles and portions of cytosol are first sequestered from the cytoplasm in an autophagic vacuole, which subsequently fuses with lysosomes to form an autophagolysosome, and the cellular components are digested by lysosomal enzymes ( Fig. 1-28 ). [64,] [65]

Interest in autophagy has been spurred by the finding that it is regulated by a defined set of “autophagy genes” (called Atgs) in single-celled organisms and mammalian cells.

The products of many of these genes function in the creation
of the autophagic vacuole, but how they do so is unknown. It has also been suggested that autophagy triggers cell death that is distinct from necrosis and apoptosis. [66]

However, the mechanism of this type of cell death is not known, nor is it clear that the cell death is caused by autophagy rather than by the stress that triggers autophagy.

Nevertheless, autophagy has been invoked as a mechanism of cell loss in various diseases, including degenerative diseases
of the nervous system and muscle; in many of these disorders, the damaged cells contain
abundant autophagic vacuoles.

Answer 179

1) a normal cellular constituent , such as water, lipids, proteins, and carbohydrates, that accumulates in excess; or

(2) an abnormal substance, either exogenous, such as a mineral or products of infectious agents, or endogenous, such as a product of abnormal synthesis or metabolism.

Note : These substances may accumulate either transiently or permanently, and they may
be harmless to the cells, but on occasion they are severely toxic. The substance may be
located in either the cytoplasm (frequently within phagolysosomes) or the nucleus. In some
instances the cell may be producing the abnormal substance, and in others it may be merely
storing products of pathologic processes occurring elsewhere in the body.

Answer 180

1. A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. Examples of this type of process are fatty
change in the liver and reabsorption protein droplets in the tubules of the kidneys (see
later).
2. An abnormal endogenous substance, typically the product of a mutated gene, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently. Examples include the accumulation of mutated α1-antitrypsin in liver cells ( Chapter 18 ) and various mutated proteins in degenerative disorders of the central nervous system ( Chapter 28 ).
3. A normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance. Examples include
diseases caused by genetic defects in enzymes involved in the metabolism of lipid and carbohydrates, resulting in intracellular deposition of these substances, largely in
lysosomes.

4. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon particles and nonmetabolizable chemicals such
as silica are examples of this type of alteration.

Answer 181

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LIPIDS
PROTEINS
HYALINE CHANGE
GLYCOGEN
PIGMENTS

```

Answer 182

The terms steatosis and fatty change describe abnormal accumulations of triglycerides within parenchymal cells. Fatty change is often seen in the liver because it is the major organ involved in fat metabolism, but it also occurs in heart, muscle, and kidney.

Answer 183

toxins,
protein malnutrition,
diabetes mellitus,
obesity, and anoxia.

Answer 184

alcohol abuse
and nonalcoholic fatty liver disease, which is often associated with diabetes and obesity

Answer 185

Different mechanisms account for triglyceride accumulation in the liver.

Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes. In the liver they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies.
Some fatty acids are synthesized from acetate as well. Release of triglycerides from the hepatocytes requires association with apoproteins to form lipoproteins, which may then be transported from the blood into the tissues ( Chapter 4 ).
Excess accumulation of triglycerides within the liver may result from excessive entry or defective metabolism and export of lipids ( Fig. 1-30A ).
Several such defects are induced by alcohol, a hepatotoxin that alters mitochondrial and microsomal functions, leading to increased synthesis and reduced breakdown of lipids ( Chapter 18 ).
CCl4 and protein malnutrition cause fatty change by reducing synthesis of apoproteins, hypoxia inhibits fatty acid oxidation, and starvation increases fatty acid mobilization from peripheral stores.

Answer 186

Fatty change is most often seen in the liver and heart. In all organs fatty change appears as clear vacuoles within parenchymal cells.

Intracellular accumulations of
water or polysaccharides (e.g., glycogen) may also produce clear vacuoles.

Answer 187

Sudan IV or Oil Red-O,

Answer 188

Liver. In the liver, mild fatty change may not affect the gross appearance.

With progressive accumulation, the organ enlarges and becomes increasingly yellow until, in extreme
instances, the liver may weigh two to four times normal and be transformed into a bright
yellow, soft, greasy organ.

Answer 189

Fatty change begins with the development of minute, membrane-bound inclusions
(liposomes) closely applied to the ER.

Accumulation of fat is first seen by light microscopy as
small vacuoles in the cytoplasm around the nucleus.

As the process progresses the
vacuoles coalesce, creating cleared spaces that displace the nucleus to the periphery of the
cell ( Fig. 1-30B ).

Occasionally contiguous cells rupture and the enclosed fat globules
coalesce, producing so-called fatty cysts.

Answer 190

Heart.

Lipid is found in cardiac muscle in the form of small droplets, occurring in two patterns.

In one, prolonged moderate hypoxia, such as that produced by profound anemia, causes intracellular deposits of fat, which create grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved myocardium (tigered

effect).

2. The other pattern of fatty change is produced by more profound hypoxia or by some forms of myocarditis (e.g., diphtheria infection) and shows more uniformly affected myocytes.

Answer 191

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Atherosclerosis
Xanthomas.
Cholesterolosis.
Niemann-Pick disease, type C.

```

Answer 192

Xanthomas.

Intracellular accumulation of cholesterol within macrophages is also characteristic of acquired and hereditary hyperlipidemic states.

Clusters of foamy cells
are found in the subepithelial connective tissue of the skin and in tendons, producing
tumorous masses known as xanthomas.

Answer 193

Cholesterolosis.

This refers to the focal accumulations of cholesterol-laden
macrophages in the lamina propria of the gallbladder ( Fig. 1-31 ). The mechanism of
accumulation is unknown.

Answer 194

This lysosomal storage disease is caused by mutations

affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol

accumulation in multiple organs

Answer 195

rounded, eosinophilic droplets,
vacuoles, or aggregates in the cytoplasm

. By electron microscopy they can be amorphous,
fibrillar, or crystalline in appearance. In some disorders, such as certain forms of amyloidosis,
abnormal proteins deposit primarily in extracellular spaces

Answer 196

Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria).
The proteins that accumulate may be normal secreted proteins that are produced in excessive amounts, as occurs in certain plasma cells engaged in active synthesis of immunoglobulins.
Defective intracellular transport and secretion of critical proteins
Accumulation of cytoskeletal proteins
Aggregation of abnormal proteins

Answer 197

pink hyaline
droplets within the cytoplasm of the tubular cell

Answer 198

The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions called Russell bodies

Answer 199

In α1-antitrypsin
deficiency, mutations in the protein significantly slow folding, resulting in the buildup of partially folded intermediates, which aggregate in the ER of the liver and are not
secreted.

The resultant deficiency of the circulating enzyme causes emphysema (
Chapter 15 ). In many of these diseases the pathology results not only from loss of
protein function but also ER stress caused by the misfolded proteins, culminating in
apoptotic death of cells (discussed above).

Answer 200

keratin filaments (characteristic of epithelial cells),
neurofilaments (neurons),
desmin filaments (muscle cells),
vimentin filaments (connective tissue cells),
and glial filaments (astrocytes).

Accumulations of keratin filaments and neurofilaments are associated with certain types of cell injury.

Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease, and is composed predominantly of keratin intermediate filaments ( Chapter 18 ).

The neurofibrillary tangle found in the brain in Alzheimer disease contains neurofilaments and other proteins.

Answer 201

Aggregation of abnormal proteins . Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions.

The deposits can be intracellular,
extracellular, or both, and the aggregates may either directly or indirectly cause the pathologic changes.

Answer 202

The term hyaline usually refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with
hematoxylin and eosin.

It is widely used as a descriptive histologic term rather than a specific marker for cell injury.

This morphologic change is produced by a variety of alterations and does not represent a specific pattern of accumulation.

Intracellular accumulations of protein,
described earlier (reabsorption droplets, Russell bodies, alcoholic hyaline), are examples of
intracellular hyaline deposits.

Answer 203

Glycogen is a readily available energy source stored in the cytoplasm of healthy cells.
Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. Whatever the clinical setting, the glycogen masses appear as clear vacuoles within the cytoplasm. Glycogen dissolves in aqueous fixatives; for its localization,
tissues are best fixed in absolute alcohol.

Staining with Best carmine or the PAS reaction
imparts a rose-to-violet color to the glycogen, and diastase digestion of a parallel section before staining serves as a further control by hydrolyzing the glycogen.

Diabetes mellitus is the prime example of a disorder of glucose metabolism.

In this disease
glycogen is found in renal tubular epithelial cells, as well as within liver cells, β cells of the islets
of Langerhans, and heart muscle cells.
Glycogen accumulates within the cells in a group of related genetic disorders that are collectively referred to as the glycogen storage diseases, or glycogenoses ( Chapter 5 ). In
these diseases enzymatic defects in the synthesis or breakdown of glycogen result in massive
accumulation, causing cell injury and cell death.

Answer 204

carbon (coal dust

Answer 205

(anthracosis)

Answer 206

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Lipofuscin
Melanin
Hemosiderin

```

Answer 207

Lipofuscin is an insoluble pigment, also known as lipochrome or wear-and-tear pigment.
Lipofuscin is composed of polymers of lipids and phospholipids in complex with protein, suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes.

Lipofuscin is not injurious to the cell or its functions.

Its importance lies in its being a telltale sign of free radical injury and lipid peroxidation.

The term is derived from the Latin
(fuscus, brown), referring to brown lipid.

Answer 208

In tissue sections it appears as a yellow-brown, finely
granular cytoplasmic, often perinuclear, pigment ( Fig. 1-33 ). It is seen in cells undergoing slow,
regressive changes and is particularly prominent in the liver and heart of aging patients or
patients with severe malnutrition and cancer cachexia.

Answer 209

Melanin, derived from the Greek (melas, black), is an en-dogenous, non-hemoglobin-derived,
brown-black pigment formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine to
dihydroxyphenylalanine in melanocytes.

Answer 210

Hemosiderin is a hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment
that serves as one of the major storage forms of iron.

Iron metabolism and hemosiderin are
considered in detail in Chapters 14 and 18 . Iron is normally carried by specific transport proteins, transferrins. In cells, it is stored in association with a protein, apoferritin, to form ferritin
micelles.

Ferritin is a constituent of most cell types. When there is a local or systemic excess of iron, ferritin forms hemosiderin granules, which are easily seen with the light microscope ( Fig.
1-34 ). Hemosiderin pigment represents aggregates of ferritin micelles. Under normal conditions small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver, which are actively engaged in red cell breakdown.

Answer 211

common bruise.

Extravasated red blood cells at the site of injury are phagocytosed overseveral days by macrophages, which break down the hemoglobin and recover the iron. After
removal of iron, the heme moiety is converted first to biliverdin (“green bile”) and then to
bilirubin (“red bile”). In parallel, the iron released from heme is incorporated into ferritin and eventually hemosiderin.

These conversions account for the often dramatic play of colors seen in a healing bruise, which typically changes from red-blue to green-blue to golden-yellow before
it is resolved.

Answer 212

1) increased absorption of dietary iron,

(2) hemolytic anemias, in which abnormal quantities of iron are
released from erythrocytes, and

(3) repeated blood transfusions because the transfused red
cells constitute an exogenous load of iron

Answer 213

Iron pigment appears as a coarse, golden, granular pigment lying within the cell's cytoplasm ( Fig. 1-34A ).

It can be visualized in tissues by the Prussian blue
histochemical reaction, in which colorless potassium ferrocyanide is converted by iron to blue-black ferric ferrocyanide ( Fig. 1-34B ).

When the underlying cause is the localized
breakdown of red cells, the hemosiderin is found initially in the phagocytes in the area.

In
systemic hemosiderosis it is found at first in the mononuclear phagocytes of the liver, bone
marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs
such as the skin, pancreas, and kidneys.

With progressive accumulation, parenchymal cells
throughout the body (principally in the liver, pancreas, heart, and endocrine organs) become
pigmented.

Answer 214

hemochromatosis

Answer 215

is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts.

Answer 216

When the deposition occurs locally in dying tissues it is known as dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism.
In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism.

Answer 217

Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat.

Calcification is almost
always present in the atheromas of advanced atherosclerosis. It also commonly develops in
aging or damaged heart valves, further hampering their function ( Fig. 1-35 ).

Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often
felt as gritty deposits. Sometimes a tuberculous lymph node is virtually converted to stone

Answer 218

basophilic, amorphous granular, sometimes clumped appearance. They can be intracellular

Answer 219

Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the
effects of exposure to exogenous influences

Answer 220

Decreased cellular replication
Accumulation of metabolic and genetic damage

Answer 221

senescence

Answer 222

cells from
patients with Werner syndrome, a rare disease characterized by symptoms of premature aging, are defective in DNA replication and have a markedly reduced
capacity to divide.

Answer 223

in omplete replication of chromosome ends (telomere shortening), which ultimately results in cell cycle arrest.

Note :Telomeres are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosomal ends and for protecting chromosomal termini from fusion and degradation. [73]

When somatic cells replicate, a small section of the telomere is
not duplicated and telomeres become progressively shortened. As the telomeres become shorter the ends of chromosomes cannot be protected and are seen as broken DNA, which activates the DNA damage response and signals cell cycle arrest.

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Telomere
length is normally maintained by nucleotide addition mediated by an enzyme called
telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes ( Fig. 1-38A ). The
activity of telomerase is repressed by regulatory proteins, which provide a mechanism for sensing telomere length and restrict unnecessary elongation. Telomerase activity is
highest in germ cells and present at lower levels in stem cells, but it is usually undetectable in most somatic tissues ( Fig. 1-38B ). Therefore, as somatic cells divide, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Thus, both accumulation of senescent cells and depletion of stem cell pools via senescence contribute to aging. Conversely, in
immortal cancer cells telomerase is reactivated and telomeres are stable, suggesting that maintenance of telomere length might be an important—possibly essential—step in
tumor formation ( Chapter 7 ). Despite such alluring observations, however, the relationship of telomerase activity and telomeric length to aging and cancer still must be
fully established

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Answer 224

increased expression of the cell cycle

inhibitor p16INK4a and by DNA damage

Answer 225

(1) variation in longevity among different species is inversely correlated with the rates of mitochondrial generation of
anion radical,

and (2) overexpression of the antioxidative enzymes
SOD and catalase extends life span in transgenic forms of Drosophila. Free radicals may have deleterious effects on DNA, leading to breaks and genome instability, thus
affecting all cellular functions.

Answer 226

recognition and repair of damaged DNA.

Answer 227

DNA helicase

Answer 228

calorie restriction

Answer 229

Sirtuins have histone deacetylase activity, and are thought to promote the expression of several genes whose products increase longevity.

These products include
proteins that increase metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit the harmful effects of oxygen free radicals. [81]

Sirtuins also increase insulin sensitivity and
glucose metabolism, and may be targets for the treatment of diabetes.

Not surprisingly,
optimistic wine-lovers have been delighted to hear that a constituent of red wine may activate sirtuins and thus increase life span! Other studies have shown that growth factors, such as insulin-like growth factor, and intracellular signaling pathways triggered by these hormones also
influence life span. [69]

Transcription factors activated by insulin receptor signaling may induce genes that reduce longevity, and insulin receptor mutations are associated with increased life span.

The relevance of these findings to aging in humans is an area of active investigation. It should be apparent that the various forms of cellular derangements and adaptations
described in this chapter cover a wide spectrum, ranging from adaptations in cell size, growth, and function; to the reversible and irreversible forms of acute cell injury; to the regulated type of cell death represented by apoptosis; to the pathologic alterations in cell organelles; and to the less ominous forms of intracellular accumulations, including pigmentations.

Reference is made
to all these alterations throughout this book, because all organ injury and ultimately all clinical
disease arise from derangements in cell structure and function.

chapter1 cellular response and adaptation Flashcards

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