chapter1 cellular response and adaptation Flashcards

Question 1

Q

This refers to the increase in the size of the cells and its functional activity.A. HyperplasiaB. AtrophyC. MetaplasiaD. Hypertrophy

Answer

A

D. Hypertrophy

Question 2

Q

A branch of pathology that is concerned with the alterations in specialized organs and tissues that are responsible for disorders that involve these organs.

Answer

A

Systemic Pathology

Question 3

Q

The aspect of a disease process that is the ‘main cause’ of that disease.A. PathogenesisB. Functional derangementsC. EtiologyD. Molecular and Morphological Changes

Answer

A

C. Etiology

Question 4

Q

He is known as the father of modern pathology.

Answer

A

Rudolf Virchow

Question 5

Q

The process in which there is a decrease in size and metabolic activity.A. HypertrophyB. HyperplasiaC. AtrophyD. Metaplasia

Answer

A

C. Atrophy

Question 6

Q

A process by which cells change its phenotype.

Answer

A

Metaplasia

Question 7

Q

TRUE or FALSE: In the process of hypertrophy, there are new and larger cells.

Answer

A

FALSE. Cells become larger but there are no new cells.

Question 8

Q

The most common stimulus for hypertrophy of muscle is _________.

Answer

A

Increased workload

Question 9

Q

The main biochemical pathway that mediates the physiologic muscle hypertrophy is _________.A. GlycolysisB. ETCC. Phosphoinositide 3-kinase/Akt pathwayD. Signaling down stream of G-protein coupled receptors

Answer

A

C. Phosphoinositide 3-kinase/Akt pathway

Question 10

Q

TRUE or FALSE: The signaling down stream of G-protein couple receptor is the main biochemical pathway for pathologic hypertrophy.

Question 11

Q

In muscle hypertrophy the alpha myosin heavy chain is converted to its ___________.

Answer

A

Beta isoform

Question 12

Q

Barbiturates show hypertrophy of this specific cell organelle in hepatocytes.

Answer

A

Smooth Endoplasmic Reticulum (SER)

Question 13

Q

In the mechanism of muscle atrophy, the degradation of cellular proteins occurs mainly by this pathway.

Answer

A

Ubiquitin-Proteasome Pathway (responsible for accelerated proteolysis)

Question 14

Q

The process in which starved cells eat its own components in attempt to find nutrients and survive.

Answer

A

Autophagy

Question 15

Q

The most common epithelial metaplasia is:A. Squamous to cuboidalB. Columnar to squamousC. Squamous to columnarD. Cuboidal to columnar

Answer

A

B. Columnar to squamous

Question 16

Q

Barrett Esophagus manifests this type of metaplasia.A. Squamous to cuboidalB. Columnar to squamousC. Squamous to columnarD. Cuboidal to columnar

Answer

A

C. Squamous to columnar

Question 17

Q

Two features of reversible cell injury that can be recognized under the light microscope.

Answer

A

Cellular swelling and fatty change

Question 18

Q

______________ is the first manifestation of almost all forms of injury to cells.

Answer

A

Cellular swelling

Question 19

Q

The following statements regarding necrosis are correct EXCEPT:A. Cells are unable to maintain membrane integrity.B. The process may present with inflammation.C. The cells usually enlarge or swell.D. Necrosis is often physiologic to maintain homeostasis.

Answer

A

D. Necrosis is often physiologic to maintain homeostasis.

Question 20

Q

Necrotic cells show increased __________ in H&E staining.A. BasophilsB. NeutrophilsC. EosinophilsD. Monocytes

Answer

A

C. Eosinophils

Question 21

Q

The glassy homogenous appearance of a necrotic cell is mainly due to the loss of _________ particles.

Question 22

Q

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

Answer

A

Karyolysis

Question 23

Q

This process is characterized by nuclear shrinkage and increased basophilia.

Question 24

Q

TRUE or FALSE: Pyknosis is also observed in apoptotic cell death.

Question 25

Q

The process in which pyknotic nucleus undergoes fragmentation.

Answer

A

Karyorrhexis

Question 26

Q

A localized area of coagulative necrosis is called an ___________.

Question 27

Q

Type of necrosis that is characterized by digestion of dead cells, resulting in the transformation of the tissue into a liquid viscous mass.

Answer

A

Liquefactive necrosis

Question 28

Q

Type of necrosis that is often encountered in foci of tuberculous infection.

Answer

A

Caseous (‘cheeselike’) Necrosis

Question 29

Q

A special form of necrosis usually seen in immune reactions involving blood vessels.

Answer

A

Fibrinoid necrosis

Question 30

Q

Most common type of cell injury.

Answer

A

Ischemic and Hypoxic Injury

Question 31

Q

This term refers reduced oxygen availability.

Question 32

Q

TRUE or FALSE: Hypoxia is a more rapid and severe cell and tissue injury than does ischemia.

Question 33

Q

________ arrests the cell cycle at G1 phase and triggers apoptosis if the damage is great.

Question 34

Q

Most common type of cell injury.

Answer

A

Ischemic and Hypoxic Injury

Question 35

Q

This term refers reduced oxygen availability.

Question 36

Q

TRUE or FALSE: Hypoxia is a more rapid and severe cell and tissue injury than does ischemia.

Question 37

Q

________ arrests the cell cycle at G1 phase and triggers apoptosis if the damage is great.

Question 38

Q

The four aspects of a disease process that form the core of pathology are:

Answer

A

<ol>
<li>its cause (etiology),</li>
<li>the mechanisms of its development (pathogenesis),</li>
<li>the biochemical and structural alterationsinduced in the cells and organs of the body (molecular and morphologic changes) , </li>
<li>and thefunctional consequences of these changes (clinical manifestations</li>
</ol>

Question 39

Q

What are Adaptations?

Answer

A

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 ).

Question 40

Q

The adaptive response may consist of an:

Answer

A

<ol>
<li>increase in thesize of cells (hypertrophy) and functional activity,</li>
<li>an increase in their number (hyperplasia), </li>
<li>adecrease in the size and metabolic activity of cells (atrophy), </li>
<li>or a change in the phenotype ofcells (metaplasia).</li>
</ol>

Question 41

Q

ALTERED PHYSIOLOGICAL STIMULI; SOME 
NONLETHAL INJURIOUS STIMULI

• Increased demand, increased stimulation (e.g., by 
growth factors, hormones) 
• Decreased nutrients, decreased stimulation 
• Chronic irritation (physical or chemical)

Answer

A

CELLULAR ADAPTATIONS

• Hyperplasia, hypertrophy 
• Atrophy 
• Metaplasia

Question 42

Q

REDUCED OXYGEN SUPPLY; CHEMICAL INJURY; 
MICROBIAL INFECTION

• Acute and transient 
• Progressive and severe (including DNA damage)

Answer

A

<p style="text-align: center;">• Acute reversible injury<br>
Cellular swelling fatty change<br>
• Irreversible injury ➙ cell death<br>
Necrosis<br>
Apoptosis</p>

Question 43

Q

What is the cellular response inMETABOLIC ALTERATIONS, GENETIC OR ACQUIRED; 
CHRONIC INJURY

Answer

A

INTRACELLULAR ACCUMULATIONS; 
CALCIFICATION

Question 44

Q

What is the cellular response in CUMULATIVE SUBLETHAL INJURY OVER LONG LIFE 
SPAN?

Answer

A

CELLULAR AGING

Question 45

Q

What is cell injury?

Answer

A

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

Question 46

Q

\_\_\_\_\_\_\_\_\_ may be stages of progressive impairment followingdifferent types of insults.

Answer

A

<ul>
<li>Adaptation,</li>
<li>reversible injury, </li>
<li>and cell death</li>
</ul>

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

irreversible injury and die

Question 47

Q

What is cell death?

Answer

A

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.

Question 48

Q

There aretwo principal pathways of cell death, \_\_\_\_ and \_\_\_\_\_\_\_

Answer

A

<ol>
<li>necrosis </li>
<li>and apoptosis</li>
</ol>

Question 49

Q

. Nutrient deprivation triggers an 
adaptive cellular response called \_\_\_\_\_\_\_\_\_ that may also culminate in cell death. We will 
return to a detailed discussion of these pathways of cell death later in the chapter.

Answer

A

autophagy

Question 50

Q

Stresses of different types may induce :

Answer

A

<ul>
<li>changes in cells and tissues other than typicaladaptations, cell injury, and death (see Table 1-1 ).</li>
<li>Metabolic derangements in cells andsublethal, chronic injury may be associated with intracellular accumulations of a number ofsubstances, including proteins, lipids, and carbohydrates. </li>
<li>Calcium is often deposited at sites ofcell death, resulting in pathologic calcification.</li>
<li>Finally, the normal process of aging itself isaccompanied by characteristic morphologic and functional changes in cells.</li>
</ul>

Question 51

Q

Adaptations of Cellular Growth and Differentiation

Answer

A

<ol>
	<li>HYPERTROPHY</li>
	<li>HYPERPLASIA</li>
	<li>ATROPHY</li>
	<li>METAPLASIA</li>
</ol>

Question 52

Q

What is hypertrophy?

Answer

A

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.

Question 53

Q

Hypertrophy is due to?

Answer

A

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.

Question 54

Q

Hypertrophy can be physiologic or pathologic and is caused by \_\_\_\_\_\_\_\_.

Answer

A

increased functional demand or 
by stimulation by hormones and growth factors

Question 55

Q

The striated muscle cells in the heart and 
skeletal muscles have only a limited capacity for division, and respond to increased metabolic 
demands mainly by undergoing\_\_\_\_\_\_\_\_\_\_\_

Answer

A

hypertrophy.

Question 56

Q

The most common stimulus for hypertrophy of 
muscle is\_\_\_\_\_\_\_\_\_\_\_.

Answer

A

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.

Question 57

Q

The massive physiologic growth of the uterus during pregnancy is a good example of hormoneinduced 
increase in the size of an organ that results mainly from \_\_\_\_\_\_\_\_\_\_ of muscle fibers ( 
Fig. 1-3 ). The cellular enlargement is stimulated by estrogenic hormones acting on smooth 
muscle estrogen receptors, eventually resulting in increased synthesis of smooth muscle 
proteins and an increase in cell size.

Answer

A

hypertrophy

Question 58

Q

What is the mechansm of hypertrophy?

Answer

A

Hypertrophy is the result of increased production of cellular proteins .

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

Question 59

Q

What induce hypertrophy?

Answer

A

Hypertrophy can be induced by 
the linked actions of :

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

Question 60

Q

The two main biochemical pathways involved in muscle 
hypertrophy seem to be the :

Answer

A

<ol>
<li>phosphoinositide 3-kinase/Akt pathway (postulated to be mostimportant in physiologic, e.g., exercise-induced, hypertrophy)</li>
<li>and signaling downstream of Gprotein-coupled receptors (induced by many growth factors and vasoactive agents, and thoughtto be more important in pathologic hypertrophy).</li>
</ol>

Question 61

Q

What pathway is mainly involved in thephysiologic hypertropy?

Answer

A

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

Question 62

Q

What pathway is important forpathologic hypertrophy?

Answer

A

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

Question 63

Q

Hypertrophy may also be associated with a 
switch of contractile proteins from adult to fetal or neonatal forms.

For example, during muscle 
hypertrophy the α isoform of myosin heavy chain is replaced by the β isoform, which has a 
slower, more energetically economical contraction.

In addition, some genes that are expressed 
only during early development are re-expressed in hypertrophic cells, and the products of these 
genes participate in the cellular response to stress.

For example, the gene for\_\_\_\_\_\_\_\_is expressed in both the atrium and the ventricle in the embryonic heart, but it is 
down-regulated after birth.

Answer

A

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.

Question 64

Q

Answer 53

A

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 54

A

dividing

Answer 55

A

(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 56

A

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 57

A

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 58

A

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 59

A

Hyperplasia

Answer 60

A

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 61

A

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 62

A

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 63

A

<ul>
<li>Decreased workload (atrophy of disuse)</li>
<li>Loss of innervation (denervation atrophy)</li>
<li>Diminished blood supply</li>
<li>Inadequate nutrition</li>
<li>Loss of endocrine stimulation</li>
</ul>

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

Answer 64

A

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 byapoptosis. Cell death by apoptosis also contributes to the atrophy of endocrine organs after 
hormone withdrawal.

Answer 65

A

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 66

A

autophagy,

Answer 67

A

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 68

A

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 69

A

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 70

A

Barrett esophagus

Answer 71

A

Connective tissueis 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 72

A

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 73

A

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 74

A

necrosis and 
apoptosis

Answer 75

A

necrosis

Answer 76

A

apoptosis

Answer 77

A

True

Answer 78

A

autophagy.

Answer 79

A

<ol>
	<li>Oxygen Deprivation.</li>
	<li>Physical Agents.</li>
	<li>Chemical Agents and Drugs.</li>
	<li>Infectious Agents.</li>
	<li>Immunologic Reactions.</li>
	<li>Genetic Derangements.</li>
	<li>Nutritional Imbalances.</li>
</ol>

Answer 80

A

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 81

A

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

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 82

A

Reversible injury is characterized by:

<ul>
<li>generalized swelling of the cell and its</li>
<li>organelles;</li>
<li>blebbing of the plasma membrane;</li>
<li>detachment of ribosomes from the ER;</li>
<li>andclumping of nuclear chromatin.</li>
</ul>

Answer 83

A

<ul>
<li>decreasedgeneration of ATP,</li>
<li>loss of cell membrane integrity, </li>
<li>defects in protein synthesis,</li>
<li>cytoskeletaldamage,</li>
<li>and DNA damage. </li>
</ul>

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

injurious stimulus abates, will return to normalcy.

Answer 84

A

necrosis

Necrosis is the principal outcome in many

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

infections, and trauma.

Answer 85

A

<ul>
<li>Cell size Enlarged (swelling)</li>
<li>Nucleus: Pyknosis ➙ karyorrhexis 
➙ karyolysis</li>
<li>Cellularcontents:Enzymatic digestion; may 
leak out of cell</li>
<li>Adjacentinflammation :Frequent</li>
<li>Physiologicorpathologicrole :Invariably pathologic 
(culmination ofirreversible cell injury)</li>
</ul>

FIPES

Answer 86

A

<ul>
<li>Cell size --Reduced (shrinkage)</li>
<li>Nucleus --Fragmentation into nucleosome-size fragments</li>
<li>Plasmamembrane -Intact; altered structure, especially orientation of lipids</li>
<li>Cellularcontents -Intact; may be released in apoptotic bodies</li>
<li>Adjacentinflammation - No</li>
<li>Physiologicorpathologicrole - Often physiologic, means of eliminating unwanted cells;may be pathologic after some forms of cell injury, 
especially DNA damage</li>
</ul>

FINS

Answer 87

A

cellular 
swelling and fatty change

Answer 88

A

Cellular swelling

Answer 89

A

Fatty change

Answer 90

A

\_\_\_\_\_\_\_\_\_\_

Answer 91

A

1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli 
2. Mitochondrial changes, including swelling and the appearance of small amorphousdensities 
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 92

A

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 contentsoften leak out, a process that may elicit inflammation in the surrounding tissue.

The enzymesthat digest the necrotic cell are derived from the lysosomes of the dying cells themselves andfrom 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 earliesthistologic 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 93

A

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 94

A

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

Answer 95

A

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

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

Answer 96

A

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 97

A

<ol>
	<li>Coagulative</li>
	<li>Liquefactive</li>
	<li>Gangenous</li>
	<li>Casseous</li>
	<li>Fatty</li>
	<li>Fibrinoid</li>
</ol>

Answer 98

A

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 maypersist 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 99

A

A localized area of 

| coagulative necrosis is called an infarct.

Answer 100

A

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 101

A

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 102

A

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 103

A

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 104

A

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 105

A

On microscopic examination, the necrotic area appears as acollection 
of fragmented or lysed cellsandamorphous granular debrisenclosed within a distinctive 
inflammatory border;this appearance is characteristic of a focus of inflammation known as a 
granuloma( Chapter 2 ).

Answer 106

A

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 acutepancreatitis ( 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 107

A

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 108

A

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 109

A

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 110

A

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 111

A

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 112

A

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

Answer 113

A

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

Answer 114

A

<ul>
<li>reduced supply of oxygen and nutrients,</li>
<li>mitochondrial damage, and the actions of sometoxins (e.g., cyanide).</li>
</ul>

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 115

A

<ul>
<li>oxidative phosphorylation of adenosine diphosphate, in a reaction thatresults in reduction of oxygen by the electron transfer system of mitochondria. </li>
<li>The second isthe glycolytic pathway, which can generate ATP in the absence of oxygen using glucose derivedeither from body fluids or from the hydrolysis of glycogen</li>
</ul>

Answer 116

A

<ul>
<li>The activity of the plasma membrane energy-dependent sodium pump (ouabainsensitive 
Na + , K + -ATPase) is reduced.</li>
<li>Cellular energy metabolism is altered</li>
<li>Failure of the Ca 2+ pump leads to influx of Ca 2+ , with damaging effects on numerous 
cellular components, described below.</li>
<li>With prolonged or worsening depletion of ATP, structural disruption of the proteinsynthetic apparatus occurs,manifested as detachment of ribosomes from the rough ERand dissociation of polysomes, with aconsequent reduction in protein synthesis.</li>
<li>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.</li>
<li>Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, andthe cell undergoes necrosis.</li>
</ul>

Answer 117

A

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 118

A

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 119

A

unfolded protein

Answer 120

A

<ul>
<li>increases ofcytosolic Ca 2+ ,</li>
<li>reactive oxygen species (discussed below), </li>
<li>and oxygen deprivation, and sothey are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins. </li>
<li>Inaddition, mutations in mitochondrial genes are the cause of some inherited diseases</li>
</ul>

Answer 121

A

<ol>
<li>Mitochondrial damage often results in the formation of a high-conductance channel in 
the mitochondrial membrane, called the mitochondrial permeability transition pore</li>
<li>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.</li>
</ol>

Answer 122

A

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 123

A

cytochrome cand 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 124

A

release of Ca 2+ from intracellular stores

Answer 125

A

<ul>
<li>The accumulation of Ca 2+ in mitochondria results in opening of the mitochondrial 
permeability transition pore and, as described above, failure of ATP generation.</li>
<li>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).</li>
<li>Increased intracellular Ca 2+ levels also result in the induction of apoptosis, by direct 
activation of caspases and by increasing mitochondrial permeability. [</li>
</ul>

Answer 126

A

<ul>
<li>chemical and radiation injury,</li>
<li>ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellularaging, </li>
<li>and microbial killing by phagocytes.</li>
</ul>

Answer 127

A

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 128

A

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 radicalsmay be present transiently at low concentrations but do not cause damage.

Answer 129

A

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, andsome 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 130

A

<ul>
<li>The reduction-oxidation reactions that occur during normal metabolic processes</li>
<li>Absorption of radiant energy</li>
<li>Rapid bursts of ROS are produced in activated leukocytes during inflammation</li>
<li>Enzymatic metabolism of exogenous chemicals or drugs can generate free radicals thatare not ROS but have similar effects</li>
<li>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</li>
</ul>

Answer 131

A

<ol>
<li>superoxide anion</li>
<li>hydrogen peroxide</li>
<li>hydroxyl ions</li>
</ol>

Answer 132

A

<ul>
<li>Antioxidants</li>
<li>iron and copper can catalyze the formation of ROS</li>
<li>enzymes acts as free radical–scavenging systems and breaks down H2O2These enzymes are lo-cated near the sites ofgeneration of the oxidants</li>
<li></li>
</ul>

Answer 133

A

<ol>
	<li>Catalase,</li>
	<li>Superoxide dismutases (SODs)</li>
	<li>Glutathione peroxidase</li>
</ol>

Answer 134

A

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

Answer 135

A

are found in many cell types and convert O2to 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 136

A

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 137

A

<ol>
<li>Lipid peroxidation in membranes</li>
<li>Oxidative modification of proteins</li>
<li>Lesions in DNA</li>
</ol>

Answer 138

A

apoptosis

Answer 139

A

<ul>
<li>Reactive oxygen species</li>
<li>Decreased phospholipid synthesis</li>
<li>Increased phospholipid breakdown</li>
<li>Cytoskeletal abnormalities</li>
</ul>

Answer 140

A

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

Answer 141

A

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 142

A

Severe cell injury is associated with increaseddegradation of membrane phospholipids, probably due to activation of endogenousphospholipases 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 themembrane or exchange with membrane phospholipids, potentially causing changes in 
permeability and electrophysiologic alterations.

Answer 143

A

Cytoskeletal abnormalities.

Cytoskeletal filaments serve as anchors connecting the 
plasma membrane to the cell interior. Activation of proteases by increased cytosoliccalcium 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 cellmembrane from the cytoskeleton, rendering it susceptible to stretching and rupture.

Answer 144

A

<ul>
	<li>Mitochondrial membrane damage.</li>
	<li>Plasma membrane damage</li>
	<li>Injury to lysosomal membranes</li>
</ul>

Answer 145

A

<ul>
<li>mitochondrialmembrane, </li>
<li>the plasma membrane, </li>
<li>and membranes of lysosomes.</li>
</ul>

Answer 146

A

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 147

A

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 148

A

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 149

A

<ul>
<li>the inability to reverse mitochondrial dysfunction (lack of oxidativephosphorylation and ATP generation) even after resolution of the original injury,</li>
<li>and profounddisturbances in membrane function.</li>
</ul>

Answer 150

A

SCHEMIC AND HYPOXIC INJURY

Answer 151

A

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

Answer 152

A

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

Answer 153

A

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

Answer 154

A

hypoxia-inducible factor-1,

Answer 155

A

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

Thistreatment 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 156

A

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 havebeen 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 tothe cells that are irreversibly damaged at the end of ischemia. This process, calledischemiareperfusioninjury, is clinically important because it contributes to tissue damage duringmyocardial and cerebral infarction and following therapies to restore blood flow ( Chapters 12

and 28 .

Answer 157

A

<ul>
<li>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. [</li>
<li>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</li>
<li>Activation of the complement system may contribute to ischemia-reperfusion injury. [</li>
</ul>

Answer 158

A

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

Answer 159

A

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 160

A

developmentandthroughout adulthood,

Answer 161

A

<ol>
<li>The programmed destruction of cells during embryogenesis , including implantation, 
organogenesis, developmental involution, and metamorphosis.</li>
<li>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.</li>
<li>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 ), Blymphocytes in germinal centers, and epithelial cells in intestinal crypts, so as tomaintain a constant number (homeostasis).</li>
<li>Elimination of potentially harmful self-reactivelymphocytes , either before or after theyhave completed their maturation, so as to prevent reactionsagainst one's own tissues</li>
<li>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</li>
</ol>

Answer 162

A

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

Answer 163

A

<ul>
<li>Cell shrinkage</li>
<li>Chromatin condensation</li>
<li>Formation of cytoplasmic blebs and apoptotic bodies</li>
<li>Phagocytosis of apoptotic cells or cell bodies, usually by macrophages</li>
</ul>

Plasma membranes are thought to remain intact during apoptosis, until the last stages, whenthey become permeable to normally retained solutes.This classical description is accuratewith respect to apoptosis during physiologic conditions such as embryogenesis and deletionpathway 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 apoptosisare not uncommon after many injurious stimuli. [39]

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

Answer 164

A

<p style="text-align: center;">On histologic examination, in tissues stained with hematoxylin and eosin, the apoptotic cellappears as a<strong> round or oval mass of intensely eosinophilic cytoplasm</strong> with fragments of dense<br>
nuclear chromatin ( Fig. 1-22A ).</p>

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

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

Answer 165

A

<ul>
	<li>Activation of Caspases</li>
	<li>DNA and Protein Breakdown.</li>
	<li>Membrane Alterations and Recognition by Phagocytes.</li>
</ul>

Answer 166

A

A specific feature of apoptosis is the activation of several members of a family of cysteineproteases 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 acidresidues.

Answer 167

A

initiator and executioner

Answer 168

A

caspase-8 and caspase-9

Answer 169

A

caspase-3 and caspase-6

Answer 170

A

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 detectableby 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 171

A

<ul>
<li>The Intrinsic (Mitochondrial) Pathway of Apoptosis</li>
<li>The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis</li>
<li>The Execution Phase of Apoptosis</li>
<li>Removal of Dead Cells</li>
</ul>

Answer 172

A

<ul>
<li>initiation phase, during which some caspasesbecome catalytically active,</li>
<li>and an execution phase, during which other caspases trigger thedegradation of critical cellular components</li>
</ul>

Answer 173

A

<ul>
<li>the intrinsic, or mitochondrial, pathway, </li>
<li>and the extrinsic, or deathreceptor–initiated, pathway</li>
</ul>

Answer 174

A

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

Answer 175

A

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 176

A

Bim, Bid, and Bad

Answer 177

A

Bax and Bak,

Answer 178

A

The net result of Bax-Bak activationcoupled with loss 
of the protective functions of the anti-apoptotic Bcl familymembers is the release into thecytoplasm 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(apoptosisactivatingfactor-1, homologous to Ced-4 in C.elegans), which forms a wheel-like hexamer thathas been called the apoptosome. [44]

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

Answer 179

A

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

Answer 180

A

| arcane names like Smac/DIABLO

Answer 181

A

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 182

A

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

Answer 183

A

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 184

A

<ul>
<li>type 1 TNF receptor (TNFR1)</li>
<li>Fas (CD95)</li>
</ul>

Answer 185

A

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 Tlymphocytes (which kill virus-infected and tumor cells)

Answer 186

A

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 thisinhibitor to protect themselves from Fas-mediated apoptosis.

Answer 187

A

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 ofcaspase-8 (and, in humans, caspase-10), again via a death domain.

Answer 188

A

Bid

Answer 189

A

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 inmotion 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 190

A

mitochondrial pathway leads to activation of the 
initiator caspase-9

Answer 191

A

caspase-8 and -10

Answer 192

A

caspase-3 and -6

Answer 193

A

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 theirmembranes that actively promote their phagocytosis so they are cleared before they undergo 
secondary necrosis and release their cellular contents (which can result in injuriousinflammation).

In healthy cells phosphatidylserine is present on the inner leaflet of the plasmamembrane, 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, andmacrophages 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 recognizedby 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 194

A

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

Answer 195

A

<ul>
<li>Hormone-sensitive cells deprived of the relevant hormone,</li>
<li>lymphocytes that are not stimulatedby antigens and cytokines,</li>
<li>and neurons deprived of nerve growth factor die by apoptosis.</li>
</ul>

In allthese situations, apoptosis is triggered by the intrinsic (mitochondrial) pathway and isattributable to decreased synthesis of Bcl-2 and Bcl-x and activation of Bim and other proapoptoticmembers of the Bcl family.

Answer 196

A

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 tobe repaired successfully, p53 triggers apoptosis.

When p53 is mutated or absent (as it is incertain cancers), it is incapable of inducing apoptosis, so that cells with damaged DNA areallowed to survive. In such cells the DNA damage may result in mutations or translocations thatlead 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 effectormachinery—the caspases—is complex but seems to involve its function in transcriptionalactivation. Among the proteins whose production is stimulated by p53 are several pro-apoptoticmembers of the Bcl family, notably Bax, Bak, and some BH3-only proteins, mentioned earlier.

Answer 197

A

Chaperones in the ER control the proper folding of newly synthesized proteins, and misfoldedpolypeptides areubiquitinated and targeted for proteolysis in proteasomes

. If, however, 
unfolded or misfolded proteins accumulate in the ER, because of inherited mutations orstresses, 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 198

A

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

This process is called ER stress.

Intracellular accumulation of abnormally folded proteins, caused by geneticutations, aging, or unknown environmental factors, is now recognized as a feature of aumber 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 199

A

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

Answer 200

A

TNF

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

ischemic death of the tumor.)

Answer 201

A

Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface ofinfected host cells ( Chapter 6 ). Upon activation, CTLs secrete perforin, a transmembrane 
pore-forming molecule, which promotes entry of the CTL granule serine proteases calledgranzymes. 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 202

A

<ul>
<li>Disorders associated with defective apoptosis and increased cell survival .
<ul>
<li>mutations in p53are subjected to DNA damage, the cells not only fail to die but are susceptible to theaccumulation of mutations because of defective DNA repair, and these abnormalitiescan give rise to cancer</li>
<li>autoimmune disorders</li>
</ul>
</li>
<li>Disorders associated with increased apoptosis and excessive cell death</li>
</ul>

Answer 203

A

(1) neurodegenerativediseases, 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 204

A

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 205

A

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

Interest in autophagy has been spurred by thefinding that it is regulated by a defined set of “autophagy genes” (called Atgs) in single-celledorganisms 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 thatautophagy triggers cell death that is distinct from necrosis and apoptosis. [66]

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

Nevertheless, autophagy hasbeen 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 206

A

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

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

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 207

A

1. A normal endogenous substance is produced at a normal or increased rate, but therate 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 todegrade the abnormal protein efficiently. Examples include the accumulation of mutatedα1-antitrypsin in liver cells ( Chapter 18 ) and various mutated proteins in degenerativedisorders of the central nervous system ( Chapter 28 ). 
3. A normal endogenous substance accumulates because of defects, usually inherited, inenzymes that are required for the metabolism of the substance. Examples include 
diseases caused by genetic defects in enzymes involved in the metabolism of lipid andcarbohydrates, resulting in intracellular deposition of these substances, largely in 
lysosomes.

4. An abnormal exogenous substance is deposited and accumulates because the cell hasneither the enzymatic machinery to degrade the substance nor the ability to transport itto other sites. Accumulations of carbon particles and nonmetabolizable chemicals such 
as silica are examples of this type of alteration.

Answer 208

A

<ul>
	<li>LIPIDS</li>
	<li>PROTEINS</li>
	<li>HYALINE CHANGE</li>
	<li>GLYCOGEN</li>
	<li>PIGMENTS</li>
</ul>

Answer 209

A

<ul>
<li>The terms steatosis and fatty change describe abnormal accumulations of triglycerides withinparenchymal cells. Fatty change is often seen in the liver because it is the major organ involvedin fat metabolism, but it also occurs in heart, muscle, and kidney. </li>
</ul>

Answer 210

A

<ul>
<li>toxins,</li>
<li>protein malnutrition, </li>
<li>diabetes mellitus, </li>
<li>obesity, and anoxia. </li>
</ul>

Answer 211

A

<ul>
<li>alcohol abuse</li>
<li>andnonalcoholic fatty liver disease, which is often associated with diabetes and obesity</li>
</ul>

Answer 212

A

Different mechanisms account for triglyceride accumulation in the liver.

<ul>
<li>Free fatty acids fromadipose tissue or ingested food are normally transported into hepatocytes. In the liver they areesterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketonebodies.</li>
<li>Some fatty acids are synthesized from acetate as well. Release of triglycerides from thehepatocytes requires association with apoproteins to form lipoproteins, which may then betransported from the blood into the tissues ( Chapter 4 ).</li>
<li>Excess accumulation of triglycerideswithin the liver may result from excessive entry or defective metabolism and export of lipids (Fig. 1-30A ).</li>
<li>Several such defects are induced by alcohol, ahepatotoxin that altersmitochondrial and microsomal functions, leading to increased synthesis and reducedbreakdown of lipids ( Chapter 18 ).</li>
<li>CCl4 and protein malnutrition cause fatty change byreducing synthesis of apoproteins, hypoxia inhibits fatty acid oxidation, and starvation increasesfatty acid mobilization from peripheral stores.</li>
</ul>

Answer 213

A

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

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

Answer 214

A

Sudan IV or Oil Red-O,

Answer 215

A

glycogen,

Answer 216

A

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

With progressiveaccumulation, 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 217

A

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 218

A

Heart.

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

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

effect).

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

Answer 219

A

<ol>
	<li>Atherosclerosis</li>
	<li>Xanthomas.</li>
	<li>Cholesterolosis.</li>
	<li>Niemann-Pick disease, type C.</li>
</ol>

Answer 220

A

Xanthomas.

Intracellular accumulation of cholesterol within macrophages is alsocharacteristic 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 221

A

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 222

A

This lysosomal storage disease is caused by mutations

affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol

accumulation in multiple organs

Answer 223

A

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 224

A

<ul>
<li>Reabsorption droplets in proximal renal tubules are seen in renal diseases associatedwith protein loss in the urine (proteinuria).</li>
<li>The proteins that accumulate may be normal secreted proteins that are produced inexcessive amounts, as occurs in certain plasma cells engaged in active synthesis ofimmunoglobulins.</li>
<li>Defective intracellular transport and secretion of critical proteins</li>
<li>Accumulation of cytoskeletal proteins</li>
<li>Aggregation of abnormal proteins</li>
</ul>

Answer 225

A

pink hyaline 
droplets within the cytoplasm of the tubular cell

Answer 226

A

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

Answer 227

A

In α1-antitrypsin 
deficiency, mutations in the protein significantly slow folding, resulting in the buildup ofpartially 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 228

A

<ol>
<li>keratin filaments(characteristic of epithelial cells),</li>
<li>neurofilaments (neurons), </li>
<li>desmin filaments (musclecells), </li>
<li>vimentin filaments (connective tissue cells),</li>
<li>and glial filaments (astrocytes).</li>
</ol>

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

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

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

Answer 229

A

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

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

Answer 230

A

The term hyaline usually refers to an alteration within cells or in the extracellular space thatgives 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 specificmarker for cell injury.

This morphologic change is produced by a variety of alterations and doesnot 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 231

A

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 eitherglucose or glycogen metabolism. Whatever the clinical setting, the glycogen masses appear asclear 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 sectionbefore 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 arecollectively 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 232

A

carbon (coal dust

Answer 233

A

(anthracosis)

Answer 234

A

Tattooing

Answer 235

A

<ul>
	<li>Lipofuscin</li>
	<li>Melanin</li>
	<li>Hemosiderin</li>
</ul>

Answer 236

A

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 subcellularmembranes.

Lipofuscin is not injurious to the cell or its functions.

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

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

Answer 237

A

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 238

A

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 239

A

melanin

Answer 240

A

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 transportproteins, 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 ofiron, ferritin forms hemosiderin granules, which are easily seen with the light microscope ( Fig. 
1-34 ). Hemosiderin pigment represents aggregates of ferritin micelles. Under normal conditionssmall 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 241

A

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 andeventually hemosiderin.

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

Answer 242

A

1) increasedabsorption 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 243

A

Iron pigment appears as a coarse, golden, granular pigment lying within thecell'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 toblue-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 scatteredmacrophages 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 244

A

hemochromatosis

Answer 245

A

Bilirubin

Answer 246

A

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

Answer 247

A

<ol>
<li>When the deposition occurs locally in dying tissues it is known as dystrophiccalcification; it occurs despite normal serum levels of calcium and in the absence ofderangements in calcium metabolism.</li>
<li>In contrast, the deposition of calcium salts in otherwisenormal tissues is known as metastatic calcification, and it almost always results fromhypercalcemia secondary to some disturbance in calcium metabolism.</li>
</ol>

Answer 248

A

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 siteof 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 249

A

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

Answer 250

A

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

Answer 251

A

<ol>
<li>Decreased cellular replication</li>
<li>Accumulation of metabolic and genetic damage</li>
</ol>

Answer 252

A

senescence

Answer 253

A

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

Answer 254

A

in omplete replication of chromosome ends (telomere shortening), which ultimatelyresults 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 completereplication of chromosomal ends and for protecting chromosomal termini from fusionand degradation. [73]

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

<p style="line-height: 38.6100387573242px; text-align: center;">Telomere<br>
length is normally maintained by nucleotide addition mediated by an enzyme called<br>
telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA asa template for adding nucleotides to the ends of chromosomes ( Fig. 1-38A ). The<br>
activity of telomerase is repressed by regulatory proteins, which provide a mechanismfor sensing telomere length and restrict unnecessary elongation. Telomerase activity is<br>
highest in germ cells and present at lower levels in stem cells, but it is usuallyundetectable 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 togenerate new cells to replace damaged ones. Thus, both accumulation of senescentcells and depletion of stem cell pools via senescence contribute to aging. Conversely, in<br>
immortal cancer cells telomerase is reactivated and telomeres are stable, suggestingthat maintenance of telomere length might be an important—possibly essential—step in<br>
tumor formation ( Chapter 7 ). Despite such alluring observations, however, therelationship of telomerase activity and telomeric length to aging and cancer still must be<br>
fully established</p>

Answer 255

A

increased expression of the cell cycle

inhibitor p16INK4a and by DNA damage

Answer 256

A

(1) variation in longevity among differentspecies 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 radicalsmay have deleterious effects on DNA, leading to breaks and genome instability, thus 
affecting all cellular functions.

Answer 257

A

recognition and repair of damaged DNA.

Answer 258

A

DNA helicase

Answer 259

A

calorie restriction

Answer 260

A

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

These products include 
proteins that increase metabolic activity, reduce apoptosis, stimulate protein folding, and inhibitthe 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 activatesirtuins and thus increase life span! Other studies have shown that growth factors, such asinsulin-like growth factor, and intracellular signaling pathways triggered by these hormones also 
influence life span. [69]

Transcription factors activated by insulin receptor signaling may inducegenes that reduce longevity, and insulin receptor mutations are associated with increased lifespan.

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 ofcell death represented by apoptosis; to the pathologic alterations in cell organelles; and to theless 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.

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