Cell Injury and Death Mechanisms

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com C H A P T E R
Cell Injury, Cell Death,

and Adaptations 2
CHAPTER OUTLINE
Introduction to Pathology 31 Other Pathways of Cell Death 40 Common Events in Cell Injury From Diverse
Overview of Cellular Responses Autophagy 40 Causes 47
to Stress and Noxious Mechanisms of Cell Injury and Cell Cellular Adaptations to Stress 48
Stimuli 31 Death 41 Hypertrophy 48
Causes of Cell Injury 32 Hypoxia and Ischemia 42 Hyperplasia 49
Sequence of Events in Cell Injury Ischemia-Reperfusion Injury 43 Atrophy 50
and Cell Death 33 Oxidative Stress 43 Metaplasia 50
Reversible Cell Injury 33 Cell Injury Caused by Toxins 45 Intracellular Accumulations 51
Cell Death 34 Endoplasmic Reticulum Stress 45 Pathologic Calcification 53
Necrosis 35 DNA Damage 47 Cellular Aging 54
Apoptosis 37 Inflammation 47
scopic appearance (morphology) of cells and tissues, and

INTRODUCTION TO PATHOLOGY biochemical alterations in body fluids (such as blood and
urine). Pathologists also use a variety of morphologic,
The field of pathology is devoted to understanding the molecular, and other techniques to define the biochemical,
causes of disease and the changes in cells, tissues, and structural, and functional changes that occur in cells,
organs that are associated with disease and give rise to the tissues, and organs in response to injury. We begin, in this
presenting signs and symptoms in patients. There are two chapter, with a discussion of cellular abnormalities induced
important terms that students will encounter throughout by a variety of internal (e.g., genetic) and external (e.g.,
their study of pathology and medicine: environmental) abnormalities and stresses.
• Etiology refers to the underlying causes and modifying
factors that are responsible for the initiation and pro-
gression of disease. It is now clear that many common OVERVIEW OF CELLULAR
diseases, such as hypertension, diabetes, and cancer, are
caused by a combination of inherited genetic suscepti- RESPONSES TO STRESS AND
bility and various environmental triggers. Elucidating NOXIOUS STIMULI
the genetic and environmental factors underlying dis-
eases is a major theme of modern medicine. Cells actively interact with their environment, constantly
• Pathogenesis refers to the mechanisms of development adjusting their structure and function to accommodate
and progression of disease, which account for the cel- changing demands and extracellular stresses. The intracel-
lular and molecular changes that give rise to the specific lular milieu of cells is normally tightly regulated such that
functional and structural abnormalities that characterize it remains fairly constant, a state referred to as homeosta-
any particular disease. Thus, etiology refers to why a sis. As cells encounter physiologic stresses (such as
disease arises and pathogenesis describes how a disease increased workload in the heart) or potentially injurious
develops (Fig. 2.1). conditions (such as nutrient deprivation), they can undergo
adaptation, achieving a new steady state and preserving
Defining the etiology and pathogenesis of disease not viability and function. If the adaptive capability is exceeded
only is essential for understanding disease but also is the or if the external stress is inherently harmful or excessive,
basis for developing rational treatments and effective pre- cell injury develops (Fig. 2.2). Within certain limits, injury
ventive measures. Thus, pathology provides the scientific is reversible, and cells return to their stable baseline;
foundation for the practice of medicine. however, if the stress is severe, persistent, or rapid in onset,
To render diagnoses and guide therapy in clinical prac- it results in irreversible injury and death of the affected cells.
tice, pathologists identify changes in the gross or micro- Cell death is one of the most crucial events in the evolution
31
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32 C H A P T E R 2 Cell Injury, Cell Death, and Adaptations
Immunologic Genetic abnormalities Nutritional

abnormalities (inherited and acquired) imbalances CAUSES OF CELL INJURY
Infections The causes of cell injury span a range from gross physical
ETIOLOGY: Trauma trauma, such as after a motor vehicle accident, to a single
CAUSES OF DISEASE
Toxins gene defect that results in a nonfunctional enzyme in a
specific metabolic disease. Most injurious stimuli can be
grouped into the following categories.
PATHOGENESIS: Hypoxia and ischemia. Hypoxia, which refers to oxygen
Biochemical Structural
changes
MECHANISMS OF DISEASE
changes
deficiency, and ischemia, which means reduced blood
supply, are among the most common causes of cell injury.
Both deprive tissues of oxygen, and ischemia, in addition,
results in a deficiency of essential nutrients and a build up
MOLECULAR, FUNCTIONAL, of toxic metabolites. The most common cause of hypoxia
AND MORPHOLOGIC is ischemia resulting from an arterial obstruction, but
ABNORMALITIES IN
CELLS AND TISSUES oxygen deficiency also can result from inadequate oxygen-
ation of the blood, as in a variety of diseases affecting the
lung, or from reduction in the oxygen-carrying capacity of
the blood, as with anemia of any cause, and carbon mon-
CLINICAL MANIFESTATIONS: oxide (CO) poisoning.
SIGNS AND SYMPTOMS Toxins. Potentially toxic agents are encountered daily
OF DISEASE in the environment; these include air pollutants, insecti-
cides, CO, asbestos, cigarette smoke, ethanol, and drugs.
Fig. 2.1 Steps in the evolution of disease. Only selected major causes (eti-
ologies) are shown.
Many drugs in therapeutic doses can cause cell or tissue
injury in a susceptible patient or in many individuals if
used excessively or inappropriately (Chapter 7). Even
of disease in any tissue or organ. It results from diverse innocuous substances, such as glucose, salt, water and
causes, including ischemia (lack of blood flow), infections, oxygen, can be toxic.
toxins, and immune reactions. Cell death also is a normal Infectious agents. All types of disease-causing patho-
and essential process in embryogenesis, the development gens, including viruses, bacteria, fungi, and protozoans,
of organs, and the maintenance of tissue homeostasis. injure cells. The mechanisms of cell injury caused by these
Because damage to cells is the basis of all disease, in this diverse agents are discussed in Chapter 9.
chapter we discuss first the causes, mechanisms, and con- Immunologic reactions. Although the immune system
sequences of the various forms of acute cell injury, includ- defends the body against pathogenic microbes, immune
ing reversible injury and cell death. We then consider reactions also can result in cell and tissue injury. Examples
cellular adaptations to stress and conclude with two other are autoimmune reactions against one’s own tissues, aller-
processes that affect cells and tissues: the deposition of gic reactions against environmental substances, and exces-
abnormal substances and cell aging. sive or chronic immune responses to microbes (Chapter 5).
In all of these situations, immune responses elicit inflam-
matory reactions, which are often the cause of damage to
cells and tissues.
NORMAL CELL Genetic abnormalities. Genetic aberrations can result in
(homeostasis)
pathologic changes as conspicuous as the congenital mal-
formations associated with Down syndrome or as subtle as
Injurious stimulus
the single amino acid substitution in hemoglobin giving
rise to sickle cell anemia (Chapter 7). Genetic defects may
REVERSIBLE cause cell injury as a consequence of deficiency of func-
INJURY tional proteins, such as enzymes in inborn errors of metab-
olism, or accumulation of damaged DNA or misfolded
Severe, progressive proteins, both of which trigger cell death when they are
beyond repair.
Nutritional imbalances. Protein–calorie insufficiency
IRREVERSIBLE among impoverished populations remains a major cause
INJURY
of cell injury, and specific vitamin deficiencies are not
uncommon even in developed countries with high stan-
dards of living (Chapter 8). Ironically, excessive dietary
intake may result in obesity and also is an important
CELL
NECROSIS DEATH APOPTOSIS underlying factor in many diseases, such as type 2 diabetes
mellitus and atherosclerosis.
Fig. 2.2 Sequence of reversible cell injury and cell death. Necrosis and Physical agents. Trauma, extremes of temperature, radi-
apoptosis are the two major pathways of cell death and are discussed in ation, electric shock, and sudden changes in atmospheric
detail later. pressure all have wide-ranging effects on cells (Chapter 8).
Sequence of Events in Cell Injury and Cell Death 33
Aging. Cellular senescence results in a diminished

ability of cells to respond to stress and, eventually, the
death of cells and of the organism. The mechanisms under-
lying cellular aging are discussed at the end of this chapter.
With this introduction, we proceed to a discussion of the NORMAL
CELL
progression and morphologic manifestations of cell injury,
and then to the biochemical mechanisms in injury caused
by different noxious stimuli.
Reversible
SEQUENCE OF EVENTS IN CELL injury Recovery
INJURY AND CELL DEATH
Swelling of
Although various injurious stimuli damage cells through endoplasmic
diverse biochemical mechanisms, all tend to induce a ste- reticulum and
mitochondria
reotypic sequence of morphologic and structural altera-
tions in most types of cells.
Reversible Cell Injury Myelin figure Membrane

blebs
Reversible injury is the stage of cell injury at which the
deranged function and morphology of the injured cells
can return to normal if the damaging stimulus is removed
(Fig. 2.3). In reversible injury, cells and intracellular organ- Progressive injury
elles typically become swollen because they take in water Breakdown of
as a result of the failure of energy-dependent ion pumps plasma membrane,
in the plasma membrane, leading to an inability to main- organelles, and
nucleus; leakage
tain ionic and fluid homeostasis. In some forms of injury, of contents
degenerated organelles and lipids may accumulate inside
the injured cells.
Inflammation
MORPHOLOGY
The two main morphologic correlates of reversible cell injury
are cellular swelling and fatty change.
• Cellular swelling (Fig. 2.4B) is commonly seen in cell injury NECROSIS
associated with increased permeability of the plasma mem-
Amorphous densities in mitochondria
brane. It may be difficult to appreciate with the light micro-
scope, but it is often apparent at the level of the whole organ. Fig. 2.3 Reversible cell injury and necrosis. The principal cellular alterations
When it affects many cells in an organ, it causes pallor (as a that characterize reversible cell injury and necrosis are illustrated. By conven-
tion, reversible injury is considered to culminate in necrosis if the injurious
result of compression of capillaries), increased turgor, and an stimulus is not removed.
increase in organ weight. Microscopic examination may show
small, clear vacuoles within the cytoplasm; these represent
with detachment of ribosomes and dissociation of polysomes;
distended and pinched-off segments of the endoplasmic reticu-
and (4) nuclear alterations, such as clumping of chromatin. The
lum (ER). This pattern of nonlethal injury is sometimes called
cytoplasm may contain so-called “myelin figures,” which are col-
hydropic change or vacuolar degeneration.
lections of phospholipids resembling myelin sheaths that are
• Fatty change is manifested by the appearance of triglyceride
derived from damaged cellular membranes.
containing lipid vacuoles in the cytoplasm. It is principally
encountered in organs that are involved in lipid metabolism,
such as the liver, and hence it is discussed in Chapter 16.
In some situations, potentially injurious insults induce
specific alterations in cellular organelles, such as the ER.
The cytoplasm of injured cells also may become redder
The smooth ER is involved in the metabolism of various
(eosinophilic), a change that becomes much more pronounced
chemicals, and cells exposed to these chemicals show
with progression to necrosis (described later). Other intracel-
hypertrophy of the ER as an adaptive response that may
lular changes associated with cell injury (Fig. 2.3) include (1)
have important functional consequences. For instance,
plasma membrane alterations such as blebbing, blunting, or dis-
many drugs, including barbiturates, which were com-
tortion of microvilli, and loosening of intercellular attachments;
monly used as sedatives in the past and are still used as a
(2) mitochondrial changes such as swelling and the appearance
treatment for some forms of epilepsy, are metabolized in
of phospholipid-rich amorphous densities; (3) dilation of the ER
the liver by the cytochrome P-450 mixed-function oxidase
system found in the smooth ER. Protracted use of
A B C
Fig. 2.4 Morphologic changes in reversible and irreversible cell injury (necrosis). (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible)
ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrotic (irreversible) injury of epithelial cells,
with loss of nuclei and fragmentation of cells and leakage of contents. (Courtesy of Drs. Neal Pinckard and M.A. Venkatachalam, University of Texas Health Sciences
Center, San Antonio, Texas.)
barbiturates leads to a state of tolerance, marked by the uncontrollable form of death that has been called “acci-
need to use increasing doses of the drug to achieve the dental” cell death. The morphological manifestation of
same effect. This adaptation stems from hypertrophy (an accidental cell death is necrosis (Greek, necros = death)
increase in volume) of the smooth ER of hepatocytes and (Table 2.1). Necrosis is the major pathway of cell death
a consequent increase in P-450 enzymatic activity. P-450– in many commonly encountered injuries, such as those
mediated modification of compounds sometimes leads to resulting from ischemia, exposure to toxins, various
their detoxification, but in other instances converts them infections, and trauma. Necrosis is traditionally consid-
into a dangerous toxin; one such example involves carbon ered the inevitable end result of severe damage that is
tetrachloride (CCl4), discussed later. Cells adapted to one beyond salvage and is not thought to be regulated by
drug demonstrate an increased capacity to metabolize specific signals or biochemical mechanisms; in other
other compounds handled by the same system. Thus, if words, necrosis happens accidentally because the injury
patients taking phenobarbital for epilepsy increase their is too severe to be repaired and many cellular constitu-
alcohol intake, they may experience a drop in blood con- ents simply fail or fall apart.
centration of the anti-seizure medication to subtherapeutic • In contrast, when the injury is less severe, or cells need
levels because of smooth ER hypertrophy in response to to be eliminated during normal processes, they activate
the alcohol. a precise set of molecular pathways that culminate in
With persistent or excessive noxious exposures, injured death. Because this kind of cell death can be manipulated
cells pass a nebulous “point of no return” and undergo cell
death. The clinical relevance of defining this transition
point is obvious—if the biochemical and molecular changes
that predict cell death can be identified, it may be possible Table 2.1 Features of Necrosis and Apoptosis
to devise strategies for preventing the transition from Feature Necrosis Apoptosis
reversible to irreversible cell injury. Although there are no
definitive morphologic or biochemical correlates of irre- Cell size Enlarged (swelling) Reduced (shrinkage)
versibility, it is consistently characterized by three phe- Nucleus Pyknosis → Fragmentation into
nomena: the inability to restore mitochondrial function karyorrhexis → nucleosome-sized
karyolysis fragments
(oxidative phosphorylation and adenosine triphosphate
[ATP] generation) even after resolution of the original Plasma Disrupted Intact; altered structure,
membrane especially orientation
injury; the loss of structure and functions of the plasma mem- of lipids
brane and intracellular membranes; and the loss of DNA and
Cellular contents Enzymatic digestion; Intact; may be released
chromatin structural integrity. As discussed in more detail may leak out of cell in apoptotic bodies
later, injury to lysosomal membranes results in the enzy-
Adjacent Frequent No
matic dissolution of the injured cell, which is the culmina- inflammation
tion of necrosis.
Physiologic or Invariably pathologic Often physiologic
pathologic (culmination of means of eliminating
Cell Death role irreversible cell unwanted cells; may
injury) be pathologic after
When cells are injured they die by different mechanisms, some forms of cell
depending on the nature and severity of the insult. injury, especially
• Severe disturbances, such as loss of oxygen and nutrient DNA and protein
damage
supply and the actions of toxins, cause a rapid and
Necrosis
Reversible Irreversible
cell injury cell injury Ultrastructural Light
changes microscopic Necrosis is a form of cell death in which cellular mem-
changes branes fall apart, and cellular enzymes leak out and ulti-
Cell Cell death mately digest the cell (Fig. 2.3). Necrosis elicits a local host
function
reaction, called inflammation, that is induced by substances
released from dead cells and which serves to eliminate the
Gross
debris and start the subsequent repair process (Chapter 3).
EFFECT
morphologic
changes The enzymes responsible for digestion of the cell are
derived from lysosomes and may come from the dying
cells themselves or from leukocytes recruited as part of the
inflammatory reaction. Necrosis often is the culmination of
reversible cell injury that cannot be corrected.
The biochemical mechanisms of necrosis vary with dif-
ferent injurious stimuli. These mechanisms include: failure
DURATION OF INJURY of energy generation in the form of ATP because of reduced
Fig. 2.5 The relationship among cellular function, cell death, and the mor- oxygen supply or mitochondrial damage; damage to cel-
phologic changes of cell injury. Note that cells may rapidly become nonfunc- lular membranes, including the plasma membrane and
tional after the onset of injury, although they are still viable, with potentially lysosomal membranes, which results in leakage of cellular
reversible damage; with a longer duration of injury, irreversible injury and contents including enzymes; irreversible damage to cellu-
cell death may result. Note also that cell death typically precedes ultrastruc- lar lipids, proteins, and nucleic acids, which may be caused
tural, light microscopic, and grossly visible morphologic changes.
by reactive oxygen species (ROS); and others. These bio-
chemical mechanisms are discussed later when we con-
sider the individual causes of cell necrosis.
by therapeutic agents or genetic mutations, it is said to
be “regulated” cell death. The morphologic appearance
of most types of regulated cell death is apoptosis (see MORPHOLOGY
Table 2.1). In some instances, regulated cell death shows
Necrosis is characterized by changes in the cytoplasm and nuclei
features of both necrosis and apoptosis, and has been
of the injured cells (Figs. 2.3 and 2.4C).
called necroptosis. The discovery of these previously
• Cytoplasmic changes. Necrotic cells show increased eosin-
unrecognized forms of cell death that were regulated by
ophilia (i.e., they are stained red by the dye eosin—the E in
identifiable genes and signaling pathways showed that
the hematoxylin and eosin [H&E] stain), attributable partly to
cell death can be a controlled process. The idea of regu-
increased binding of eosin to denatured cytoplasmic proteins
lated cell death also raises the possibility that specific
and partly to loss of basophilic ribonucleic acid (RNA) in the
molecular pathways can be targeted therapeutically to
cytoplasm (basophilia stems from binding of the blue dye
prevent the loss of cells in pathologic conditions. Apop-
hematoxylin—the H in “H&E”). Compared with viable cells, the
tosis is a process that eliminates cells with a variety of
cell may have a glassy, homogeneous appearance, mostly
intrinsic abnormalities and promotes clearance of the
because of the loss of lighter staining glycogen particles. Myelin
fragments of the dead cells without eliciting an inflam-
figures are more prominent in necrotic cells than in cells with
matory reaction. This “clean” form of cell suicide occurs
reversible injury. When enzymes have digested cytoplasmic
in pathologic situations when a cell’s DNA or proteins
organelles, the cytoplasm becomes vacuolated and appears
are damaged beyond repair or the cell is deprived of
“moth-eaten.” By electron microscopy, necrotic cells are char-
necessary survival signals. But unlike necrosis, which
acterized by discontinuities in plasma and organelle mem-
is always an indication of a pathologic process, apop-
branes, marked dilation of mitochondria associated with the
tosis also occurs in healthy tissues. It serves to elimi-
appearance of large amorphous intramitrochondrial densities,
nate unwanted cells during normal development and to
disruption of lysosomes, and intracytoplasmic myelin figures.
maintain constant cell numbers, so it is not necessarily
• Nuclear changes. Nuclear changes assume one of three pat-
associated with pathologic cell injury. These types of
terns, all resulting from a breakdown of DNA and chromatin.
physiologic cell death are also called programmed cell
Pyknosis is characterized by nuclear shrinkage and increased
death.
basophilia; the DNA condenses into a dark shrunken mass.The
pyknotic nucleus can undergo fragmentation; this change is
It is important to point out that cellular function may
called karyorrhexis. Ultimately, the nucleus may undergo
be lost long before cell death occurs, and that the mor-
karyolysis, in which the basophilia fades because of digestion
phologic changes of cell injury (or death) lag far behind
of DNA by deoxyribonuclease (DNase) activity. In 1 to 2 days,
loss of function and viability (Fig. 2.5). For example, myo-
the nucleus in a dead cell may completely disappear.
cardial cells become noncontractile after 1 to 2 minutes
• Fates of necrotic cells. Necrotic cells may persist for some
of ischemia, but may not die until 20 to 30 minutes of
time or may be digested by enzymes and disappear. Dead cells
ischemia have elapsed. Morphologic features indica-
may be replaced by myelin figures, which are either phagocy-
tive of the death of ischemic myocytes appear by elec-
tosed by other cells or further degraded into fatty acids. These
tron microscopy within 2 to 3 hours after the death of the
fatty acids bind calcium salts, which may result in the dead cells
cells, but are not evident by light microscopy until 6 to 12
ultimately becoming calcified.
hours later.
A B
Fig. 2.6 Coagulative necrosis. (A) A wedge-shaped kidney infarct (yellow) with preservation of the outlines. (B) Microscopic view of the edge of the infarct,
with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is
present (difficult to discern at this magnification).
Morphologic Patterns of Tissue Necrosis infection, the material is frequently creamy yellow and is called
In severe pathologic conditions, large areas of a tissue or pus (Chapter 3).
even entire orgrans may undergo necrosis. This may • Although gangrenous necrosis is not a distinctive pattern
happen in association with marked ischemia, infections, of cell death, the term is still commonly used in clinical practice.
and certain inflammatory reactions. There are several mor- It usually refers to the condition of a limb (generally the lower
phologically distinct patterns of tissue necrosis that may leg) that has lost its blood supply and has undergone coagula-
provide etiologic clues. Although the terms that describe tive necrosis involving multiple tissue layers. When bacterial
these patterns do not reflect underlying mechanisms, such infection is superimposed, the morphologic appearance
terms are commonly used and their implications are under- changes to liquefactive necrosis because of the destructive
stood by pathologists and clinicians. contents of the bacteria and the attracted leukocytes (resulting
in so-called “wet gangrene”).
• Caseous necrosis is most often encountered in foci of tuber-
MORPHOLOGY culous infection. Caseous means “cheeselike,” referring to the
Most of the types of necrosis described here have distinctive friable yellow-white appearance of the area of necrosis on
gross appearances; the exception is fibrinoid necrosis, which is gross examination (Fig. 2.8). On microscopic examination, the
detected only by histologic examination. necrotic focus appears as a collection of fragmented or lysed
• Coagulative necrosis is a form of necrosis in which the cells with an amorphous granular pink appearance in H&E-
underlying tissue architecture is preserved for at least several stained tissue sections. Unlike coagulative necrosis, the tissue
days after death of cells in the tissue (Fig. 2.6). The affected
tissues take on a firm texture. Presumably the injury denatures
not only structural proteins but also enzymes, thereby blocking
the proteolysis of the dead cells; as a result, eosinophilic,
anucleate cells may persist for days or weeks. Leukocytes are
recruited to the site of necrosis, and the dead cells are ulti-
mately digested by the action of lysosomal enzymes of the
leukocytes.The cellular debris is then removed by phagocytosis
mediated primarily by infiltrating neutrophils and macrophages.
Coagulative necrosis is characteristic of infarcts (areas of
necrosis caused by ischemia) in all solid organs except the
brain.
• Liquefactive necrosis is seen in focal bacterial and, occasion-
ally, fungal infections because microbes stimulate rapid accu-
mulation of inflammatory cells, and the enzymes of leukocytes
digest (“liquefy”) the tissue. For obscure reasons, hypoxic
death of cells within the central nervous system often evokes
liquefactive necrosis (Fig. 2.7). Whatever the pathogenesis, the
dead cells are completely digested, transforming the tissue into
a viscous liquid that is eventually removed by phagocytes. If the
process is initiated by acute inflammation, as in a bacterial Fig. 2.7 Liquefactive necrosis. An infarct in the brain shows dissolution of
the tissue.
Fig. 2.10 Fibrinoid necrosis in an artery in a patient with polyarteritis

nodosa. The wall of the artery shows a circumferential bright pink area of
necrosis with protein deposition and inflammation.
Fig. 2.8 Caseous necrosis. Tuberculosis of the lung, with a large area of • Fibrinoid necrosis is a special form of necrosis. It usually
caseous necrosis containing yellow-white (cheesy) debris.
occurs in immune reactions in which complexes of antigens
and antibodies are deposited in the walls of blood vessels, but
architecture is completely obliterated and cellular outlines it also may occur in severe hypertension. Deposited immune
cannot be discerned. Caseous necrosis is often surrounded by complexes and plasma proteins that leak into the wall of
a collection of macrophages and other inflammatory cells; this damaged vessels produce a bright pink, amorphous appearance
appearance is characteristic of a nodular inflammatory lesion on H&E preparations called fibrinoid (fibrinlike) by pathologists
called a granuloma (Chapter 3). (Fig. 2.10). The immunologically mediated diseases (e.g., poly-
• Fat necrosis refers to focal areas of fat destruction, typically arteritis nodosa) in which this type of necrosis is seen are
resulting from the release of activated pancreatic lipases into described in Chapter 5.
the substance of the pancreas and the peritoneal cavity. This
occurs in the calamitous abdominal emergency known as acute Leakage of intracellular proteins through the damaged
pancreatitis (Chapter 17). In this disorder, pancreatic enzymes cell membrane and ultimately into the circulation pro-
that have leaked out of acinar cells and ducts liquefy the mem- vides a means of detecting tissue-specific necrosis using
branes of fat cells in the peritoneum, and lipases split the tri- blood or serum samples. Cardiac muscle, for example,
glyceride esters contained within fat cells. The released fatty contains a unique isoform of the enzyme creatine kinase
acids combine with calcium to produce grossly visible chalky and of the contractile protein troponin, whereas hepatic
white areas (fat saponification), which enable the surgeon and bile duct epithelium contains the enzyme alkaline phos-
the pathologist to identify the lesions (Fig. 2.9). On histologic phatase, and hepatocytes contain transaminases. Irrevers-
examination, the foci of necrosis contain shadowy outlines of ible injury and cell death in these tissues elevate the serum
necrotic fat cells surrounded by basophilic calcium deposits levels of these proteins, which makes them clinically useful
and an inflammatory reaction. markers of tissue damage.
Apoptosis
Apoptosis is a pathway of cell death in which cells acti-
vate enzymes that degrade the cells’ own nuclear DNA
and nuclear and cytoplasmic proteins (Fig. 2.11). Frag-
ments of the apoptotic cells then break off, giving the
appearance that is responsible for the name (apoptosis,
“falling off”). The plasma membrane of the apoptotic cell
remains intact, but the membrane is altered in such a way
that the fragments, called apoptotic bodies, become highly
“edible,” leading to their rapid consumption by phago-
cytes. The dead cell and its fragments are cleared with little
leakage of cellular contents, so apoptotic cell death does
not elicit an inflammatory reaction. Thus, apoptosis differs
in many respects from necrosis (Table 2.1).
Fig. 2.9 Fat necrosis in acute pancreatitis.The areas of white chalky deposits
Causes of Apoptosis
represent foci of fat necrosis with calcium soap formation (saponification) Apoptosis occurs in many normal situations and serves to
at sites of lipid breakdown in the mesentery. eliminate potentially harmful cells and cells that have
Table 2.2 Physiologic and Pathologic Conditions Associated

With Apoptosis
Condition Mechanism of Apoptosis
Physiologic
NORMAL During embryogenesis Loss of growth factor signaling
CELL (presumed mechanism)
Turnover of proliferative tissues Loss of growth factor signaling
(e.g., intestinal epithelium, (presumed mechanism)
lymphocytes in bone marrow,
and thymus)
Involution of hormone- Decreased hormone levels lead
dependent tissues (e.g., to reduced survival signals
Condensation endometrium)
of chromatin Decline of leukocyte numbers Loss of survival signals as
at the end of immune and stimulus for leukocyte
inflammatory responses activation is eliminated
Membrane blebs Elimination of potentially Strong recognition of self
harmful self-reactive antigens induces apoptosis by
lymphocytes both the mitochondrial and
death receptor pathways
Pathologic
DNA damage Activation of proapoptotic
proteins by BH3-only sensors
Accumulation of misfolded Activation of proapoptotic
Cellular proteins proteins by BH3-only sensors,
fragmentation possibly direct activation of
caspases
Infections, especially certain Activation of the mitochondrial
viral infections pathway by viral proteins
Killing of infected cells by
APOPTOSIS cytotoxic T lymphocytes, which
Apoptotic activate caspases
body
• Apoptosis in pathologic conditions. Apoptosis eliminates

Phagocytosis cells that are damaged beyond repair. This is seen when
Phagocyte of apoptotic cells there is severe DNA damage, for example, after expo-
and fragments sure to radiation and cytotoxic drugs. The accumulation
of misfolded proteins also triggers apoptotic death; the
underlying mechanisms of this cause of cell death and
its significance in disease are discussed later, in the
context of ER stress. Certain infectious agents, particu-
Fig. 2.11 Apoptosis. The cellular alterations in apoptosis are illustrated.
Contrast these with the changes that characterize necrotic cell death, shown
larly some viruses, induce apoptotic death of infected
in Fig. 2.3. cells.
Mechanisms of Apoptosis
outlived their usefulness (Table 2.2). It also occurs as a Apoptosis is regulated by biochemical pathways that
pathologic event when cells are damaged, especially when control the balance of death- and survival-inducing
the damage affects the cell’s DNA or proteins; thus, the signals and ultimately the activation of enzymes called
irreparably damaged cell is eliminated. caspases. Caspases were so named because they are cyste-
• Physiologic apoptosis. During normal development of an ine proteases that cleave proteins after aspartic acid resi-
organism, some cells die and are replaced by new ones. dues. Two distinct pathways converge on caspase
In mature organisms, highly proliferative and hormone- activation: the mitochondrial pathway and the death recep-
responsive tissues undergo cycles of proliferation and tor pathway (Fig. 2.12). Although these pathways can
cell loss that are often determined by the levels of intersect, they are generally induced under different condi-
growth factors. In these situations, the cell death is tions, involve different molecules, and serve distinct roles
always by apoptosis, ensuring that unwanted cells are in physiology and disease. The end result of apoptotic cell
eliminated without eliciting potentially harmful inflam- death is the clearance of apoptotic bodies by phagocytes.
mation. In the immune system, apoptosis eliminates • The mitochondrial (intrinsic) pathway seems to be
excess leukocytes left at the end of immune responses responsible for apoptosis in most physiologic and
as well as lymphocytes that recognize self-antigens and pathologic situations. Mitochondria contain several
could cause autoimmune diseases if they were not proteins that are capable of inducing apoptosis, includ-
purged. ing cytochrome c. When mitochondrial membranes
MITOCHONDRIAL (INTRINSIC) DEATH RECEPTOR (EXTRINSIC)

PATHWAY PATHWAY
Receptor-ligand interactions
• Fas
• TNF receptor
Cell injury Mitochondria
• Growth factor
withdrawal Adaptor proteins
• DNA damage
(by radiation, Phagocyte
Cytochrome c
toxins, free Bcl-2 family Caspase
and other
radicals) effectors (Bax, Bak) activation
pro-apoptotic
• Protein proteins
misfolding Regulators
(ER stress) BH3 (Bcl-2, Bcl-xL)
sensors
Endonuclease Breakdown of
activation cytoskeleton
Nuclear
fragmentation
Ligands for
phagocytic
cell receptors
Apoptotic body
Fig. 2.12 Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases.
In the mitochondrial pathway, BH3-only proteins, which are related to members of the Bcl-2 family, sense a lack of survival signals or DNA or protein damage.
These BH3-only proteins activate effector molecules that increase mitochondrial permeability. In concert with a deficiency of Bcl-2 and other proteins that
maintain mitochondrial permeability, the mitochondria become leaky and various substances, such as cytochrome c, enter the cytosol and activate caspases.
Activated caspases induce the changes that culminate in cell death and fragmentation. In the death receptor pathway, signals from plasma membrane receptors
lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same.
become permeable, cytochrome c leaks out into the receptors, that trigger apoptosis. Most of these are
cytoplasm, triggering caspase activation and apoptotic members of the tumor necrosis factor (TNF) receptor
death. A family of more than 20 proteins, the proto- family, which contain in their cytoplasmic regions a
type of which is Bcl-2, controls the permeability of conserved “death domain,” so named because it medi-
mitochondria. In healthy cells, Bcl-2 and the related ates interaction with other proteins involved in cell
protein Bcl-xL, which are produced in response to death. The prototypic death receptors are the type I TNF
growth factors and other stimuli, maintain the integrity receptor and Fas (CD95). Fas ligand (FasL) is a mem-
of mitochondrial membranes, in large part by holding brane protein expressed mainly on activated T lympho-
two proapoptotic members of the family, Bax and Bak, cytes. When these T cells recognize Fas-expressing
in check. When cells are deprived of growth factors targets, Fas molecules are crosslinked by FasL and bind
and survival signals, or are exposed to agents that adaptor proteins via the death domain. These then
damage DNA, or accumulate unacceptable amounts of recruit and activate caspase-8, which, in turn, activates
misfolded proteins, a number of sensors are activated. downstream caspases. The death receptor pathway is
These sensors are called BH3 proteins because they involved in the elimination of self-reactive lymphocytes
contan the third domain seen in Bcl-family proteins. and in the killing of target cells by some cytotoxic T
They in turn shift this delicate, life-sustaining balance in lymphocytes (CTLs) that express FasL.
favor of pro-apoptotic Bak and Bax. As a result, Bak and In either pathway, after caspase-9 or caspase-8 is acti-
Bax dimerize, insert into the mitochondrial membrane, vated, it cleaves and thereby activates additional cas-
and form channels through which cytochrome c and pases that cleave numerous targets and ultimately
other mitochondrial proteins escape into the cytosol. activate enzymes that degrade the cells’ proteins and
After cytochrome c enters the cytosol, it, together with nucleus. The end result is the characteristic cellular frag-
certain cofactors, activates caspase-9. The net result is mentation of apoptosis.
the activation of a caspase cascade, ultimately leading • Clearance of apoptotic cells. Apoptotic cells and their
to nuclear fragmentation and formation of apoptotic fragments entice phagocytes by producing a number of
bodies. “eat-me” signals. For instance, in normal cells, phospha-
• The death receptor (extrinsic) pathway of apoptosis. tidylserine is present on the inner leaflet of the plasma
Many cells express surface molecules, called death membrane, but in apoptotic cells this phospholipid
“flips” to the outer leaflet, where it is recognized by

tissue macrophages, leading to phagocytosis of the
apoptotic cells. Cells that are dying by apoptosis also
secrete soluble factors that recruit phagocytes. The
plasma membrane alterations and secreted proteins
facilitate prompt clearance of the dead cells before the
cells undergo membrane damage and release their con-
tents (which can induce inflammation). Numerous mac-
rophage receptors have been shown to be involved in
the binding and engulfment of apoptotic cells. The
phagocytosis of apoptotic cells is so efficient that dead
cells disappear without leaving a trace, and inflamma-
tion is virtually absent.
MORPHOLOGY
In H&E-stained tissue sections, the nuclei of apoptotic cells show
various stages of chromatin condensation and aggregation and,
ultimately, karyorrhexis (Fig. 2.13); at the molecular level, this is
reflected in the fragmentation of DNA into nucleosome-sized
pieces. The cells rapidly shrink, form cytoplasmic buds, and frag-
ment into apoptotic bodies that are composed of membrane-
bound pieces of cytosol and organelles (Fig. 2.11). Because these
fragments are quickly extruded and phagocytosed without elicit-
ing an inflammatory response, even substantial apoptosis may be
Fig. 2.13 Morphologic appearance of apoptotic cells. Apoptotic cells (some
histologically undetectable. indicated by arrows) in colonic epithelium are shown. (Some preparative
regimens for colonoscopy may induce apoptosis in epithelial cells, which
explains the presence of dead cells in this biopsy.) Note the fragmented
Other Pathways of Cell Death nuclei with condensed chromatin and the shrunken cell bodies, some with
pieces falling off. (Courtesy of Dr. Sanjay Kakar, Department of Pathology, Univer-
In addition to necrosis and apoptosis, two other patterns sity of California San Francisco, San Francisco, California.)
of cell death have been described that have unusual fea-
tures. Although the importance of these pathways in microbes cause the death of infected cells. Its role in
disease remains to be established, they are the subjects of other pathologic situations is unknown.
considerable current research, and it is useful to be aware
of the basic concepts. Autophagy
• Necroptosis. This form of cell death is initiated by engage-
ment of TNF receptors as well as other, poorly defined Autophagy (“self-eating”) refers to lysosomal digestion
triggers. Unlike the extrinsic pathway of apoptosis, which of the cell’s own components. It is a survival mechanism
also is downstream of TNF receptors, in necroptosis, in times of nutrient deprivation, so that the starved cell can
kinases called receptor-interacting protein (RIP) kinases live by eating its own contents and recycling these contents
are activated, initiating a series of events that result in the to provide nutrients and energy. In this process, intracel-
dissolution of the cell, much like necrosis. The name lular organelles and portions of cytosol are first seques-
necroptosis implies that there are features of both necro- tered within an ER-derived autophagic vacuole, whose
sis and apoptosis. Some infections are believed to kill formation is initiated by cytosolic proteins that sense
cells by this pathway, and it has been hypothesized to nutrient deprivation (Fig. 2.14). The vacuole fuses with
play a role in ischemic injury and other pathologic situa- lysosomes to form an autophagolysosome, in which lyso-
tions, especially those associated with inflammatory reac- somal enzymes digest the cellular components. In some
tions in which the cytokine TNF is produced. However, circumstances, autophagy may be associated with atrophy
when and why it occurs and how significant it is in of tissues (discussed later) and may represent an adapta-
human diseases is not well understood. tion that helps cells survive lean times. If, however, the
• Pyroptosis. This form of cell death is associated with starved cell can no longer cope by devouring its contents,
activation of a cytosolic danger-sensing protein complex autophagy may eventually lead to apoptotic cell death.
called the inflammasome (Chapter 5). The net result of Extensive autophagy is seen in ischemic injury and
inflammasome activation is the activation of caspases, some types of myopathies. Polymorphisms in a gene
some of which induce the production of cytokines that involved in autophagy have been associated with inflam-
induce inflammation, often manifested by fever, and matory bowel disease, but the mechanistic link between
others trigger apoptosis. Thus, apoptosis and inflamma- autophagy and intestinal inflammation is not known. The
tion coexist. The name pyroptosis stems from the asso- role of autophagy in cancer is discussed in Chapter 6. Thus,
ciation of apoptosis with fever (Greek, pyro = fire). It is a once little-appreciated survival pathway in cells may
thought to be one mechanism by which some infectious prove to have wide-ranging roles in human disease.
Mechanisms of Cell Injury and Cell Death 41
Nutrient depletion
Autophagy
signal
Lysosome
Cytoplasmic
organelles Enzymatic
Formation of autophagic vacuole digestion of
Fusion of vacuole contents
with lysosomes
Used as sources
of nutrients
Fig. 2.14 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes, which initiate the formation of membrane-bound vesicles in
which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide
nutrients for the cell. The same process can trigger apoptosis by mechanisms that are not well defined.
SUMMARY MECHANISMS OF CELL INJURY AND

PATTERNS OF CELL INJURY AND CELL DEATH CELL DEATH
• Reversible cell injury: cell swelling, fatty change, plasma mem-
Before discussing individual mechanisms of cell injury and
brane blebbing and loss of microvilli, mitochondrial swelling,
death, some general principles should be emphasized.
dilation of the ER, eosinophilia (resulting from decreased cyto-
• The cellular response to injurious stimuli depends on
plasmic RNA)
the type of injury, its duration, and its severity. Thus,
• Necrosis: Accidental cell death manifested by increased cyto-
low doses of toxins or a brief period of ischemia may
plasmic eosinophilia; nuclear shrinkage, fragmentation, and dis-
lead to reversible cell injury, whereas larger toxin doses
solution; breakdown of plasma membrane and organellar
or longer ischemic times may result in irreversible injury
membranes; abundant myelin figures; leakage and enzymatic
and cell death.
digestion of cellular contents
• The consequences of an injurious stimulus also
• Morphologic types of tissue necrosis: under different condi-
depend on the type, status, adaptability, and genetic
tions, necrosis in tissues may assume specific patterns: coagula-
makeup of the injured cell. The same injury has vastly
tive, liquefactive, gangrenous, caseous, fat, and fibrinoid.
different outcomes depending on the cell type. For
• Apoptosis: regulated mechanism of cell death that serves to
instance, striated skeletal muscle in the leg tolerates
eliminate unwanted and irreparably damaged cells, with the
complete ischemia for 2 to 3 hours without irreversible
least possible host reaction, characterized by enzymatic deg-
injury, whereas cardiac muscle dies after only 20 to 30
radation of proteins and DNA, initiated by caspases; and by
minutes of ischemia. The nutritional (or hormonal)
rapid recognition and removal of dead cells by phagocytes
status also can be important; understandably, a
• Apoptosis is initiated by two major pathways:
glycogen-replete hepatocyte will survive ischemia
• Mitochondrial (intrinsic) pathway is triggered by loss of
better than one that has just burned its last glucose
survival signals, DNA damage, and accumulation of
molecule. Genetically determined diversity in meta-
misfolded proteins (ER stress); associated with leakage of
bolic pathways can contribute to differences in
proapoptotic proteins from mitochondrial membrane into
responses to injurious stimuli. For instance, when
the cytoplasm, where they trigger caspase activation;
exposed to the same dose of a toxin, individuals who
inhibited by anti-apoptotic members of the Bcl family,
inherit variants in genes encoding cytochrome P-450
which are induced by survival signals including growth
may catabolize the toxin at different rates, leading to
factors.
different outcomes. Much effort is now directed toward
• Death receptor (extrinsic) pathway is responsible for
understanding the role of genetic polymorphisms in
elimination of self-reactive lymphocytes and damage by
responses to drugs and toxins, a field of study called
CTLs; is initiated by engagement of death receptors
pharmacogenomics. In fact, genetic variations influ-
(members of the TNF receptor family) by ligands on
ence susceptibility to many complex diseases as well as
adjacent cells.
responsiveness to various therapeutic agents. Using
• Two other unusual pathways of cell death are necroptosis
the genetic makeup of the individual patient to guide
(which, as the name implies, includes features of both necrosis
therapy is one example of “precision medicine.”
and apoptosis and is regulated by particular signaling pathways)
• Cell injury usually results from functional and bio-
and pyroptosis, which can lead to the release of proinflamma-
chemical abnormalities in one or more of a limited
tory cytokines and may initiate apoptosis.
number of essential cellular components (Fig. 2.15).
• Autophagy is an adaptation to nutrient deprivation in which
As we discuss in more detail later, different external
cells digest their own organelles and recycle them to provide
insults and endogenous perturbations typically affect
energy and substrates. If the stress is too severe for the
different cellular organelles and biochemical pathways.
process to cope with it, it results in cell death by apoptosis.
For instance, deprivation of oxygen and nutrients (as
Hypoxia, Multiple Mutations, cell Radiation, Infections,

ischemia injurious stimuli stress, infections other insults immunologic disorders
ATP ROS Accumulation of

misfolded proteins DNA damage Inflammation
Energy- Damage to ER Nucleus

dependent lipids, proteins,
functions nucleic acids Toxic molecules
Cell injury Apoptosis Apoptosis Necrosis or

apoptosis
Necrosis
Fig. 2.15 The principal biochemical mechanisms and sites of damage in cell injury. Note that causes and mechanisms of cell death by necrosis and apoptosis
are shown as being independent but there may be overlap; for instance, both may contribute to cell death caused by ischemia, oxidative stress, or radiation.
ATP, Adenosine triphosphate; ROS, reactive oxygen species.
in hypoxia and ischemia) primarily impairs energy- are induced by transcription factors of the hypoxia-
dependent cellular functions, culminating in necrosis, inducible factor 1 (HIF-1) family. HIF-1 simulates the syn-
whereas damage to proteins and DNA triggers apop- thesis of several proteins that help the cell to survive in the
tosis. However, it should be emphasized that the very face of low oxygen. Some of these proteins, such as vascu-
same injurious agent may trigger multiple and overlap- lar endothelial growth factor (VEGF), stimulate the growth
ping biochemical pathways. Not surprisingly, therefore, of new vessels and thus attempt to increase blood flow
it has proved difficult to prevent cell injury by targeting and the supply of oxygen. Other proteins induced by
an individual pathway. HIF-1 cause adaptive changes in cellular metabolism by
stimulating the uptake of glucose and glycolysis and
As we discussed in the beginning of this chapter and dampening mitochondrial oxidative phosphorylation.
have alluded to throughout, there are numerous and diverse Anaerobic glycolysis can generate ATP in the absence of
causes of cell injury and cell death. Similarly, there are many oxygen using glucose derived either from the circulation
biochemical pathways that can initiate the sequence of or from the hydrolysis of intracellular glycogen. Under-
events that lead to cell injury and culminate in cell death. standably, normal tissues with a greater glycolytic capac-
Some of these pathways are recognized to play important ity because of the presence of glycogen (e.g., the liver and
roles in human diseases. In the following section, we orga- striated muscle) are more likely to survive hypoxia and
nize our discussion of the mechanisms of cell injury along decreased oxidative phosphorylation than tissues with
its major causes and pathways, and discuss the principal limited glucose stores (e.g., the brain). Although it seems
biochemical alterations in each. For the sake of clarity and counterintuitive, rapidly proliferating normal cells and
simplicity, we emphasize the unique mechanisms in each cancer cells rely on aerobic glycolysis to produce much of
pathway, but it is important to point out that any initiating their energy, a phenomenon referred to as the Warburg
trigger may activate one or more of these mechanisms, and effect. The reason for this is that although glycolysis yields
several mechanisms may be active simultaneously. less ATP per molecule of glucose burned than oxidative
phosphorylation, metabolites generated by glycolysis and
Hypoxia and Ischemia the TCA cycle serve as precursors for the synthesis of cel-
lular constituents (e.g., proteins, lipids, and nucleic acids)
Deficiency of oxygen leads to failure of many energy- that are needed for cell growth and division. Alterations in
dependent metabolic pathways, and ultimately to death cellular metabolism are frequently seen in cancer cells, so
of cells by necrosis. Most cellular ATP is produced from they are discussed in more detail in Chapter 6.
adenosine diphosphate (ADP) by oxidative phosphoryla- Persistent or severe hypoxia and ischemia ultimately
tion during reduction of oxygen in the electron transport lead to failure of ATP generation and depletion of ATP
system of mitochondria. High-energy phosphate in the in cells. Loss of this critical energy store has deleterious
form of ATP is required for membrane transport, protein effects on many cellular systems (Fig. 2.16).
synthesis, lipogenesis, and the deacylation-reacylation • Reduced activity of plasma membrane ATP-dependent sodium
reactions necessary for phospholipid turnover. It is esti- pumps, resulting in intracellular accumulation of sodium
mated that in total, the cells of a healthy human burn 50 to and efflux of potassium. The net gain of solute is accom-
75 kg of ATP every day! Not surprisingly, therefore, cells panied by isoosmotic gain of water, causing cell swelling
deprived of oxygen are at risk of suffering catastrophic and dilation of the ER.
failure of many essential functions. Oxygen deprivation is • The compensatory increase in anaerobic glycolysis leads to
one of the most frequent causes of cell injury and necrosis lactic acid accumulation, decreased intracellular pH,
in clinical medicine. and decreased activity of many cellular enzymes.
Cells subjected to the stress of hypoxia that do not • Prolonged or worsening depletion of ATP causes struc-
immediately die activate compensatory mechanisms that tural disruption of the protein synthetic apparatus,
Ischemia tissue damage, especially after myocardial and cerebral

ischemia.
Several mechanisms may account for the exacerbation
of cell injury resulting from reperfusion of ischemic tissues:
• New damage may be initiated during reoxygenation by
increased generation of ROS (described in more detail
Mitochondrion below). Some of the ROS may be generated by injured
cells with damaged mitochondria that cannot carry out
the complete reduction of oxygen, and at the same time
Oxidative phosphorylation cellular anti-oxidant defense mechanisms may be com-
promised by ischemia, exacerbating the situation. ROS
ATP generated by infiltrating leukocytes also may contribute
to the damage of vulnerable injured cells.
• The inflammation that is induced by ischemic injury
Na+ pump Anaerobic glycolysis Detachment may increase with reperfusion because it enhances the
of ribosomes
influx of leukocytes and plasma proteins. The products
Influx of Ca2+ of activated leukocytes may cause additional tissue
H2O, and Na+ Glycogen Lactic pH Protein
acid
injury (Chapter 3). Activation of the complement system
synthesis
Efflux of K+ also may contribute to ischemia-reperfusion injury.
Complement proteins may bind to the injured tissues,
ER swelling or to antibodies that are deposited in the tissues, and
Cellular swelling
Loss of microvilli
subsequent complement activation generates byprod-
Blebs ucts that exacerbate the cell injury and inflammation.
Fig. 2.16 The functional and morphologic consequences of hypoxia and
ischemia. ER, Endoplasmic reticulum. Oxidative Stress
Oxidative stress refers to cellular abnormalities that are
manifested as detachment of ribosomes from the rough induced by ROS, which belong to a group of molecules
ER (RER) and dissociation of polysomes into mono- known as free radicals. Free radical-mediated cell injury
somes, with a consequent reduction in protein is seen in many circumstances, including chemical and
synthesis. radiation injury, hypoxia, cellular aging, tissue injury
• It also has been suggested that hypoxia per se increases caused by inflammatory cells, and ischemia-reperfusion
the accumulation of ROS. Whether this is true is a matter injury. In all these cases, cell death may be by necrosis,
of debate; however, there is ample evidence that hypoxia apoptosis, or the mixed pattern of necroptosis.
predisposes cells to ROS-mediated damage if blood Free radicals are chemical species with a single unpaired
flow (and oxygen delivery) is reestablished, a phenom- electron in an outer orbit. Such chemical states are extremely
enon called reperfusion injury (described later). unstable, and free radicals readily react with inorganic and
• Ultimately, there is irreversible damage to mitochondrial organic molecules; when generated in cells, they avidly
and lysosomal membranes, and the cell undergoes necro- attack nucleic acids as well as a variety of cellular proteins
sis. Membrane damage is a late event in cell injury and lipids. In addition, free radicals initiate reactions in
caused by diverse mechanisms, and is discussed later. which molecules that react with the free radicals are them-
Although necrosis is the principal form of cell death selves converted into other types of free radicals, thereby
caused by hypoxia, apoptosis by the mitochondrial propagating the chain of damage.
pathway is also thought to contribute.
Generation and Removal of Reactive Oxygen Species
The functional consequences of hypoxia and ischemia The accumulation of ROS is determined by their rates of
depend on the severity and duration of the deficit. For production and removal (Fig. 2.17). ROS are produced by
instance, the heart muscle ceases to contract within 60 two major pathways.
seconds of coronary occlusion. If hypoxia continues, wors- • ROS are produced normally in small amounts in all
ening ATP depletion causes further deterioration, under- cells during the reduction-oxidation (redox) reactions
going the sequence of changes illustrated in Fig. 2.3 and that occur during mitochondrial respiration and energy
described earlier. generation. In this process, molecular oxygen is reduced
in mitochondria to generate water by the sequential
Ischemia-Reperfusion Injury addition of four electrons. This reaction is imperfect,
however, and small amounts of highly reactive but
Under certain circumstances, the restoration of blood short-lived toxic intermediates are generated when
flow to ischemic but viable tissues results, paradoxically, oxygen is only partially reduced. These intermediates
in increased cell injury. This is the reverse of the expected include superoxide (O 2• ), which is converted to hydro-
outcome of the restoration of blood flow, which normally gen peroxide (H2O2) spontaneously and by the action of
results in the recovery of reversibly injured cells. This the enzyme superoxide dismutase (SOD). H2O2 is more
so-called “ischemia-reperfusion injury” is a clinically stable than O 2• and can cross biologic membranes. In the
important process that may contribute significantly to presence of metals, such as Fe2+, H2O2 is converted to the
Pathologic effects
Radiation
Toxins Production of ROS: Lipid peroxidation Membrane damage
Reperfusion
O2 H2O2 OH
Superoxide Hydrogen Hydroxyl Protein Breakdown,
peroxide radical modifications misfolding
DNA damage Mutations
Conversion Decomposition to
to H2O2 H2O by glutathione
by SOD peroxidase, catalase
Removal of free radicals
Fig. 2.17 The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli.
These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumula-
tion of free radicals in cells, which may damage lipids (by peroxidation), proteins, and DNA, resulting in cell injury. SOD, Superoxide dismutase.
highly reactive hydroxyl radical • OH by the Fenton • The enzymatic metabolism of exogenous chemicals
reaction. The properties and pathologic effects of the (e.g., carbon tetrachloride—see later)
major ROS are summarized in Table 2.3. • Inflammation, in which free radicals are produced by
• ROS are produced in phagocytic leukocytes, mainly leukocytes (Chapter 3)
neutrophils and macrophages, as a weapon for destroy- • Reperfusion of ischemic tissues, as already described.
ing ingested microbes and other substances during
inflammation and host defense (Chapter 3). The ROS are Cells have developed mechanisms to remove free radi-
generated in the phagosomes and phagolysosomes cals and thereby minimize their injurious effects. Free
of leukocytes by a process that is similar to mitochon- radicals are inherently unstable and decay spontaneously.
drial respiration and is called the respiratory burst (or There also are nonenzymatic and enzymatic systems,
oxidative burst). In this process, a phagosome mem- sometimes called free radical scavengers, serving to inacti-
brane enzyme catalyzes the generation of superoxide, vate free radicals (Fig. 2.17).
which is converted to H2O2. H2O2 is in turn converted • The rate of decay of superoxide is significantly increased
to a highly reactive compound, hypochlorite (the major by the action of superoxide dismutase (SOD).
component of household bleach), by the enzyme myelo- • Glutathione (GSH) peroxidases are a family of enzymes
peroxidase, which is present in leukocytes. The role of whose major function is to protect cells from oxidative
ROS in inflammation is described in Chapter 3. damage. The most abundant member of this family,
• Nitric oxide (NO) is another reactive free radical pro- GSH peroxidase 1, is found in the cytoplasm of all cells.
duced in macrophages and other leukocytes. It can react It catalyzes the breakdown of H2O2 by the reaction
with O −2 to form a highly reactive compound, peroxyni- 2GSH + H2O2 → GS-SG + 2H2O. The intracellular ratio
trite, which also participates in cell injury. of oxidized GSH to reduced GSH is a reflection of this
enzyme’s activity and thus of the cell’s ability to catabo-
The generation of free radicals is increased under several lize free radicals.
circumstances: • Catalase, present in peroxisomes, catalyzes the decom-
• The absorption of radiant energy (e.g., ultraviolet (UV) position of hydrogen peroxide (2H2O2 → O2 + 2H2O). It
light, x-rays). Ionizing radiation can hydrolyze water is one of the most active enzymes known, capable of
into hydroxyl (•OH) and hydrogen (H•) free radicals. degrading millions of molecules of H2O2 per second.
Table 2.3 Principal Free Radicals Involved in Cell Injury

Free Radical Mechanisms of Production Mechanisms of Removal Pathologic Effects
Superoxide (O2• ) Incomplete reduction of O2 during Conversion to H2O2 and O2 by Direct damaging effects on lipids
mitochondrial oxidative superoxide dismutase (peroxidation), proteins, and
phosphorylation; by phagocyte DNA
oxidase in leukocytes
Hydrogen peroxide (H2O2) Mostly from superoxide by action of Conversion to H2O and O2 by Can be converted to .OH and
superoxide dismutase catalase, glutathione peroxidase OCl−, which destroy microbes
and cells
Hydroxyl radical ( • OH) Produced from H2O, H2O2, and O2− by Conversion to H2O by glutathione Direct damaging effects on lipids,
various chemical reactions peroxidase proteins, and DNA
Peroxynitrite (ONOO• ) Interaction of O2− and NO mediated Conversion to nitrite by enzymes Direct damaging effects on lipids,
by NO synthase in mitochondria and cytosol proteins, and DNA
• Endogenous or exogenous anti-oxidants (e.g., vitamins E, P-450 in the smooth ER of the liver and other organs.
A, and C and β-carotene) may either block the formation Although the metabolites might cause membrane
of free radicals or scavenge them after they have formed. damage and cell injury by direct covalent binding to
protein and lipids, the most important mechanism of
Cell Injury Caused by Reactive cell injury involves the formation of free radicals. Carbon
Oxygen Species tetrachloride (CCl4)—once widely used in the dry clean-
ROS causes cell injury by damaging multiple compo- ing industry but now banned—and the analgesic acet-
nents of cells (Fig. 2.17): aminophen belong in this category. The effect of CCl4 is
• Lipid peroxidation of membranes. Double bonds in mem- still instructive as an example of chemical injury. CCl4 is
brane polyunsaturated lipids are vulnerable to attack by converted to a toxic free radical, principally in the liver,
oxygen-derived free radicals. The lipid–radical interac- and this free radical is the cause of cell injury, mainly
tions yield peroxides, which are themselves unstable by membrane phospholipid peroxidation. In less than
and reactive, and an autocatalytic chain reaction ensues. 30 minutes after exposure to CCl4, there is sufficient
Damage to plasma membranes as well as mitochondrial damage to the ER membranes of hepatocytes to cause
and lysosomal membranes can have devastating conse- a decline in the synthesis of enzymes and plasma pro-
quences, as discussed earlier in the context of ischemia teins; within 2 hours, swelling of the smooth ER and
and hypoxia. dissociation of ribosomes from the RER have occurred.
• Crosslinking and other changes in proteins. Free radicals There also is decreased synthesis of apoproteins that
promote sulfhydryl-mediated protein crosslinking, form complexes with triglycerides and thereby facilitate
resulting in enhanced degradation or loss of enzymatic triglyceride secretion; this defect results in the accu-
activity. Free radical reactions also may directly cause mulation of lipids in hepatocytes and other cells and
polypeptide fragmentation. Damaged proteins may the “fatty liver” of CCl4 poisoning. Mitochondrial injury
fail to fold properly, triggering the unfolded protein follows, and subsequently diminished ATP stores result
response, described later. in defective ion transport and progressive cell swelling;
• DNA damage. Free radical reactions with thymine resi- the plasma membranes are further damaged by fatty
dues in nuclear and mitochondrial DNA produce single- aldehydes produced by lipid peroxidation in the ER.
strand breaks. Such DNA damage has been implicated The end result can be cell death.
in apoptotic cell death, aging, and malignant transfor-
mation of cells. Endoplasmic Reticulum Stress
• In addition to the role of ROS in cell injury and the
killing of microbes, low concentrations of ROS are The accumulation of misfolded proteins in a cell can stress
involved in numerous signaling pathways in cells and compensatory pathways in the ER and lead to cell death
thus in many physiologic reactions. Therefore, these by apoptosis. During normal protein synthesis, chaperones
molecules are produced normally but, to avoid their in the ER control the proper folding of newly synthesized
harmful effects, their intracellular concentrations are proteins, and misfolded polypeptides are ubiquitinated
tightly regulated in healthy cells. and targeted for proteolysis. If unfolded or misfolded pro-
teins accumulate in the ER, they first induce a protective
Cell Injury Caused by Toxins cellular response that is called the unfolded protein response
(Fig. 2.18). This adaptive response activates signaling
Toxins, including environmental chemicals and sub- pathways that increase the production of chaperones and
stances produced by infectious pathogens, induce cell decrease protein translation, thus reducing the levels of
injury that culminates primarily in necrotic cell death. misfolded proteins in the cell. When a large amount of mis-
Different types of toxins induce cell injury by two general folded protein accumulates and cannot be handled by the
mechanism: adaptive response, the signals that are generated result in
• Direct-acting toxins. Some toxins act directly by combin- activation of proapoptotic sensors of the BH3-only family
ing with a critical molecular component or cellular organ- as well as direct activation of caspases, leading to apoptosis
elle. For example, in mercuric chloride poisoning (as may by the mitochondrial (intrinsic) pathway.
occur from ingestion of contaminated seafood) (Chapter Intracellular accumulation of misfolded proteins may
8), mercury binds to the sulfhydryl groups of various cell be caused by abnormalities that increase the production
membrane proteins, causing inhibition of ATP-dependent of misfolded proteins or reduce the ability to eliminate
transport and increased membrane permeability. Many them. This may result from gene mutations that lead to
anti-neoplastic chemotherapeutic agents also induce cell the production of proteins that cannot fold properly; aging,
damage by direct cytotoxic effects. Also included in this which is associated with a decreased capacity to correct
class are toxins made by microorganisms (described in misfolding; infections, especially viral infections, when large
Chapter 9). These often cause damage by targeting host amounts of microbial proteins are synthesized within cells,
cell molecules that are needed for essential functions, more than the cell can handle; increased demand for secre-
such as protein synthesis and ion transport. tory proteins such as insulin in insulin-resistant states; and
• Latent toxins. Many toxic chemicals are not intrinsically changes in intracellular pH and redox state. Protein misfold-
active but must first be converted to reactive metabo- ing is thought to be the fundamental cellular abnormality in
lites, which then act on target cells. Understandably, several neurodegenerative diseases (Chapter 23). Depriva-
such toxins typically affect the cells in which they are tion of glucose and oxygen, as in ischemia and hypoxia, also
activated. This is usually accomplished by cytochrome may increase the burden of misfolded proteins.
Mild ER Stress Severe ER Stress

Misfolded proteins
ER lumen
ER membrane
P P
P P
P
P
P P P P
Sensor of misfolded
proteins (e.g., IRE1) Signaling Signaling
Cytosol Increased Reduced Increased

Activation of Activation of
synthesis of protein protein
BH3 proteins caspases
chaperones synthesis degradation
Reduced load of misfolded proteins
ADAPTIVE TERMINAL UNFOLDED PROTEIN

UNFOLDED PROTEIN RESPONSE RESPONSE: APOPTOSIS
Fig. 2.18 The unfolded protein response and endoplasmic reticulum (ER) stress. The presence of misfolded proteins in the ER is detected by sensors in the
ER membrane, such as the kinase IRE-1, which form oligomers that are activated by phosphorylation. This triggers an adaptive unfolded protein response,
which can protect the cell from the harmful consequences of the misfolded proteins. When the amount of misfolded proteins is too great to be corrected,
excessive activation of ER sensors activates the mitochondrial pathway of apoptosis and the irreparably damaged cell dies; this is also called the terminal
unfolded protein response.
Protein misfolding within cells may cause disease by • Cell death as a result of protein misfolding is recognized
creating a deficiency of an essential protein or by induc- as a feature of a number of diseases, including the neu-
ing apoptosis (Table 2.4). rodegenerative disorders Alzheimer disease, Hunting-
• Misfolded proteins often lose their activity and are rapidly ton disease, and Parkinson disease, and may underlie
degraded, both of which can contribute to a loss of func- type 2 diabetes as well (Table 2.4).
tion. If this function is essential, cellular injury ensues.
One important disease in which this occurs is cystic fibro- As discussed later in the chapter, improperly folded
sis, which is caused by inherited mutations in a mem- proteins can also accumulate in extracellular tissues, as in
brane transport protein that prevent its normal folding. amyloidosis.
Table 2.4 Diseases Caused by Misfolded Proteinsa

Disease Affected Protein Pathogenesis
Diseases Caused by Mutant Proteins That Are Degraded, Leading to Their Deficiency
Cystic fibrosis CFTR Loss of CFTR leads to defects in chloride transport and death of affected cells
Familial hypercholesterolemia LDL receptor Loss of LDL receptor leads to hypercholesterolemia
Tay-Sachs disease Hexosaminidase β subunit Lack of the lysosomal enzyme leads to storage of GM2 gangliosides in neurons
Diseases Caused by Misfolded Proteins That Result in ER Stress-Induced Cell Loss
Retinitis pigmentosa Rhodopsin Abnormal folding of rhodopsin causes photoreceptor loss and cell death, resulting in
blindness
Creutzfeldt-Jacob disease Prions Abnormal folding of PrPsc causes neuronal cell death
Alzheimer disease Aβ peptide Abnormal folding of Aβ peptide causes aggregation within neurons and apoptosis
Diseases Caused by Misfolded Proteins That Result From Both ER Stress-Induced Cell Loss and Functional Deficiency of
the Protein
Alpha-1-anti-trypsin α-1 anti-trypsin Storage of nonfunctional protein in hepatocytes causes apoptosis; absence of enzymatic
deficiency activity in lungs causes destruction of elastic tissue giving rise to emphysema
a
Selected illustrative examples of diseases are shown in which protein misfolding is thought to be the major mechanism of functional derangement or cell or tissue injury.
CFTR, Cystic fibrosis transmembrane conductance regulator; LDL, low-density lipoprotein.
DNA Damage O2 supply Survival signals

Toxins DNA, protein
Exposure of cells to radiation or chemotherapeutic agents,
Radiation damage
intracellular generation of ROS, and acquisition of muta-
tions may all induce DNA damage, which if severe may
trigger apoptotic death. Damage to DNA is sensed by Pro-apototic proteins
intracellular sentinel proteins, which transmit signals that
Anti-apoptotic proteins
lead to the accumulation of p53 protein. p53 first arrests
the cell cycle (at the G1 phase) to allow the DNA to be
repaired before it is replicated (Chapter 6). However, if the
damage is too great to be repaired successfully, p53 trig-
gers apoptosis, mainly by stimulating BH3-only sensor Mitochondrial damage
proteins that ultimately activate Bax and Bak, proapoptotic or dysfunction
members of the Bcl-2 family. When p53 is mutated or
absent (as it is in certain cancers), cells with damaged DNA
that would otherwise undergo apoptosis survive. In such ATP Production
generation of ROS Leakage of
cells, the DNA damage may result in mutations or DNA mitochondrial
rearrangements (e.g., translocations) that lead to neoplastic proteins
transformation (Chapter 6).
Multiple cellular abnormalities
Inflammation
NECROSIS APOPTOSIS
A common cause of injury to cells and tissues is the inflam-
Fig. 2.19 Role of mitochondria in cell injury and death. Mitochondria are
matory reaction that is elicited by pathogens, necrotic cells, affected by a variety of injurious stimuli and their abnormalities lead to
and dysregulated immune responses, as in autoimmune necrosis or apoptosis. This pathway of apoptosis is described in more detail
diseases and allergies. In all these situations, inflammatory later. ATP, Adenosine triphosphate; ROS, reactive oxygen species.
cells, including neutrophils, macrophages, lymphocytes,
and other leukocytes, secrete products that evolved to
destroy microbes but also may damage host tissues. These
injurious immune reactions are classified under hypersen- permeability transition pore. The opening of this channel
sitivity. Their mechanisms and significance are discussed leads to the loss of mitochondrial membrane potential
in Chapter 5. and pH changes, further compromising oxidative
phosphorylation.
Common Events in Cell Injury From • Mitochondria also contain proteins such as cytochrome
Diverse Causes c that, when released into the cytoplasm, tell the cell
there is internal injury and activate a pathway of apop-
In the previous discussion, we addressed the mechanisms tosis, as discussed earlier.
of cell injury according to the initiating cause, and high-
lighted the principal pathways of injury that are triggered Defects in Membrane Permeability
in different pathophysiologic situations. Some abnormali- Increased membrane permeability leading ultimately to
ties characterize cell injury regardless of the cause, and are overt membrane damage is a feature of most forms of cell
thus seen in a variety of pathologic situations. Two of these injury that culminate in necrosis. The most important sites
changes are described next. of membrane damage during cell injury are the mitochon-
drial membrane, the plasma membrane, and membranes
Mitochondrial Dysfunction of lysosomes. As noted earlier, increased permeability of
Mitochondria may be viewed as “mini-factories” that the plasma membrane and lysosomal membranes is not a
produce life-sustaining energy in the form of ATP. Not feature of apoptosis.
surprisingly, therefore, they also are critical players in cell • Mitochondrial membrane damage. As discussed earlier,
injury and death. Mitochondria are sensitive to many types damage to mitochondrial membranes results in
of injurious stimuli, including hypoxia, chemical toxins, decreased production of ATP, with many deleterious
and radiation (Fig. 2.19). Mitochondrial changes occur in effects culminating in necrosis.
necrosis and apoptosis. They may result in several bio- • Plasma membrane damage. Plasma membrane damage
chemical abnormalities: leads to loss of osmotic balance and influx of fluids and
• Failure of oxidative phosphorylation leads to progres- ions, as well as loss of cellular contents. The cells may
sive depletion of ATP, culminating in necrosis of the also leak metabolites that are vital for the reconstitution
cell, as described earlier. of ATP, thus further depleting energy stores.
• Abnormal oxidative phosphorylation also leads to the • Injury to lysosomal membranes results in leakage of their
formation of ROS, which have many deleterious effects, enzymes into the cytoplasm and activation of the acid
as already described. hydrolases in the acidic intracellular pH of the injured
• Damage to mitochondria is often associated with (e.g., ischemic) cell. Activation of these enzymes leads
the formation of a high-conductance channel in the to enzymatic digestion of cell components, and the cells
mitochondrial membrane, called the mitochondrial die by necrosis.
uterus during pregnancy), or to the demands of mechani-

SUMMARY cal stress (in the case of bones and muscles). Pathologic
MECHANISMS OF CELL INJURY adaptations are responses to stress that allow cells to modu-
• Different initiating events cause cell injury and death by diverse late their structure and function and thus escape injury, but
mechanisms. at the expense of normal function, such as squamous meta-
• Hypoxia and ischemia lead to ATP depletion and failure of plasia of bronchial epithelium in smokers. Physiologic and
many energy-dependent functions, resulting first in reversible pathologic adaptations can take several distinct forms, as
injury and, if not corrected, in necrosis. described in the following text.
• In ischemia-reperfusion injury, restoration of blood flow to an
ischemic tissue exacerbates damage by increasing production Hypertrophy
of ROS and by inflammation.
• Oxidative stress refers to accumulation of ROS, which can Hypertrophy is an increase in the size of cells resulting
damage cellular lipids, proteins, and DNA, and is associated in an increase in the size of the organ. In contrast, hyper-
with numerous initiating causes. plasia (discussed next) is an increase in cell number. Stated
• Protein misfolding depletes essential proteins and, if the mis- another way, in pure hypertrophy there are no new cells,
folded proteins accumulate within cells, results in apoptosis. just bigger cells containing increased amounts of structural
• DNA damage (e.g., by radiation) also can induce apoptosis if proteins and organelles. Hyperplasia is an adaptive
it is not repaired. response in cells capable of replication, whereas hypertro-
• Inflammation is associated with cell injury because of the damag- phy occurs when cells have a limited capacity to divide.
ing actions of the products of inflammatory leukocytes. Hypertrophy and hyperplasia also can occur together,
and obviously both result in an enlarged organ.
Hypertrophy can be physiologic or pathologic and is
We have now concluded the discussion of cell injury and caused either by increased functional demand or by
cell death. As we have seen, these processes are the root growth factor or hormonal stimulation.
cause of many common diseases. We end this chapter with • The massive physiologic enlargement of the uterus
brief considerations of three other processes: cellular adapta- during pregnancy occurs as a consequence of estrogen-
tions to stresses; intracellular accumulations of various sub- stimulated smooth muscle hypertrophy and smooth
stances and extracellular deposition of calcium, both of muscle hyperplasia (Fig. 2.20). In contrast, in response
which are often associated with cell injury; and aging. to increased workload the striated muscle cells in both
the skeletal muscle and the heart undergo only hyper-
trophy because adult muscle cells have a limited capac-
CELLULAR ADAPTATIONS TO STRESS ity to divide. Therefore, the chiseled physique of the
avid weightlifter stems solely from the hypertrophy of
Adaptations are reversible changes in the number, size, individual skeletal muscles.
phenotype, metabolic activity, or functions of cells in • An example of pathologic hypertrophy is the cardiac
response to changes in their environment. Physiologic adap- enlargement that occurs with hypertension or aortic
tations usually represent responses of cells to normal stim- valve disease (Fig. 2.21). The differences between
ulation by hormones or endogenous chemical mediators normal, adapted, and irreversibly injured cells are illus-
(e.g., the hormone-induced enlargement of the breast and trated by the responses of the heart to different types of
A B C
Fig. 2.20 Physiologic hypertrophy of the uterus during pregnancy. (A) Gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed
for postpartum bleeding. (B) Small spindle-shaped uterine smooth muscle cells from a normal uterus. (C) Large, plump hypertrophied smooth muscle cells
from a gravid uterus; compare with B. (B and C, Same magnification.)
Cellular Adaptations to Stress 49
Normal myocyte
Ischemia
leading to
cell injury
Adaptation: Reversibly injured
response to myocyte
increased load
Adapted
myocyte
(hypertrophy)
Cell death
Fig. 2.21 The relationship among normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, the
cause of reversible injury is ischemia, and the irreversible injury is ischemic coagulative necrosis. In the example of myocardial hypertrophy (lower left), the
left ventricular wall is thicker than 2 cm (normal, 1–1.5 cm). Reversibly injured myocardium shows functional effects without any gross or light microscopic
changes, or reversible changes such as cellular swelling and fatty change (shown here). In the specimen showing necrosis (lower right) the transmural light area
in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections of myocardium were stained with triphenyltetra-
zolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme loss after cell death.
stress. Myocardium subjected to a persistently increased in the myocardial fibers, of which the most important are
workload, as in hypertension or with a narrowed (ste- fragmentation and loss of myofibrillar contractile elements.
notic) valve, adapts by undergoing hypertrophy to gen- Why hypertrophy progresses to these regressive changes
erate the required higher contractile force. If, on the is incompletely understood. There may be finite limits on
other hand, the myocardium is subjected to reduced the abilities of the vasculature to adequately supply the
blood flow (ischemia) due to an occluded coronary enlarged fibers, the mitochondria to supply ATP, or the
artery, the muscle cells may undergo injury. biosynthetic machinery to provide sufficient contractile
proteins or other cytoskeletal elements. The net result of
The mechanisms driving cardiac hypertrophy involve these degenerative changes is ventricular dilation and ulti-
at least two types of signals: mechanical triggers, such as mately cardiac failure.
stretch, and soluble mediators that stimulate cell growth,
such as growth factors and adrenergic hormones. These Hyperplasia
stimuli turn on signal transduction pathways that lead to
the induction of a number of genes, which in turn stimulate Hyperplasia is an increase in the number of cells in an
synthesis of many cellular proteins, including growth organ that stems from increased proliferation, either of
factors and structural proteins. The result is the synthesis differentiated cells or, in some instances, less differenti-
of more proteins and myofilaments per cell, which increases ated progenitor cells. As discussed earlier, hyperplasia
the force generated with each contraction, enabling the cell takes place if the tissue contains cell populations capable
to meet increased work demands. There may also be a of replication; it may occur concurrently with hypertrophy
switch of contractile proteins from adult to fetal or neonatal and often in response to the same stimuli.
forms. For example, during muscle hypertrophy, the Hyperplasia can be physiologic or pathologic; in both
α-myosin heavy chain is replaced by the fetal β form of the situations, cellular proliferation is stimulated by growth
myosin heavy chain, which produces slower, more ener- factors that are produced by a variety of cell types.
getically economical contraction. • The two types of physiologic hyperplasia are (1) hor-
An adaptation to stress such as hypertrophy can pro monal hyperplasia, exemplified by the proliferation of
gress to functionally significant cell injury if the stress is the glandular epithelium of the female breast at puberty
not relieved. Whatever the cause of hypertrophy, a limit is and during pregnancy, and (2) compensatory hyperpla-
reached beyond which the enlargement of muscle mass can sia, in which residual tissue grows after removal or loss
no longer compensate for the increased burden. When this of part of an organ. For example, when part of a liver is
happens in the heart, several degenerative changes occur resected, mitotic activity in the remaining cells begins as
A B
Fig. 2.22 Atrophy as seen in the brain. (A) Normal brain of a young adult. (B) Atrophy of the brain in an 82-year-old man with atherosclerotic disease.
Atrophy of the brain is caused by aging and reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges
have been stripped from the bottom half of each specimen to show the surface of the brain.
early as 12 hours later, eventually restoring the liver to involved, the entire tissue or organ is reduced in size, or
its normal size. The stimuli for hyperplasia in this setting atrophic (Fig. 2.22). Although atrophic cells may have
are polypeptide growth factors produced by uninjured diminished function, they are not dead.
hepatocytes as well as nonparenchymal cells in the liver Causes of atrophy include a decreased workload (e.g.,
(Chapter 3). After restoration of the liver mass, various immobilization of a limb to permit healing of a fracture),
growth inhibitors turn off cell proliferation. loss of innervation, diminished blood supply, inadequate
• Most forms of pathologic hyperplasia are caused by nutrition, loss of endocrine stimulation, and aging (senile
excessive hormonal or growth factor stimulation. For atrophy). Although some of these stimuli are physiologic
example, after a normal menstrual period there is a burst (e.g., the loss of hormone stimulation in menopause) and
of uterine epithelial proliferation that is normally tightly others are pathologic (e.g., denervation), the fundamental
regulated by the stimulatory effects of pituitary hor- cellular changes are similar. They represent a retreat by the
mones and ovarian estrogen and the inhibitory effects of cell to a smaller size at which survival is still possible; a
progesterone. A disturbance in this balance leading to new equilibrium is achieved between cell size and dimin-
increased estrogenic stimulation causes endometrial ished blood supply, nutrition, or trophic stimulation.
hyperplasia, which is a common cause of abnormal men- Cellular atrophy results from a combination of
strual bleeding. Benign prostatic hyperplasia is another decreased protein synthesis and increased protein
common example of pathologic hyperplasia induced in degradation.
responses to hormonal stimulation by androgens. Stimu- • Protein synthesis decreases because of reduced meta-
lation by growth factors also is involved in the hyperpla- bolic activity.
sia that is associated with certain viral infections; for • The degradation of cellular proteins occurs mainly by
example, papillomaviruses cause skin warts and mucosal the ubiquitin-proteasome pathway. Nutrient deficiency
lesions that are composed of masses of hyperplastic epi- and disuse may activate ubiquitin ligases, which attach
thelium. Here the growth factors may be encoded by multiple copies of the small peptide ubiquitin to cellular
viral genes or by the genes of the infected host cells. proteins and target them for degradation in protea-
somes. This pathway is also thought to be responsible
An important point is that in all of these situations, the for the accelerated proteolysis seen in a variety of cata-
hyperplastic process remains controlled; if the signals bolic conditions, including the cachexia associated with
that initiate it abate, the hyperplasia disappears. It is this cancer.
responsiveness to normal regulatory control mechanisms • In many situations, atrophy also is associated with
that distinguishes pathologic hyperplasias from cancer, in autophagy, with resulting increases in the number of
which the growth control mechanisms become perma- autophagic vacuoles. As discussed previously, autoph-
nently dysregulated or ineffective (Chapter 6). Neverthe- agy is the process in which the starved cell eats its own
less, in many cases, pathologic hyperplasia constitutes a organelles in an attempt to survive.
fertile soil in which cancers may eventually arise. For
example, patients with hyperplasia of the endometrium Metaplasia
are at increased risk of developing endometrial cancer
(Chapter 19). Metaplasia is a change in which one adult cell type (epi-
thelial or mesenchymal) is replaced by another adult cell
Atrophy type. In this type of cellular adaptation, a cell type sensitive
to a particular stress is replaced by another cell type better
Atrophy is shrinkage in the size of cells by the loss of able to withstand the adverse environment. Metaplasia
cell substance. When a sufficient number of cells are is thought to arise by the reprogramming of stem cells
Intracellular Accumulations 51
SUMMARY
CELLULAR ADAPTATIONS TO STRESS
• Hypertrophy: increased cell and organ size, often in response
to increased workload; induced by growth factors produced in
response to mechanical stress or other stimuli; occurs in
tissues incapable of cell division
Basement Normal Squamous
membrane columnar metaplasia
• Hyperplasia: increased cell numbers in response to hormones
epithelium and other growth factors; occurs in tissues whose cells are
A
able to divide or contain abundant tissue stem cells
• Atrophy: decreased cell and organ size, as a result of decreased
nutrient supply or disuse; associated with decreased synthesis
of cellular building blocks and increased breakdown of cellular
organelles and autophagy
• Metaplasia: change in phenotype of differentiated cells, often in
response to chronic irritation, that makes cells better able to
withstand the stress; usually induced by altered differentiation
pathway of tissue stem cells; may result in reduced functions
or increased propensity for malignant transformation
Fig. 2.23 Metaplasia of normal columnar (left) to squamous epithelium INTRACELLULAR ACCUMULATIONS
(right) in a bronchus, shown schematically (A) and histologically (B).
Under some circumstances, cells may accumulate abnor-
mal amounts of various substances, which may be harm-
to differentiate along a new pathway rather than a pheno- less or may cause varying degrees of injury. The substance
typic change (transdifferentiation) of already differentiated may be located in the cytoplasm, within organelles
cells. (typically lysosomes), or in the nucleus, and it may be
Epithelial metaplasia is exemplified by the change that synthesized by the affected cells or it may be produced
occurs in the respiratory epithelium of habitual cigarette elsewhere.
smokers, in whom the normal ciliated columnar epithelial The main pathways of abnormal intracellular accumula-
cells of the trachea and bronchi often are replaced by strati- tions are inadequate removal and degradation or excessive
fied squamous epithelial cells (Fig. 2.23). The rugged strati- production of an endogenous substance, or deposition of
fied squamous epithelium may be able to survive the an abnormal exogenous material (Fig. 2.24). Selected exam-
noxious chemicals in cigarette smoke that the more fragile ples of each are described as follows.
specialized epithelium would not tolerate. Although the Fatty Change. Fatty change, also called steatosis, refers
metaplastic squamous epithelium has survival advantages, to any accumulation of triglycerides within parenchymal
important protective mechanisms are lost, such as mucus cells. It is most often seen in the liver, since this is the major
secretion and ciliary clearance of particulate matter. Epi- organ involved in fat metabolism, but also may occur in
thelial metaplasia is therefore a double-edged sword. heart, skeletal muscle, kidney, and other organs. Steatosis
Because vitamin A is essential for normal epithelial dif- may be caused by toxins, protein malnutrition, diabetes
ferentiation, its deficiency also may induce squamous mellitus, obesity, or anoxia. Alcohol abuse and diabetes
metaplasia in the respiratory epithelium. associated with obesity are the most common causes of
Metaplasia need not always occur in the direction of fatty change in the liver (fatty liver) in industrialized
columnar to squamous epithelium; in chronic gastric nations. This process is discussed in more detail in
reflux, the normal stratified squamous epithelium of the Chapter 16.
lower esophagus may undergo metaplastic transformation Cholesterol and Cholesteryl Esters. Cellular cholesterol
to gastric or intestinal-type columnar epithelium. Metapla- metabolism is tightly regulated to ensure normal genera-
sia also may occur in mesenchymal cells, but in these situ- tion of cell membranes (in which cholesterol is a key com-
ations it is generally a reaction to some pathologic alteration ponent) without significant intracellular accumulation.
and not an adaptive response to stress. For example, bone However, phagocytic cells may become overloaded with
is occasionally formed in soft tissues, particularly in foci of lipid (triglycerides, cholesterol, and cholesteryl esters) in
injury. several different pathologic processes, mostly character-
The influences that induce metaplastic change in an ized by increased intake or decreased catabolism of lipids.
epithelium, if persistent, may predispose to malignant Of these, atherosclerosis is the most important. The role of
transformation. In fact, squamous metaplasia of the respi- lipid and cholesterol deposition in the pathogenesis of ath-
ratory epithelium often coexists with lung cancers com- erosclerosis is discussed in Chapter 10.
posed of malignant squamous cells. It is thought that Proteins. Morphologically visible protein accumula-
cigarette smoking initially causes squamous metaplasia, tions are less common than lipid accumulations; they may
and cancers arise later in some of these altered foci. occur when excesses are presented to the cells or if the cells
synthesize excessive amounts. In the kidney, for example,

trace amounts of albumin filtered through the glomerulus
1 are normally reabsorbed by pinocytosis in the proximal
Abnormal convoluted tubules. However, in disorders with heavy
metabolism
protein leakage across the glomerular filter (e.g., nephrotic
syndrome), much more of the protein is reabsorbed, and
vesicles containing this protein accumulate, giving the his-
tologic appearance of pink, hyaline cytoplasmic droplets.
The process is reversible: if the proteinuria abates, the
protein droplets are metabolized and disappear. Another
Normal cell Fatty liver example is the marked accumulation of newly synthesized
immunoglobulins that may occur in the RER of some
plasma cells, forming rounded, eosinophilic Russell bodies.
Other examples of protein aggregation are discussed
Protein mutation 2 elsewhere in this book (e.g., “alcoholic hyaline” in the
Defect in liver in Chapter 16; neurofibrillary tangles in neurons in
protein Chapter 23).
folding, Glycogen. Excessive intracellular deposits of glycogen
transport
are associated with abnormalities in the metabolism of
either glucose or glycogen. In poorly controlled diabetes
mellitus, the prime example of abnormal glucose metabo-
lism, glycogen accumulates in renal tubular epithelium,
cardiac myocytes, and β cells of the islets of Langerhans.
Accumulation of Glycogen also accumulates within cells in a group of
abnormal proteins related genetic disorders collectively referred to as glyco-
gen storage diseases, or glycogenoses (Chapter 7).
Pigments. Pigments are colored substances that are
either exogenous, coming from outside the body, such as
carbon, or are endogenous, synthesized within the body
3 itself, such as lipofuscin, melanin, and certain derivatives
Lack of of hemoglobin.
enzyme
The most common exogenous pigment is carbon, a
ubiquitous air pollutant of urban life. When inhaled, it is
phagocytosed by alveolar macrophages and transported
Complex Soluble
substrate products
through lymphatic channels to the regional tracheobron-
Complex
Enzyme substrate chial lymph nodes. Aggregates of the pigment blacken the
draining lymph nodes and pulmonary parenchyma (anthra-
Lysosomal storage disease: cosis) (Chapter 13).
accumulation of
endogenous materials
• Lipofuscin, or “wear-and-tear pigment,” is an insoluble
brownish-yellow granular intracellular material that
accumulates in a variety of tissues (particularly the
heart, liver, and brain) with aging or atrophy. Lipofus-
cin represents complexes of lipid and protein that are
4
produced by the free radical–catalyzed peroxidation of
Ingestion of polyunsaturated lipids of subcellular membranes. It is
indigestible
materials not injurious to the cell but is a marker of past free
radical injury. The brown pigment (Fig. 2.25), when
present in large amounts, imparts an appearance to the
tissue that is called brown atrophy.
• Melanin is an endogenous, brown-black pigment that
is synthesized by melanocytes located in the epidermis
and acts as a screen against harmful UV radiation.
Accumulation of
exogenous materials Although melanocytes are the only source of melanin,
adjacent basal keratinocytes in the skin can accumu-
Fig. 2.24 Mechanisms of intracellular accumulation: (1) Abnormal metabo-
late the pigment (e.g., in freckles), as can dermal
lism, as in fatty change in the liver. (2) Mutations causing alterations in protein
folding and transport, so that defective molecules accumulate intracellularly. macrophages.
(3) A deficiency of critical enzymes responsible for breaking down certain • Hemosiderin is a hemoglobin-derived granular pigment
compounds, causing substrates to accumulate in lysosomes, as in lysosomal that is golden yellow to brown and accumulates in
storage diseases. (4) An inability to degrade phagocytosed particles, as in tissues when there is a local or systemic excess of iron.
carbon pigment accumulation. Iron is normally stored within cells in association with
the protein apoferritin, forming ferritin micelles. Hemo-
siderin pigment represents large aggregates of these
Pathologic Calcification 53
areas of necrosis of any type. It is virtually ubiquitous

in the arterial lesions of advanced atherosclerosis
(Chapter 10). Although dystrophic calcification may be
an incidental finding indicating insignificant past cell
injury, it also may be a cause of organ dysfunction. For
example, calcification can develop in aging or damaged
heart valves, resulting in severely compromised valve
motion. Dystrophic calcification of the aortic valves is
an important cause of aortic stenosis in elderly persons
(Chapter 11).
Dystrophic calcification is initiated by the extracel-
lular deposition of crystalline calcium phosphate in
membrane-bound vesicles, which may be derived from
injured cells, or the intracellular deposition of calcium
in the mitochondria of dying cells. It is thought that the
extracellular calcium is concentrated in vesicles by its
affinity for membrane phospholipids, whereas phos-
phates accumulate as a result of the action of membrane-
Fig. 2.25 Lipofuscin granules in cardiac myocytes (deposits indicated by bound phosphatases. The crystals are then propagated,
arrows). forming larger deposits.
• Metastatic calcification. This form is associated with hyper-
calcemia and can occur in normal tissues. The major
ferritin micelles, readily visualized by light and electron causes of hypercalcemia are (1) increased secretion of para-
microscopy; the iron can be unambiguously identified thyroid hormone, due to either primary parathyroid
by the Prussian blue histochemical reaction (Fig. 2.26). tumors or production of parathyroid hormone–related
Although hemosiderin accumulation is usually patho- protein by other malignant tumors; (2) destruction of bone
logic, small amounts of this pigment are normal in the due to the effects of accelerated turnover (e.g., Paget
mononuclear phagocytes of the bone marrow, spleen, disease), immobilization, or tumors (increased bone
and liver, where aging red cells are normally degraded. catabolism associated with multiple myeloma, leuke-
Excessive deposition of hemosiderin, called hemo- mia, or diffuse skeletal metastases); (3) vitamin D–related
siderosis, and more extensive accumulations of iron disorders including vitamin D intoxication and sarcoidosis
seen in hereditary hemochromatosis are described in (in which macrophages activate a vitamin D precursor);
Chapter 16. and (4) renal failure, in which phosphate retention leads
to secondary hyperparathyroidism.
PATHOLOGIC CALCIFICATION
Pathologic calcification, a common process in a wide MORPHOLOGY
variety of disease states, is the result of an abnormal
Regardless of the site, calcium salts are seen on gross examina-
deposition of calcium salts, together with smaller amounts
tion as fine white granules or clumps, often felt as gritty deposits.
of iron, magnesium, and other minerals. It can occur in two
Dystrophic calcification is common in areas of caseous necrosis
ways.
in tuberculosis. Sometimes a tuberculous lymph node is essen-
• Dystrophic calcification. In this form, calcium metabolism
tially converted to radiopaque stone. On histologic examination,
is normal but it deposits in injured or dead tissue, such as
A B
Fig. 2.26 Hemosiderin granules in liver cells. (A) Hematoxylin-eosin–stained section showing golden-brown, finely granular pigment. (B) Iron deposits shown
by a special staining process called the Prussian blue reaction.
Shock 115
inadequate perfusion by collateral arterial supplies is typical; (4) in Factors That Influence Infarct Development
previously congested tissues (as a consequence of sluggish venous
The effects of vascular occlusion range from inconse-
outflow); and (5) when flow is reestablished after infarction has
quential to tissue necrosis leading to organ dysfunction
occurred (e.g., after angioplasty of an arterial obstruction).
and sometimes death. The range of outcomes is influenced
White infarcts occur with arterial occlusions in solid organs
by the following three variables:
with end-arterial circulations (e.g., heart, spleen, and kidney), and
• Anatomy of the vascular supply. The presence or absence
where tissue density limits the seepage of blood from adjoining
of an alternative blood supply is the most important
patent vascular beds (Fig. 4.17B). Infarcts tend to be wedge-
factor in determining whether occlusion of an individ-
shaped, with the occluded vessel at the apex and the organ
ual vessel causes damage. The dual supply of the lung
periphery forming the base (Fig. 4.17); when the base is a serosal
by the pulmonary and bronchial arteries means that
surface, there is often an overlying fibrinous exudate. Lateral
obstruction of the pulmonary arterioles does not cause
margins may be irregular, reflecting flow from adjacent vessels.
lung infarction unless the bronchial circulation also is
The margins of acute infarcts typically are indistinct and slightly
compromised. Similarly, the liver, which receives blood
hemorrhagic; with time, the edges become better defined by a
from the hepatic artery and the portal vein, and the
narrow rim of hyperemia attributable to inflammation.
hand and forearm, with its parallel radial and ulnar
Infarcts resulting from arterial occlusions in organs without
arterial supply, are resistant to infarction. By contrast,
a dual circulation typically become progressively paler and more
the kidney and the spleen both have end-arterial circula-
sharply defined with time (Fig. 4.17B). By comparison, hemor-
tions, and arterial obstruction generally leads to infarc-
rhagic infarcts are the rule in the lung and other spongy organs
tion in these tissues.
(Fig. 4.17A). Extravasated red cells in hemorrhagic infarcts are
• Rate of occlusion. Slowly developing occlusions are less
phagocytosed by macrophages, and the heme iron is converted
likely to cause infarction because they allow time for the
to intracellular hemosiderin. Small amounts do not impart any
development of collateral blood supplies. For example,
appreciable color to the tissue, but extensive hemorrhages leave
small interarteriolar anastomoses, which normally carry
a firm, brown residue.
minimal blood flow, interconnect the three major coro-
In most tissues, the main histologic finding associated with
nary arteries. If one coronary artery is slowly occluded
infarcts is ischemic coagulative necrosis (Chapter 2). An
(e.g., by encroaching atherosclerotic plaque), flow in this
inflammatory response begins to develop along the margins of
collateral circulation may increase sufficiently to prevent
infarcts within a few hours and usually is well defined within 1
infarction—even if the original artery becomes com-
to 2 days. Eventually, inflammation is followed by repair, beginning
pletely occluded.
in the preserved margins (Chapter 3). In some tissues, parenchy-
• Tissue vulnerability to hypoxia. Neurons undergo irre-
mal regeneration can occur at the periphery of the infarct, where
versible damage when deprived of their blood supply
the underlying stromal architecture has been spared. Most
for only 3 to 4 minutes. Myocardial cells, although
infarcts, however, are ultimately replaced by scar (Fig. 4.18). The
hardier than neurons, still die after only 20 to 30 minutes
brain is an exception to these generalizations; ischemic tissue
of ischemia. By contrast, fibroblasts within myocardium
injury in the central nervous system results in liquefactive
remain viable after many hours of ischemia.
necrosis (Chapter 2).
Septic infarctis occur when infected cardiac valve vegeta-
tions embolize, or when microbes seed necrotic tissue. In these SUMMARY
cases the infarct is converted into an abscess, with a correspond- INFARCTION
ingly greater inflammatory response and healing by organization
and fibrosis (Chapter 3). • Infarcts are areas of ischemic necrosis most commonly caused
by arterial occlusion (typically resulting from thrombosis or
embolization); venous outflow obstruction is a less frequent
cause.
• Infarcts caused by venous occlusion or occurring in spongy
tissues typically are hemorrhagic (red); those caused by arterial
occlusion in compact tissues typically are pale (white).
• Whether or not vascular occlusion causes tissue infarction is
influenced by collateral blood supplies, the rate at which an
obstruction develops, intrinsic tissue susceptibility to ischemic
injury, and blood oxygenation.
SHOCK
Shock is a state in which diminished cardiac output or
reduced effective circulating blood volume impairs tissue
perfusion and leads to cellular hypoxia. At the outset, the
cellular injury is reversible; however, prolonged shock even-
Fig. 4.18 Remote kidney infarct, now replaced by a large fibrotic scar. tually leads to irreversible tissue injury and is often fatal.
116 C H A P T E R 4 Hemodynamic Disorders, Thromboembolism, and Shock
Table 4.3 Three Major Types of Shock

Type of Shock Clinical Examples Principal Pathogenic Mechanisms
Cardiogenic Myocardial infarction 

Ventricular rupture 
 Failure of myocardial pump resulting from intrinsic myocardial
Arrhythmia 
Cardiac tamponade  damage, extrinsic pressure, or obstruction to outflow

Pulmonary embolism 

Hypovolemic Hemorrhage 
 Inadequate blood or plasma volume
Fluid loss (e.g., vomiting, diarrhea, burns, trauma) 
Septic Overwhelming microbial infections 
Gram-negative sepsis  Peripheral vasodilation and pooling of blood; endothelial


Gram-positive septicemia  activation/injury; leukocyte-induced damage; disseminated
Fungal sepsis 
 intravascular coagulation; activation of cytokine cascades
Superantigens (e.g., toxic shock syndrome) 

Shock may complicate severe hemorrhage, extensive trauma improvements in care, the mortality remains at a stagger-
or burns, myocardial infarction, pulmonary embolism, and ing 20% to 30%.
microbial sepsis. Its causes fall into three general categories Septic shock is most frequently triggered by gram-
(Table 4.3): positive bacterial infections, followed by gram-negative
• Cardiogenic shock results from low cardiac output bacteria and fungi. Hence, an older synonym, “endotoxic
as a result of myocardial pump failure. It may be shock,” is no longer appropriate.
caused by myocardial damage (infarction), ventricular The ability of diverse microorganisms to cause septic
arrhythmias, extrinsic compression (cardiac tampon- shock is consistent with the idea that a variety of microbial
ade) (Chapter 12), or outflow obstruction (e.g., pulmo- constituents can trigger the process. As mentioned in
nary embolism). Chapter 3, macrophages, neutrophils, dendritic cells, endo-
• Hypovolemic shock results from low cardiac output due thelial cells, and soluble components of the innate immune
to loss of blood or plasma volume (e.g., resulting from system (e.g., complement) recognize and are activated by
hemorrhage or fluid loss from severe burns). several substances derived from microorganisms. After
• Septic shock is triggered by microbial infections and is associ- activation, these cells and factors initiate a number of
ated with severe systemic inflammatory response syndrome inflammatory responses that interact in a complex, incom-
(SIRS). In addition to microbes, SIRS may be triggered pletely understood fashion to produce septic shock and
by a variety of insults, including burns, trauma, and/or multiorgan dysfunction (Fig. 4.19).
pancreatitis. The common pathogenic mechanism is a Factors believed to play major roles in the pathophysiol-
massive outpouring of inflammatory mediators from ogy of septic shock include the following:
innate and adaptive immune cells that produce arterial • Inflammatory and counterinflammatory responses. In sepsis,
vasodilation, vascular leakage, and venous blood various microbial cell wall constituents engage recep-
pooling. These cardiovascular abnormalities result in tors on cells of the innate immune system, triggering
tissue hypoperfusion, cellular hypoxia, and metabolic proinflammatory responses. Likely initiators of inflam-
derangements that lead to organ dysfunction and, if mation in sepsis are signaling pathways that lie down-
severe and persistent, organ failure and death. The stream of Toll-like receptors (TLRs) (Chapter 5), which
pathogenesis of shock is discussed in detail below. recognize a host of microbe-derived substances contain-
ing so-called “pathogen-associated molecular patterns”
Less commonly, shock can result from a loss of vascular (PAMPs), as well as G-protein–coupled receptors that
tone associated with anesthesia or secondary to a spinal detect bacterial peptides, and C-type lectin receptors
cord injury (neurogenic shock). Anaphylactic shock results such as Dectins. On activation, innate immune cells
from systemic vasodilation and increased vascular perme- produce numerous cytokines, including TNF, IL-1, IFN-
ability that is triggered by an immunoglobulin E–mediated γ, IL-12, and IL-18, as well as other inflammatory media-
hypersensitivity reaction (Chapter 5). tors such as high-mobility group box 1 protein (HMGB1).
Markers of acute inflammation such as C-reactive
Pathogenesis of Septic Shock protein and procalcitonin are also elevated. The latter is
a clinically useful indicator of septic shock. Reactive
Septic shock is responsible for 2% of all hospital admis- oxygen species and lipid mediators such as prostaglan-
sions in the United States. Of these, 50% require treatment dins and platelet-activating factor (PAF) are also elabo-
in intensive care units. The number of cases in the United rated. These effector molecules induce endothelial cells
States exceeds 750,000/year and the incidence is rising, (and other cell types) to upregulate adhesion molecule
which is ironically due to improvements in life support for expression and further stimulate cytokine and chemo-
critically ill patients, as well as the growing ranks of immu- kine production. The complement cascade is also activated
nocompromised hosts (because of chemotherapy, immu- by microbial components, both directly and through the
nosuppression, advanced age, or human immunodeficiency proteolytic activity of plasmin (Chapter 3), resulting in
virus infection) and the increasing prevalence of multidrug- the production of anaphylotoxins (C3a, C5a), chemotac-
resistant organisms in the hospital setting. Despite tic fragments (C5a), and opsonins (C3b), all of which
Shock 117
Microbial products
(PAMPs)
Neutrophil and monocyte
activation
Complement Endothelial
Factor XII activation activation
C3a
C3
TNF, IL-1, HMGB1
Direct and indirect
Cytokines and cytokine-like mediators
Procoagulant Anti-fibrinolytic IL-6, IL-8, NO, PAF, IL-10, apoptosis,

reactive oxygen species, STNFR
TF PAI-1 etc.
TFPI, thrombomodulin, Secondary anti-inflammatory
protein C mediators
VASODILATION
MICROVASCULAR SYSTEMIC IMMUNOSUPPRESSION
INCREASED PERMEABILITY
THROMBOSIS (DIC) EFFECTS
DECREASED PERFUSION
Fever, diminished
myocardial contractility,
TISSUE ISCHEMIA metabolic abnormalities
Adrenal insufficiency MULTIORGAN FAILURE
Fig. 4.19 Major pathogenic pathways in septic shock. Microbial products activate endothelial cells and cellular and humoral elements of the innate immune
system, initiating a cascade of events that lead to end-stage multiorgan failure. Additional details are provided in the text. DIC, Disseminated intravascular
coagulation; HMGB1, high-mobility group box 1 protein; NO, nitric oxide; PAF, platelet-activating factor; PAI-1, plasminogen activator inhibitor-1; PAMP, pathogen-
associated molecular pattern; STNFR, soluble tumor necrosis factor receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor.
contribute to the proinflammatory state. In addition, edema, which have deleterious effects on both nutrient
microbial components can activate coagulation directly delivery and waste removal. One effect of inflammatory
through factor XII and indirectly through altered endo- cytokines is to loosen endothelial cell tight junctions,
thelial function (discussed later). The accompanying making vessels leaky and resulting in the accumulation
widespread activation of thrombin may further augment of protein-rich edema fluid throughout the body. This
inflammation by triggering protease activated receptors alteration impedes tissue perfusion and may be exacer-
on inflammatory cells. bated by attempts to support the patient with intrave-
The hyperinflammatory state, initiated by sepsis, nous fluids. Activated endothelium also upregulates
triggers counterregulatory immunosuppressive mecha- production of nitric oxide (NO) and other vasoactive
nisms, which may involve both innate and adaptive inflammatory mediators (e.g., C3a, C5a, and PAF),
immune cells. As a result, septic patients may oscillate which may contribute to vascular smooth muscle relax-
between hyperinflammatory and immunosuppressed ation and systemic hypotension.
states during their clinical course. Proposed mecha- • Induction of a procoagulant state. The derangement in
nisms for the immune suppression include a shift from coagulation is sufficient to produce the formidable com-
proinflammatory (TH1) to anti-inflammatory (TH2) cyto- plication of disseminated intravascular coagulation in up to
kines (Chapter 5), production of anti-inflammatory half of septic patients. Sepsis alters the expression of
mediators (e.g., soluble TNF receptor, IL-1 receptor many factors so as to favor coagulation. Proinflamma-
antagonist, and IL-10), lymphocyte apoptosis, the tory cytokines increase tissue factor production by
immunosuppressive effects of apoptotic cells, and the monocytes and possibly endothelial cells as well, and
induction of cellular anergy. In some patients the coun- decrease the production of endothelial anti-coagulant
terregulatory mechanisms overshoot the inflammatory factors, such as tissue factor pathway inhibitor, throm-
responses and the resultant immune suppression bomodulin, and protein C (see Fig. 4.11). They also
renders such patients susceptible to superinfections. dampen fibrinolysis by increasing plasminogen activa-
• Endothelial activation and injury. The proinflammatory tor inhibitor-1 expression (see Fig. 4.10). The vascular
state and endothelial cell activation associated with leak and tissue edema decrease blood flow at the level
sepsis lead to widespread vascular leakage and tissue of small vessels, producing stasis and diminishing the
118 C H A P T E R 4 Hemodynamic Disorders, Thromboembolism, and Shock
washout of activated coagulation factors. Acting in T-lymphocyte activators that induce the release of high
concert, these effects lead to systemic activation of levels of cytokines that result in a variety of clinical mani-
thrombin and the deposition of fibrin-rich thrombi in festations, ranging from a diffuse rash to vasodilation,
small vessels, often throughout the body, further com- hypotension, shock, and death.
promising tissue perfusion. In full-blown disseminated
intravascular coagulation, the consumption of coagula- Stages of Shock
tion factors and platelets is so great that deficiencies of
these factors appear, leading to concomitant bleeding Shock is a progressive disorder that leads to death if the
and hemorrhage (Chapter 12). underlying problems are not corrected. The exact mecha-
• Metabolic abnormalities. Septic patients exhibit insulin nisms of sepsis-related death are still unclear; aside from
resistance and hyperglycemia. Cytokines such as TNF increased lymphocyte and enterocyte apoptosis, cellular
and IL-1, stress-induced hormones (such as glucagon, necrosis is minimal. Death typically follows the failure of
growth hormone, and glucocorticoids), and catechol- multiple organs, which usually offer no morphological
amines all drive gluconeogenesis. At the same time, clues to explain their dysfunction. For hypovolemic and
the proinflammatory cytokines suppress insulin release cardiogenic shock, however, the pathways leading to a
while simultaneously promoting insulin resistance patient’s demise are reasonably well understood. Unless the
in the liver and other tissues, likely by impairing the insult is massive and rapidly lethal (e.g., exsanguination
surface expression of GLUT-4, a glucose transporter. from a ruptured aortic aneurysm), shock tends to evolve
Hyperglycemia decreases neutrophil function—thereby through three general (albeit somewhat artificial) stages.
suppressing bactericidal activity—and causes increased These stages have been documented most clearly in hypo-
adhesion molecule expression on endothelial cells. volemic shock but are common to other forms as well:
Although sepsis is initially associated with an acute • An initial nonprogressive stage during which reflex
surge in glucocorticoid production, this phase may compensatory mechanisms are activated and vital organ
be followed by adrenal insufficiency and a functional perfusion is maintained,
deficit of glucocorticoids. This may stem from depres- • A progressive stage characterized by tissue hypo-
sion of the synthetic capacity of intact adrenal glands perfusion and onset of worsening circulatory and meta-
or frank adrenal necrosis resulting from disseminated bolic derangement, including acidosis,
intravascular dissemination (Waterhouse-Friderichsen • An irreversible stage in which cellular and tissue injury
syndrome) (Chapter 20). Finally, cellular hypoxia and is so severe that even if the hemodynamic defects are
diminished oxidative phosphorylation lead to increased corrected, survival is not possible.
lactate production and lactic acidosis.
• Organ dysfunction. Systemic hypotension, interstitial In the early nonprogressive phase of shock, various neu-
edema, and small vessel thrombosis all decrease the rohumoral mechanisms help maintain cardiac output and
delivery of oxygen and nutrients to the tissues that, blood pressure. These mechanisms include baroreceptor
because of cellular hypoxia, fail to properly use those reflexes, release of catecholamines and anti-diuretic
nutrients that are delivered. Mitochondrial damage hormone, activation of the renin-angiotensin-aldersterone
resulting from oxidative stress impairs oxygen use. axis, and generalized sympathetic stimulation. The net
High levels of cytokines and secondary mediators effect is tachycardia, peripheral vasoconstriction, and renal
diminish myocardial contractility and cardiac output, fluid conservation; cutaneous vasoconstriction causes the
and increased vascular permeability and endothelial characteristic “shocky” skin coolness and pallor (notably,
injury can lead to the acute respiratory distress syndrome septic shock can initially cause cutaneous vasodilation, so
(Chapter 13). Ultimately, these factors may conspire to the patient may present with warm, flushed skin). Coro-
cause the failure of multiple organs, particularly the nary and cerebral vessels are less sensitive to sympathetic
kidneys, liver, lungs, and heart, culminating in death. signals and maintain relatively normal caliber, blood flow,
and oxygen delivery. Thus, blood is shunted away from
The severity and outcome of septic shock are likely the skin to the vital organs such as the heart and the brain.
dependent on the extent and virulence of the infection; the If the underlying causes are not corrected, shock passes
immune status of the host; the presence of other comorbid imperceptibly to the progressive phase, which as noted is
conditions; and the pattern and level of mediator produc- characterized by widespread tissue hypoxia. In the setting
tion. The multiplicity of factors and the complexity of the of persistent oxygen deficit, intracellular aerobic respira-
interactions that underlie sepsis explain why most attempts tion is replaced by anaerobic glycolysis with excessive pro-
to intervene therapeutically with antagonists of specific duction of lactic acid. The resultant metabolic lactic acidosis
mediators have not been effective and may even have had lowers the tissue pH, which blunts the vasomotor response;
deleterious effects in some cases. The standard of care arterioles dilate, and blood begins to pool in the microcir-
remains antibiotics to treat the underlying infection and culation. Peripheral pooling not only worsens the cardiac
intravenous fluids, pressors, and supplemental oxygen to output but also puts endothelial cells at risk for the devel-
maintain blood pressure and limit tissue hypoxia. Suffice opment of anoxic injury with subsequent DIC. With wide-
it to say that even in the best of clinical centers, septic shock spread tissue hypoxia, vital organs are affected and begin
remains an obstinate clinical challenge. to fail.
An additional group of secreted bacterial proteins called In the absence of appropriate intervention, or in severe
superantigens also cause a syndrome similar to septic shock cases, the process eventually enters an irreversible stage.
(e.g., toxic shock syndrome). Superantigens are polyclonal Widespread cell injury is reflected in lysosomal enzyme
Shock 119
leakage, further aggravating the shock state. Myocardial

• The major types of shock are cardiogenic (e.g., myocardial
contractile function worsens, in part because of increased
infarction), hypovolemic (e.g., blood loss), and septic (e.g.,
NO synthesis. The ischemic bowel may allow intestinal
infections).
flora to enter the circulation, and thus bacteremic shock
• Shock of any form can lead to hypoxic tissue injury if not
may be superimposed. Commonly, further progression to
corrected.
renal failure occurs as a consequence of ischemic injury of
• Septic shock is caused by the host response to bacterial or
the kidney (Chapter 14), and despite the best therapeutic
fungal infections; it is characterized by endothelial cell activa-
interventions, the downward spiral frequently culminates
tion, vasodilation, edema, disseminated intravascular coagula-
in death.
tion, and metabolic derangements.
MORPHOLOGY
The cellular and tissue effects of shock are essentially those of
hypoxic injury (Chapter 2) and are caused by a combination of
hypoperfusion and microvascular thrombosis. Although
SUGGESTED READINGS
any organ can be affected, the brain, heart, kidneys, adrenals, and Akhtar S: Fat embolism, Anesthesiol Clin 27:533, 2009. [Recent overview
gastrointestinal tract are most commonly involved. Fibrin of the pathogenesis and clinical issues in fat embolism syndrome.]
thrombi can form in any tissue but typically are most readily Alberelli MA, De Candia E: Functional role of protease activated
receptors in vascular biology, Vascul Pharmacol 62:72–81, 2014. [An
visualized in kidney glomeruli. Adrenal cortical cell lipid
exhaustive review of the role played by PARs in hemostasis.]
depletion is akin to that seen in all forms of stress and reflects
Angus DC, van der Poll T: Severe sepsis and septic shock, N Engl J
increased use of stored lipids for steroid synthesis. Whereas the Med 840:2013. [An excellent review of clinical features, pathogenesis, and
lungs are resistant to hypoxic injury in hypovolemic shock occur- outcome of septic shock.]
ring after hemorrhage, sepsis or trauma can precipitate diffuse Benson MD: Current concepts of immunology and diagnosis in amni-
alveolar damage (Chapter 13), leading to so-called “shock otic fluid embolism, Clin Dev Immunol doi:10.1155/2012/946576:
lung.” Except for neuronal and cardiomyocyte loss, affected 2012. [Discussion of the pathophysiology of amniotic fluid embolism.]
tissues can recover completely if the patient survives. Cawcutt KA, Peters SG: Severe sepsis and septic shock: clinical over-
view and update on management, Mayo Clin Proc 89:1572, 2014.
[A brief clinical review of sepsis.]
Clinical Features Chapman JC, Hajjar KA: Fibrinolysis and the control of blood coagula-
tion, Blood Rev 29:17, 2015. [An updated discussion of fibrinolysis and
The clinical manifestations of shock depend on the pre-
its role in the regulation of coagulation.]
cipitating insult. In hypovolemic and cardiogenic shock,
Chaturvedi S, McCrae KR: Recent advances in the antiphospholipid
patients exhibit hypotension, a weak rapid pulse, tachy- antibody syndrome, Curr Opin Hematol 21:371, 2014. [A discussion of
pnea, and cool, clammy, cyanotic skin. As already noted, in the pathophysiology of this important and complex entity.]
septic shock, the skin may be warm and flushed owing to periph- Coleman DM, Obi A, Henke PK: Update in venous thromboembolism:
eral vasodilation. The primary threat to life is the underlying pathophysiology, diagnosis, and treatment for surgical patients,
initiating event (e.g., myocardial infarction, severe hemor- Curr Probl Surg 52:233, 2015. [An exhaustive review of this common
rhage, bacterial infection). However, the cardiac, cerebral, clinical condition.]
and pulmonary changes rapidly aggravate the situation. If Ellery PE, Adams MJ: Tissue factor pathway inhibitor: then and now,
patients survive the initial period, worsening renal func- Semin Thromb Hemost 40:881, 2014. [Advances in understanding the role
of tissue factor in coagulation.]
tion can provoke a phase dominated by progressive oligu-
Esmon CT, Esmon NL: The link between vascular features and throm-
ria, acidosis, and electrolyte imbalances.
bosis, Annu Rev Physiol 2011. [An excellent review of the interactions of
Prognosis varies with the origin of shock and its dura- endothelium, blood flow, and hemostasis/thrombosis.]
tion. Thus, more than 90% of young, otherwise healthy Greinacher A: Heparin induced thrombocytopenia, N Engl J Med
patients with hypovolemic shock survive with appropriate 373:3, 2015. [A nice review on this common and enigmatic condition.]
management; by comparison, septic or cardiogenic shock Osinbowale O, Ali L, Chi YW: Venous thromboembolism: a clinical
is associated with substantially worse outcomes, even with review, Postgrad Med 122:54, 2010. [Good review at a medical student/
state-of-the-art care. house officer level.]
Rao LVM, Esom CT, Pendurthi UR: Endothelial cell protein C recep-
tor: a multiliganded and multifunctional receptor, Blood 124:1553,
2014. [A discussion of this novel receptor in limiting coagulation.]
SUMMARY Renne T, Schmaier AH, Nickel KF, et al: In vivo roles of factor XII,
Blood 120:4296–4303, 2012. [A review summarizing new insights into
SHOCK the still-uncertain in vivo functions of factor XII in thrombosis and vas-
• Shock is defined as a state of systemic tissue hypoperfusion cular biology.]
resulting from reduced cardiac output and/or reduced effective Versteeg HH, Heemskerk JWM, Levi M, et al: New fundamentals in
hemostasis, Physiol Rev 93:327, 2013. [An update in several issues in
circulating blood volume.
hemostasis.]

Cell Injury and Death Mechanisms

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See Targeted Therapy available online at studentconsult.

Cell Injury, Cell Death,

scopic appearance (morphology) of cells and tissues, and

Immunologic Genetic abnormalities Nutritional

Aging. Cellular senescence results in a diminished

Reversible Cell Injury Myelin figure Membrane

Fig. 2.10 Fibrinoid necrosis in an artery in a patient with polyarteritis

Table 2.2 Physiologic and Pathologic Conditions Associated

• Apoptosis in pathologic conditions. Apoptosis eliminates

MITOCHONDRIAL (INTRINSIC) DEATH RECEPTOR (EXTRINSIC)

“flips” to the outer leaflet, where it is recognized by

SUMMARY MECHANISMS OF CELL INJURY AND

Hypoxia, Multiple Mutations, cell Radiation, Infections,

ATP ROS Accumulation of

Energy- Damage to ER Nucleus

Cell injury Apoptosis Apoptosis Necrosis or

Ischemia tissue damage, especially after myocardial and cerebral

DNA damage Mutations

Removal of free radicals

Table 2.3 Principal Free Radicals Involved in Cell Injury

Mild ER Stress Severe ER Stress

Cytosol Increased Reduced Increased

Reduced load of misfolded proteins

ADAPTIVE TERMINAL UNFOLDED PROTEIN

Table 2.4 Diseases Caused by Misfolded Proteinsa

DNA Damage O2 supply Survival signals

uterus during pregnancy), or to the demands of mechani-

synthesize excessive amounts. In the kidney, for example,

areas of necrosis of any type. It is virtually ubiquitous

Table 4.3 Three Major Types of Shock

Procoagulant Anti-fibrinolytic IL-6, IL-8, NO, PAF, IL-10, apoptosis,

Adrenal insufficiency MULTIORGAN FAILURE

leakage, further aggravating the shock state. Myocardial

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