INTRODUCTION TO PATHOLOGY e) Genetic abnormalities

Genetic aberrations can result in pathologic changes as conspicuous as the

congenital malformations associated with Down syndrome or as subtle as the
single amino acid substitution in hemoglobin giving rise to sickle cell anemia
Genetic defects may cause cell injury as a consequence of deficiency of
functional proteins, such as enzymes in inborn errors of metabolism, or
accumulation of damaged DNA or misfolded proteins, both of which trigger
cell death when they are beyond repair.
f) Nutritional imbalances
Proteincalorie insufficiency among impoverished populations remains a major
cause of cell injury, and specific vitamin deficiencies are not uncommon even
in developed countries with high standards of living
Ironically, excessive dietary intake may result in obesity and also is an
important underlying factor in many diseases, such as type 2 diabetes mellitus
and atherosclerosis.
g) Physical agents
Trauma, extremes of temperature, radiation, electric shock, and sudden
changes in atmospheric pressure all have wide-ranging effects on cells
h) Aging
Cellular senescence results in a diminished ability of cells to respond to stress
and, eventually, the death of cells and of the organism.

Steps in the evolution of disease

Only selected major causes (etiologies) are shown
Pathology
Devoted to understanding the causes of disease and the changes in cells, tissues, and organs
that are associated with disease and give rise to the presenting signs and symptoms in
patients.
There are two important terms that students will encounter throughout their study of
pathology and medicine:
1. Etiology: refers to the underlying causes and modifying factors that are responsible
for the initiation and progression of disease
2. Pathogenesis: refers to the mechanisms of development and progression of disease,
which account for the cellular and molecular changes that give rise to the specific
functional and structural abnormalities that characterize any particular disease.
Thus, etiology refers to why a disease arises and pathogenesis describes how a disease
develops
To render diagnoses and guide therapy in clinical practice, pathologists identify changes in
the gross or microscopic appearance (morphology) of cells and tissues, and biochemical
alterations in body fluids (such as blood and urine)
Pathologists also use a variety of morphologic, molecular, and other techniques to define the
biochemical, structural, and functional changes that occur in cells, tissues, and organs in
response to injury.

Reversible cell injury and necrosis

The principal cellular alterations that characterize reversible cell injury and necrosis are illustrated.
By convention, reversible injury is considered to culminate in necrosis if the injurious stimulus is not removed

SEQUENCE OF EVENTS IN CELL INJURY AND CELL DEATH

Although various injurious stimuli damage cells through diverse biochemical mechanisms,
all tend to induce a stereotypic sequence of morphologic and structural alterations in most
types of cells.

Reversible Cell Injury

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
Cells and intracellular organelles typically become swollen because they take in water as a
result of the failure of energy-dependent ion pumps in the plasma membrane, leading to an
Sequence of reversible cell injury and cell death inability to maintain ionic and fluid homeostasis.
Necrosis and apoptosis are the two major pathways of cell death detail In some forms of injury, degenerated organelles and lipids may accumulate inside the injured
cells.
OVERVIEW OF CELLULAR RESPONSES TO STRESS AND NOXIOUS STIMULI
Cells actively interact with their environment, constantly adjusting their structure and
function to accommodate changing demands and extracellular stresses.
The intracellular milieu of cells is normally tightly regulated such that it remains fairly
constant, a state referred to as homeostasis.
As cells encounter physiologic stresses (such as increased workload in the heart) or
potentially injurious conditions (such as nutrient deprivation), they can undergo
adaptation, achieving a new steady state and preserving viability and function.
If the adaptive capability is exceeded or if the external stress is inherently harmful or
excessive, cell injury develops
Within certain limits, injury is reversible, and cells return to their stable baseline
Morphologic changes in reversible and irreversible cell injury (necrosis). (A) Normal kidney tubules with viable epithelial cells
However, if the stress is severe, persistent, or rapid in onset, it results in irreversible (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells.
injury and death of the affected cells. (C) Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents

Cell Death
Results from diverse causes, including ischemia (lack of blood flow), infections, toxins, and MORPHOLOGY
immune reactions Two main morphologic correlates of reversible cell injury are cellular swelling and fatty
Also a normal and essential process in embryogenesis, the development of organs, and the change.
maintenance of tissue homeostasis. 1) Cellular Swelling
Commonly seen in cell injury associated with increased permeability of the
CAUSES OF CELL INJURY plasma membrane.
Span a range from gross physical trauma, such as after a motor vehicle accident, to a single When it affects many cells in an organ, it causes pallor (as a result of
gene defect that results in a nonfunctional enzyme in a specific metabolic disease. compression of capillaries), increased turgor, and an increase in organ weight.
Most injurious stimuli can be grouped into the following categories. Microscopic examination may show small, clear vacuoles within the cytoplasm;
a) Hypoxia and ischemia these represent distended and pinched-off segments of the endoplasmic
Hypoxia, which refers to oxygen deficiency, and ischemia, which means reticulum (ER).
reduced blood supply, are among the most common causes of cell injury. This pattern of nonlethal injury is sometimes called hydropic change or
Both deprive tissues of oxygen, and ischemia, in addition, results in a vacuolar degeneration.
deficiency of essential nutrients and a buildup of toxic metabolites 2) Fatty Change
Most common cause of hypoxia is ischemia resulting from an arterial Manifested by the appearance of triglyceride containing lipid vacuoles in the
obstruction cytoplasm.
Oxygen deficiency also can result from inadequate oxygenation of the blood, as It is principally encountered in organs that are involved in lipid metabolism,
in a variety of diseases affecting the lung, or from reduction in the oxygen- such as the liver
carrying capacity of the blood, as with anemia of any cause, and carbon The cytoplasm of injured cells also may become redder (eosinophilic), a change
monoxide (CO) poisoning. that becomes much more pronounced with progression to necrosis
b) Toxins Other intracellular changes associated with cell injury include
Potentially toxic agents are encountered daily in the environment: air a) Plasma membrane alterations such as blebbing, blunting, or distortion of
microvilli, and loosening of intercellular attachments
pollutants, insecticides, CO, asbestos, cigarette smoke, ethanol, and drugs.
b) Mitochondrial changes such as swelling and the appearance of
Many drugs in therapeutic doses can cause cell or tissue injury in a susceptible
phospholipid-rich amorphous densities
patient or in many individuals if used excessively or inappropriately
c) Dilation of the ER with detachment of ribosomes and dissociation of
Even innocuous substances, such as glucose, salt, water and oxygen, can be
polysomes
toxic.
d) Nuclear alterations, such as clumping of chromatin.
c) Infectious agents
Cytoplasm may contain so-called myelin figures, which are collections of
All types of disease-causing pathogens, including viruses, bacteria, fungi, and
phospholipids resembling myelin sheaths that are derived from damaged
protozoans, injure cells.
cellular membranes.
d) Immunologic reactions
The smooth ER is involved in the metabolism of various chemicals, and cells exposed to
Although the immune system defends the body against pathogenic microbes,
these chemicals show hypertrophy of the ER as an adaptive response that may have
immune reactions also can result in cell and tissue injury.
important functional consequences.
Examples are autoimmune reactions against ones own tissues, allergic
For instance, many drugs, including barbiturates, which were commonly used as
reactions against environmental substances, and excessive or chronic immune
sedatives in the past and are still used as a treatment for some forms of epilepsy,
responses to microbes are metabolized in the liver by the cytochrome P-450 mixed-function oxidase
In all of these situations, immune responses elicit inflammatory reactions, system found in the smooth ER.
which are often the cause of damage to cells and tissues.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 1 of 10
Protracted use of barbiturates leads to a state of tolerance, marked by the need
to use increasing doses of the drug to achieve the same effect. MORPHOLOGY
This adaptation stems from hypertrophy (an increase in volume) of the Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells
smooth ER of hepatocytes and a consequent increase in P-450 enzymatic Cytoplasmic changes
activity. P-450 mediated modification of compounds sometimes leads to Necrotic cells show increased eosinophilia attributable partly to increased
their detoxification, but in other instances converts them into a dangerous binding of eosin to denatured cytoplasmic proteins and partly to loss of
toxin basophilic ribonucleic acid (RNA) in the cytoplasm
Cells adapted to one drug demonstrate an increased capacity to They are stained red by the dye eosin, the E in the hematoxylin and eosin
metabolize other compounds handled by the same system. [H&E] stain
Thus, if patients taking phenobarbital for epilepsy increase their alcohol Basophilia stems from binding of the blue dye hematoxylin, the H in
intake, they may experience a drop in blood concentration of the anti- H&E
seizure medication to subtherapeutic levels because of smooth ER Cell may have a glassy, homogeneous appearance because of the loss of
hypertrophy in response to the alcohol. lighter staining glycogen particles.
With persistent or excessive noxious exposures, injured cells pass a nebulous point of Myelin figures are more prominent in necrotic cells than in cells with
no return and undergo cell death. reversible injury.
The clinical relevance of defining this transition point is obvious, if the When enzymes have digested cytoplasmic organelles, the cytoplasm
biochemical and molecular changes that predict cell death can be identified, it becomes vacuolated and appears moth-eaten.
may be possible to devise strategies for preventing the transition from reversible By electron microscopy, necrotic cells are characterized
to irreversible cell injury. Discontinuities in plasma and organelle membranes
Although there are no definitive morphologic or biochemical correlates of Marked dilation of mitochondria associated with the appearance of
irreversibility, it is consistently characterized by three phenomena: large amorphous intramitrochondrial densities
Inability to restore mitochondrial function Disruption of lysosomes, and intracytoplasmic myelin figures.
Oxidative phosphorylation and adenosine triphosphate [ATP] generation) Nuclear changes
even after resolution of the original injury Assume one of three patterns, all resulting from a breakdown of DNA and
Loss of structure and functions of the plasma membrane and intracellular chromatin.
membranes Pyknosis: nuclear shrinkage and increased basophilia
Loss of dna and chromatin structural integrity. o The DNA condenses into a dark shrunken mass
Injury to lysosomal membranes results in the enzymatic dissolution of the injured cell, o Pyknotic nucleus can undergo fragmentation
which is the culmination of necrosis. (Karyorrhexis)
o Ultimately, the nucleus may undergo Karyolysis, in which
the basophilia fades because of digestion of DNA by
deoxyribonuclease (DNase) activity.
o In 1 to 2 days, the nucleus in a dead cell may completely
disappear.
Fates of Necrotic Cells
Necrotic cells may persist for some time or may be digested by enzymes
and disappear.
Dead cells may be replaced by myelin figures, which are either
phagocytosed by other cells or further degraded into fatty acids.
These fatty acids bind calcium salts, which may result in the dead cells
ultimately becoming calcified.

Cell Death
When cells are injured they die by different mechanisms, depending on the nature and
severity of the insult.
Severe disturbances, such as loss of oxygen and nutrient supply and the actions of toxins,
The relationship among cellular function, cell death, and the morphologic changes of cell injury
cause a rapid and uncontrollable form of death that has been called accidental cell death. Note that cells may rapidly become nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; with a
The morphological manifestation of accidental cell death is Necrosis (Greek, Necros longer duration of injury, irreversible injury and cell death may result. Note also that cell death typically precedes ultrastructural, light microscopic,
and grossly visible morphologic changes.
= death)
Traditionally considered the inevitable end result of severe damage that is beyond Morphologic Patterns of Tissue Necrosis
salvage and is not thought to be regulated by specific signals or biochemical Most of the types of necrosis described here have distinctive gross appearances; the
mechanisms exception is Fibrinoid Necrosis, which is detected only by histologic examination.
Happens accidentally because the injury is too severe to be repaired and many cellular a) Coagulative Necrosis
constituents simply fail or fall apart. Form of necrosis in which the underlying tissue architecture is preserved for at
When the injury is less severe, or cells need to be eliminated during normal processes, they least several days after death of cells in the tissue
activate a precise set of molecular pathways that culminate in death. The affected tissues take on a firm texture.
Because this kind of cell death can be manipulated by therapeutic agents or genetic Presumably the injury denatures not only structural proteins but also enzymes,
mutations, it is said to be regulated cell death. thereby blocking the proteolysis of the dead cells; as a result, eosinophilic,
The morphologic appearance of most types of regulated cell death is apoptosis anucleate cells may persist for days or weeks.
In some instances, regulated cell death shows features of both necrosis and apoptosis, and Leukocytes are recruited to the site of necrosis, and the dead cells are
has been called Necroptosis. ultimately digested by the action of lysosomal enzymes of the leukocytes.
The discovery of these previously unrecognized forms of cell death that were regulated by The cellular debris is then removed by phagocytosis mediated primarily by
identifiable genes and signaling pathways showed that cell death can be a controlled process. infiltrating neutrophils and macrophages.
The idea of regulated cell death also raises the possibility that specific molecular pathways Characteristic of infarcts (areas of necrosis caused by ischemia) in all solid
can be targeted therapeutically to prevent the loss of cells in pathologic conditions. organs except the brain.
Apoptosis b) Liquefactive Necrosis
Process that eliminates cells with a variety of intrinsic abnormalities and promotes Seen in focal bacterial and, occasionally, fungal infections because microbes
clearance of the fragments of the dead cells without eliciting an inflammatory stimulate rapid accumulation of inflammatory cells, and the enzymes of
reaction. leukocytes digest (Liquefy) the tissue.
This clean form of cell suicide occurs in pathologic situations when a cells DNA or For obscure reasons, hypoxic death of cells within the central nervous system
proteins are damaged beyond repair or the cell is deprived of necessary survival often evokes liquefactive necrosis
signals. Whatever the pathogenesis, the dead cells are completely digested,
But unlike necrosis, which is always an indication of a pathologic process, transforming the tissue into
apoptosis also occurs in healthy tissues. a viscous liquid that is eventually removed by phagocytes.
It serves to eliminate unwanted cells during normal development and to maintain If the process is initiated by acute inflammation, as in a bacterial infection, the
constant cell numbers, so it is not necessarily associated with pathologic cell injury. material is frequently creamy yellow and is called Pus
These types of physiologic cell death are also called Programmed Cell Death. c) Gangrenous Necrosis
It is important to point out that cellular function may be lost long before cell death Refers to the condition of a limb (generally the lower leg) that has lost its blood
occurs, and that the morphologic changes of cell injury (or death) lag far behind loss supply and has undergone coagulative necrosis involving multiple tissue layers
of function and viability When bacterial infection is superimposed, the morphologic appearance
Myocardial cells become non-contractile after 1 to 2 minutes of ischemia, but may not changes to liquefactive necrosis because of the destructive contents of the
die until 20 to 30 minutes of ischemia have elapsed. bacteria and the attracted leukocytes (resulting in so-called Wet Gangrene).
d) Caseous Necrosis
Morphologic features indicative of the death of ischemic myocytes appear by electron
Most often encountered in foci of tuberculous infection.
microscopy within 2 to 3 hours after the death of the cells, but are not evident by light
Caseous means cheese-like, referring to the friable yellow-white appearance
microscopy until 6 to 12 hours later.
of the area of necrosis on gross examination
Necrosis
On microscopic examination, the necrotic focus appears as a collection of
Form of cell death in which cellular membranes fall apart, and cellular enzymes leak
fragmented or lysed cells with an amorphous granular pink appearance in H&E
out and ultimately digest the cell
Elicits a local host reaction, called inflammation, that is induced by substances released stained tissue sections
Unlike coagulative necrosis, the tissue architecture is completely obliterated
from dead cells and which serves to eliminate the debris and start the subsequent repair
and cellular outlines cannot be discerned.
process
Often surrounded by a collection of macrophages and other inflammatory cells;
The enzymes responsible for digestion of the cell are derived from lysosomes and may come
this appearance is characteristic of a nodular inflammatory lesion called a
from the dying cells themselves or from leukocytes recruited as part of the inflammatory
Granuloma
reaction.
e) Fat Necrosis
The culmination of reversible cell injury that cannot be corrected.
Refers to focal areas of fat destruction, typically resulting from the release of
The biochemical mechanisms of necrosis vary with different injurious stimuli.
activated pancreatic lipases into the substance of the pancreas and the
Failure of energy generation in the form of ATP because of reduced oxygen supply or
peritoneal cavity.
mitochondrial damage
This occurs in the calamitous abdominal emergency known as Acute
Damage to cellular membranes, including the plasma membrane and lysosomal
Pancreatitis
membranes, which results in leakage of cellular contents including enzymes
Pancreatic enzymes that have leaked out of acinar cells and ducts
Irreversible damage to cellular lipids, proteins, and nucleic acids, which may be
liquefy the membranes of fat cells in the peritoneum, and lipases split
caused by reactive oxygen species (ROS)
the triglyceride esters contained within fat cells.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 2 of 10
The released fatty acids combine with calcium to produce grossly visible Causes of Apoptosis
chalky white areas (fat saponification), which enable the surgeon and Apoptosis occurs in many normal situations and serves to eliminate potentially harmful cells
the pathologist to identify the lesions and cells that have outlived their usefulness
On histologic examination, the foci of necrosis contain shadowy outlines of It also occurs as a pathologic event when cells are damaged, especially when the damage
necrotic fat cells surrounded by basophilic calcium deposits and an affects the cells DNA or proteins; thus, the irreparably damaged cell is eliminated.
inflammatory reaction. a) Physiologic Apoptosis
f) Fibrinoid Necrosis During normal development of an organism, some cells die and are replaced by new
Special form of necrosis. ones
It usually occurs in immune reactions in which complexes of antigens and In mature organisms, highly proliferative and hormone responsive tissues undergo
antibodies are deposited in the walls of blood vessels, but it also may occur in cycles of proliferation and cell loss that are often determined by the levels of growth
severe hypertension. factors.
Deposited immune complexes and plasma proteins that leak into the wall of In these situations, the cell death is always by apoptosis, ensuring that unwanted cells
damaged vessels produce a bright pink, amorphous appearance on h&e are eliminated without eliciting potentially harmful inflammation.
preparations called fibrinoid (fibrin-like) by pathologists In the immune system, apoptosis eliminates excess leukocytes left at the end of
Type of necrosis is seen in immunologically mediated diseases (e.g., immune responses as well as lymphocytes that recognize self-antigens and could
polyarteritis nodosa) cause autoimmune diseases if they were not purged.
b) Apoptosis in pathologic conditions
Apoptosis eliminates cells that are damaged beyond repair.
This is seen when there is severe DNA damage, for example, after exposure 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, particularly some viruses, induce apoptotic death of infected
cells.

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).

Liquefactive necrosis Caseous necrosis

An infarct in the brain shows dissolution of the tissue Tuberculosis of the lung, with a large area of caseous
necrosis containing yellow-white (cheesy) debris

Fibrinoid necrosis in an artery in a patient with polyarteritis Fat necrosis in acute pancreatitis
nodosa The areas of white chalky deposits represent foci of fat necrosis
The wall of the artery shows a circumferential bright pink area of with calcium soap formation (saponification) at sites of lipid
necrosis with protein deposition and inflammation. breakdown in the mesentery

Leakage of intracellular proteins through the damaged cell membrane and ultimately into
the circulation provides a means of detecting tissue-specific necrosis using blood or serum Table 2.2 Physiologic and Pathologic Conditions Associated With Apoptosis
samples.
Cardiac muscle, for example, contains a unique isoform of the enzyme creatine kinase Mechanisms of Apoptosis
and of the contractile protein troponin, whereas hepatic bile duct epithelium contains Apoptosis is regulated by biochemical pathways that control the balance of death- and
the enzyme alkaline phosphatase, and hepatocytes contain transaminases. survival-inducing signals and ultimately the activation of enzymes called Caspases.
Irreversible injury and cell death in these tissues elevate the serum levels of these Named because they are cysteine proteases that cleave proteins after aspartic acid
proteins, which makes them clinically useful markers of tissue damage. residues.
Two distinct pathways converge on caspase activation: the mitochondrial pathway
and the death receptor pathway
Although these pathways can intersect, they are generally induced under different
conditions, involve different molecules, and serve distinct roles in physiology and
disease.
The end result of apoptotic cell death is the clearance of apoptotic bodies by
phagocytes.
The mitochondrial (intrinsic) pathway seems to be responsible for apoptosis in most
physiologic and pathologic situations.
Mitochondria contain several proteins that are capable of inducing apoptosis,
including cytochrome c.
When mitochondrial membranes become permeable, cytochrome c leaks out into the
cytoplasm, triggering caspase activation and apoptotic death.
A family of more than 20 proteins, the prototype of which is Bcl-2, controls the
permeability of mitochondria.
In healthy cells, Bcl-2 and the related protein Bcl-xL, which are produced in response
to growth factors and other stimuli, maintain the integrity of mitochondrial
membranes, in large part by holding two proapoptotic members of the family, Bax
and Bak, in check.
When cells are deprived of growth factors and survival signals, or are exposed to
agents that damage DNA, or accumulate unacceptable amounts of misfolded proteins,
a number of sensors are activated.
These sensors are called BH3 proteins because they contain the third domain seen in
Bcl-family proteins.
They in turn shift this delicate, life-sustaining balance in favor of pro-apoptotic
Bak and Bax.
As a result, Bak and Bax dimerize, insert into the mitochondrial membrane,
and form channels through which cytochrome c and other mitochondrial
proteins escape into the cytosol.
After cytochrome c enters the cytosol, it, together with certain cofactors, activates
caspase-9.
The net result is the activation of a caspase cascade, ultimately leading to nuclear
fragmentation and formation of apoptotic bodies.
The death receptor (extrinsic) pathway of apoptosis.
Many cells express surface molecules, called death receptors that trigger apoptosis.
Apoptosis Most of these are members of the tumor necrosis factor (TNF) receptor family, which
The cellular alterations in apoptosis are illustrated.
Contrast these with the changes that characterize necrotic cell death
contain in their cytoplasmic regions a conserved death domain, so named because
Apoptosis it mediates interaction with other proteins involved in cell death.
Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the The prototypic death receptors are the type I TNF receptor and Fas (CD95).
cells own nuclear DNA and nuclear and cytoplasmic proteins Fas ligand (FasL) is a membrane protein expressed mainly on activated T
Fragments of the apoptotic cells then break off, giving the appearance that is responsible for lymphocytes.
the name (apoptosis, falling off). When these T cells recognize Fas-expressing targets, Fas molecules are crosslinked by
The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in FasL and bind adaptor proteins via the death domain.
such a way that the fragments, called apoptotic bodies, become highly edible, leading to These then recruit and activate caspase-8, which, in turn, activates downstream
their rapid consumption by phagocytes. caspases.
The dead cell and its fragments are cleared with little leakage of cellular contents, so
apoptotic cell death does not elicit an inflammatory reaction.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 3 of 10
The death receptor pathway is involved in the elimination of self-reactive lymphocytes
and in the killing of target cells by some cytotoxic T lymphocytes (CTLs) that express
FasL.
In either pathway, after caspase-9 or caspase-8 is activated, it cleaves and thereby
activates additional caspases that cleave numerous targets and ultimately activate
enzymes that degrade the cells proteins and nucleus.
The end result is the characteristic cellular fragmentation of apoptosis.
Clearance of apoptotic cells
Apoptotic cells and their fragments entice phagocytes by producing a number of eat-
me signals. Autophagy
Cellular stresses, such as nutrient deprivation, activate autophagy genes, which initiate the formation of membrane -bound vesicles in which
For instance, in normal cells, phosphatidylserine is present on the inner leaflet of the cellular organelles are sequestered.
plasma membrane, but in apoptotic cells this phospholipid flips to the outer leaflet, 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.
where it is recognized by tissue macrophages, leading to phagocytosis of the apoptotic
cells.
Autophagy
Cells that are dying by apoptosis also secrete soluble factors that recruit phagocytes. Autophagy (self-eating) refers to lysosomal digestion of the cells own components.
The plasma membrane alterations and secreted proteins facilitate prompt clearance of It is a survival mechanism in times of nutrient deprivation, so that the starved cell can live by
the dead cells before the cells undergo membrane damage and release their contents eating its own contents and recycling these contents to provide nutrients and energy.
(which can induce inflammation). In this process, intracellular organelles and portions of cytosol are first sequestered within an
Numerous macrophage receptors have been shown to be involved in the binding and ER-derived autophagic vacuole, whose formation is initiated by cytosolic proteins that sense
engulfment of apoptotic cells. nutrient deprivation
The phagocytosis of apoptotic cells is so efficient that dead cells disappear without The vacuole fuses with lysosomes to form an autophagolysosome, in which lysosomal
leaving a trace, and inflammation is virtually absent. enzymes digest the cellular components.
In some circumstances, autophagy may be associated with atrophy of tissues (discussed later)
MORPHOLOGY and may represent an adaptation that helps cells survive lean times.
In H&E-stained tissue sections, the nuclei of apoptotic cells show various stages of If, however, the starved cell can no longer cope by devouring its contents, autophagy may
chromatin condensation and aggregation and, ultimately, karyorrhexis eventually lead to apoptotic cell death.
At the molecular level, this is reflected in the fragmentation of DNA into Extensive autophagy is seen in ischemic injury and some types of myopathies.
nucleosome-sized pieces. Polymorphisms in a gene involved in autophagy have been associated with inflammatory
The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies bowel disease, but the mechanistic link between autophagy and intestinal inflammation is
that are composed of membrane bound pieces of cytosol and organelles not known.
Because these fragments are quickly extruded and phagocytosed without eliciting an Thus, a once little-appreciated survival pathway in cells may prove to have wide-ranging
inflammatory response, even substantial apoptosis may be histologically undetectable. roles in human disease.

SUMMARYERNS OF CELL INJURY AND CELL DEATH

Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing and loss
of microvilli, mitochondrial swelling, dilation of the ER, eosinophilia (resulting from
decreased cytoplasmic RNA)
Necrosis
Accidental cell death manifested by increased cytoplasmic eosinophilia
Nuclear shrinkage, fragmentation, and dissolution
Breakdown of plasma membrane and organellar membranes
Abundant myelin figures
Leakage and enzymatic digestion of cellular contents
Morphologic types of tissue necrosis
Under different conditions, necrosis in tissues may assume specific patterns
Coagulative, liquefactive, gangrenous, caseous, fat and fibrinoid
Apoptosis
Regulated mechanism of cell death that serves to eliminate unwanted and
irreparably damaged cells, with the least possible host reaction
Characterized by enzymatic degradation of proteins and DNA
Initiated by caspases
By rapid recognition and removal of dead cells by phagocytes
Apoptosis is initiated by two major pathways:
1) Mitochondrial (intrinsic) pathway is triggered by loss of survival signals,
DNA damage, and accumulation of misfolded proteins (ER stress)
Mechanisms of apoptosis Associated with leakage of proapoptotic proteins from mitochondrial
The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. membrane into the cytoplasm, where they trigger caspase activation
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. Inhibited by anti-apoptotic members of the Bcl family, which are induced
These BH3-only proteins activate effector molecules that increase mitochondrial permeability. In concert with a deficiency of Bcl -2 and other by survival signals including growth factors
proteins that maintain mitochondrial permeability, the mitochondria become leaky and various substances, such as cytochrome c, enter the
cytosol and activate caspases. 2) Death receptor (extrinsic) pathway is responsible for elimination of self-
Activated caspases induce the changes that culminate in cell death and fragmentation. In the death receptor pathway, signals from plasma reactive lymphocytes and damage by CTLs

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 Initiated by engagement of death receptors (members of the TNF receptor
family) by ligands on adjacent cells.
Two other unusual pathways of cell death are necroptosis (which, as the name
Morphologic appearance of apoptotic cells implies, includes features of both necrosis and apoptosis and is regulated by particular
Apoptotic cells (some indicated by arrows) in colonic epithelium are shown. (Some signaling pathways) and pyroptosis, which can lead to the release of proinflammatory
preparative regimens for colonoscopy may induce apoptosis in epithelial cells, which
explains the presence of dead cells in this biopsy.) cytokines and may initiate apoptosis.
Note the fragmented nuclei with condensed chromatin and the shrunken cell bodies, some Autophagy
with pieces falling off.
An adaptation to nutrient deprivation in which cells digest their own organelles
and recycle them to provide energy and substrates.
If the stress is too severe for the process to cope with it, it results in cell death by
apoptosis

MECHANISMS OF CELL INJURY AND CELL DEATH

Before discussing individual mechanisms of cell injury and death, some general principles should be
emphasized.
The cellular response to injurious stimuli depends on the type of injury, its duration,
and its severity
Thus, low doses of toxins or a brief period of ischemia may lead to reversible cell
injury, whereas larger toxin doses or longer ischemic times may result in irreversible
injury and cell death.
The consequences of an injurious stimulus also depend on the type, status,
Other Pathways of Cell Death adaptability, and genetic makeup of the injured cell
In addition to necrosis and apoptosis, two other patterns of cell death have been described The same injury has vastly different outcomes depending on the cell type.
that have unusual features. For instance, striated skeletal muscle in the leg tolerates complete ischemia for 2 to 3
Although the importance of these pathways in disease remains to be established, they are the hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30
subjects of considerable current research, and it is useful to be aware of the basic concepts. minutes of ischemia.
a) Necroptosis The nutritional (or hormonal) status also can be important; understandably, a
This form of cell death is initiated by engagement of TNF receptors as well as glycogen-replete hepatocyte will survive ischemia better than one that has just burned
other, poorly defined triggers. its last glucose molecule.
Unlike the extrinsic pathway of apoptosis, which also is downstream of TNF
Genetically determined diversity in metabolic pathways can contribute to differences
receptors, in necroptosis, kinases called receptor-interacting protein (RIP) in responses to injurious stimuli.
kinases are activated, initiating a series of events that result in the dissolution
For instance, when exposed to the same dose of a toxin, individuals who inherit
of the cell, much like necrosis.
variants in genes encoding cytochrome P-450 may catabolize the toxin at different
The name implies that there are features of both necrosis and apoptosis.
rates, leading to different outcomes.
Some infections are believed to kill cells by this pathway, and it has been
Much effort is now directed toward understanding the role of genetic polymorphisms
hypothesized to play a role in ischemic injury and other pathologic situations,
in responses to drugs and toxins, a field of study called pharmacogenomics.
especially those associated with inflammatory reactions in which the cytokine
In fact, genetic variations influence susceptibility to many complex diseases as well as
TNF is produced.
responsiveness to various therapeutic agents.
However, when and why it occurs and how significant it is in human diseases is
Using the genetic makeup of the individual patient to guide therapy is one example of
not well understood.
precision medicine.
b) Pyroptosis
Cell injury usually results from functional and biochemical abnormalities in one or
This form of cell death is associated with activation of a cytosolic danger-
sensing protein complex called the inflammasome more of a limited number of essential cellular components
The net result of inflammasome activation is the activation of caspases, some of Different external insults and endogenous perturbations typically affect different
which induce the production of cytokines that induce inflammation, often cellular organelles and biochemical pathways.
manifested by fever, and others trigger apoptosis. For instance, deprivation of oxygen and nutrients (as in hypoxia and ischemia)
Thus, apoptosis and inflammation coexist. primarily impairs energy dependent cellular functions, culminating in necrosis,
The name stems from the association of apoptosis with fever (Greek, pyro = whereas damage to proteins and DNA triggers apoptosis.
fire) It has proved difficult to prevent cell injury by targeting an individual pathway.
It is thought to be one mechanism by which some infectious microbes cause
the death of infected cells.
Its role in other pathologic situations is unknown.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 4 of 10
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 cellular anti-
oxidant defense mechanisms may be compromised by ischemia, exacerbating the
situation.
ROS generated by infiltrating leukocytes also may contribute to the damage of
vulnerable injured cells.
The inflammation that is induced by ischemic injury may increase with reperfusion because
it enhances the influx of leukocytes and plasma proteins.
The products of activated leukocytes may cause additional tissue injury
Activation of the complement system also may contribute to ischemia-reperfusion
injury.
Complement proteins may bind to the injured tissues, or to antibodies that are
deposited in the tissues, and subsequent complement activation generates byproducts
The principal biochemical mechanisms and sites of damage in cell injury Note that causes and mechanisms of cell death by necrosis and apoptosis are that exacerbate the cell injury and inflammation.
shown as being independent but there may be overlap
For instance, both may contribute to cell death caused by ischemia, oxidative stress, or radiation.

Hypoxia and Ischemia

Deficiency of oxygen leads to failure of many energy dependent metabolic pathways, and
ultimately to death of cells by necrosis.
Most cellular ATP is produced from adenosine diphosphate (ADP) by oxidative
phosphorylation during reduction of oxygen in the electron transport system of
mitochondria. High-energy phosphate in the form of ATP is required for membrane
transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary
for phospholipid turnover
It is estimated that in total, the cells of a healthy human burn 50 to 75 kg of ATP every day
Cells deprived of oxygen are at risk of suffering catastrophic failure of many essential
functions.
Oxygen deprivation is one of the most frequent causes of cell injury and necrosis in clinical The generation, removal, and role of reactive oxygen species (ROS) in cell injury
The production of ROS is increased by many injurious stimuli.
medicine. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to
Cells subjected to the stress of hypoxia that do not immediately die activate compensatory accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and DNA, resulting in cell injury
mechanisms that are induced by transcription factors of the hypoxia inducible factor 1
(HIF-1) family Oxidative Stress
HIF-1 simulates the synthesis of several proteins that help the cell to survive in the Oxidative stress refers to cellular abnormalities that are induced by ROS, which
face of low oxygen. belong to a group of molecules known as Free Radicals.
Some of these proteins, such as vascular endothelial growth factor (VEGF), stimulate Free radical-mediated cell injury is seen in many circumstances, including chemical and
the growth of new vessels and thus attempt to increase blood flow and the supply of radiation injury, hypoxia, cellular aging, tissue injury caused by inflammatory cells, and
oxygen. ischemia-reperfusion injury.
Other proteins induced by HIF-1 cause adaptive changes in cellular metabolism by In all these cases, cell death may be by necrosis, apoptosis, or the mixed pattern of
stimulating the uptake of glucose and glycolysis and dampening mitochondrial necroptosis.
oxidative phosphorylation. Free radicals are chemical species with a single unpaired electron in an outer orbit. Such
Anaerobic glycolysis can generate ATP in the absence of oxygen using glucose derived either chemical states are extremely unstable, and free radicals readily react with inorganic and
from the circulation or from the hydrolysis of intracellular glycogen. organic molecules; when generated in cells, they avidly attack nucleic acids as well as a
Normal tissues with a greater glycolytic capacity because of the presence of glycogen variety of cellular proteins and lipids.
(e.g., the liver and striated muscle) are more likely to survive hypoxia and decreased Free radicals initiate reactions in which molecules that react with the free radicals are
oxidative phosphorylation than tissues with limited glucose stores (e.g., the brain). themselves converted into other types of free radicals, thereby propagating the chain of
Although it seems counterintuitive, rapidly proliferating normal cells and cancer cells damage.
rely on aerobic glycolysis to produce much of their energy, a phenomenon referred to
as the Warburg effect. Generation and Removal of Reactive Oxygen Species
The reason for this is that although glycolysis yields less ATP per molecule of The accumulation of ROS is determined by their rates of production and removal
glucose burned than oxidative phosphorylation, metabolites generated by ROS are produced by two major pathways.
glycolysis and the TCA cycle serve as precursors for the synthesis of cellular 1) ROS are produced normally in small amounts in all cells during the reduction-
constituents (e.g., proteins, lipids, and nucleic acids) that are needed for cell oxidation (redox) reactions that occur during mitochondrial respiration and energy
growth and division. generation.
In this process, molecular oxygen is reduced in mitochondria to generate water
Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation and by the sequential addition of four electrons.
depletion of ATP in cells. This reaction is imperfect, however, and small amounts of highly reactive but
Loss of this critical energy store has deleterious effects on many cellular systems short-lived toxic intermediates are generated when oxygen is only partially
reduced.
Reduced activity of plasma membrane ATP-dependent sodium pumps, resulting in
intracellular accumulation of sodium and efflux of potassium These intermediates include superoxide (O2), which is converted to hydrogen
The net gain of solute is accompanied by isoosmotic gain of water, causing cell peroxide (H2O2) spontaneously and by the action of the enzyme superoxide
swelling and dilation of the ER. dismutase (SOD)
The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation, H2O2 is more stable than O2 and can cross biologic membranes.
decreased intracellular pH, and decreased activity of many cellular enzymes. In the presence of metals, such as Fe2+, H2O2 is converted to the highly reactive
Prolonged or worsening depletion of ATP causes structural disruption of the hydroxyl radical OH by the Fenton reaction.
protein synthetic apparatus manifested as detachment of ribosomes from the rough 2) ROS are produced in phagocytic leukocytes, mainly neutrophils and
ER (RER) and dissociation of polysomes into monosomes, with a consequent macrophages, as a weapon for destroying ingested microbes and other substances
reduction in protein synthesis. during inflammation and host defense
The ROS are generated in the phagosomes and phagolysosomes of leukocytes
It also has been suggested that hypoxia per se increases the accumulation of ROS.
Hypoxia predisposes cells to ROS-mediated damage if blood flow (and oxygen by a process that is similar to mitochondrial respiration and is called the
Respiratory Burst (or Oxidative Burst).
delivery) is reestablished, a phenomenon called Reperfusion Injury
In this process, a phagosome membrane enzyme catalyzes the generation of
Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes,
superoxide, which is converted to H2O2
and the cell undergoes necrosis.
H2O2 is in turn converted to a highly reactive compound, Hypochlorite (the
Membrane damage is a late event in cell injury caused by diverse mechanisms,
major component of household bleach), by the enzyme myeloperoxidase,
and is discussed later.
which is present in leukocytes
Although necrosis is the principal form of cell death caused by hypoxia, apoptosis by the
Nitric oxide (NO) is another reactive free radical produced in macrophages and other
mitochondrial pathway is also thought to contribute.
The functional consequences of hypoxia and ischemia depend on the severity and duration of leukocytes. It can react with O2 to form a highly reactive compound, Peroxynitrite, which
the deficit. also participates in cell injury.
For instance, the heart muscle ceases to contract within 60 seconds of coronary occlusion. If
The generation of free radicals is increased under several circumstances:
hypoxia continues, worsening ATP depletion causes further deterioration, undergoing the
sequence of changes The absorption of radiant energy (e.g., ultraviolet (UV) light, x-rays). Ionizing radiation can
hydrolyze water into hydroxyl (OH) and hydrogen (H) free radicals.
The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride)
Inflammation, in which free radicals are produced by leukocytes
Reperfusion of ischemic tissues, as already described.

Cells have developed mechanisms to remove free radicals and thereby minimize their
injurious effects
Free radicals are inherently unstable and decay spontaneously.
There also are non-enzymatic and enzymatic systems, sometimes called free radical
scavengers, serving to inactivate free radicals
The rate of decay of superoxide is significantly increased by the action of Superoxide
Dismutase (SOD).
Glutathione (GSH) Peroxidases are a family of enzymes whose major function is to protect
cells from oxidative damage.
The most abundant member of this family, GSH Peroxidase 1, is found in the
cytoplasm of all cells.
It catalyzes the breakdown of H2O2 by the reaction 2GSH + H2O2 GS-SG +
2H2O.
The intracellular ratio of oxidized GSH to reduced GSH is a reflection of this
enzymes activity and thus of the cells ability to catabolize free radicals.
Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide (2H2O2
O2 + 2H2O)
It is one of the most active enzymes known, capable of degrading millions of
The functional and morphologic consequences of hypoxia and ischemia molecules of H2O2 per second.
Endogenous or exogenous anti-oxidants (e.g., vitamins E, A, and C and -carotene)
Ischemia-Reperfusion Injury may either block the formation of free radicals or scavenge them after they have
Under certain circumstances, the restoration of blood flow to ischemic but viable formed.
tissues results, paradoxically, in increased cell injury
This is the reverse of the expected outcome of the restoration of blood flow, which normally Cell Injury Caused by Reactive Oxygen Species
results in the recovery of reversibly injured cells. ROS causes cell injury by damaging multiple components of cells:
This so-called Ischemia-Reperfusion Injury is a clinically important process that Lipid peroxidation of membranes
may contribute significantly to tissue damage, especially after myocardial and cerebral Double bonds in membrane polyunsaturated lipids are vulnerable to attack by
ischemia. oxygen-derived free radicals
Several mechanisms may account for the exacerbation of cell injury resulting from reperfusion of The lipidradical interactions yield peroxides, which are themselves unstable and
ischemic tissues: reactive, and an autocatalytic chain reaction ensues.
New damage may be initiated during reoxygenation by increased generation of ROS

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 5 of 10
Damage to plasma membranes as well as mitochondrial and lysosomal membranes Aging, which is associated with a decreased capacity to correct misfolding
can have devastating consequences Infections, especially viral infections, when large amounts of microbial proteins are
Crosslinking and other changes in proteins synthesized within cells, more than the cell can handle
Free radicals promote sulfhydryl-mediated protein crosslinking, resulting in enhanced Increased demand for secretory proteins such as insulin in insulin-resistant states
degradation or loss of enzymatic activity. changes in intracellular pH and redox state.
Free radical reactions also may directly cause polypeptide fragmentation. Protein misfolding is thought to be the fundamental cellular abnormality in several
Damaged proteins may fail to fold properly, triggering the unfolded protein response neurodegenerative diseases
DNA damage Deprivation of glucose and oxygen, as in ischemia and hypoxia, also may increase the burden
Free radical reactions with thymine residues in nuclear and mitochondrial DNA of misfolded proteins
produce single strand breaks. Such DNA damage has been implicated in apoptotic cell
death, aging, and malignant transformation of cells.
In addition to the role of ROS in cell injury and the killing of microbes, low concentrations of
ROS are involved in numerous signaling pathways in cells and thus in many physiologic
reactions.
Therefore, these molecules are produced normally but, to avoid their harmful effects, their
intracellular concentrations are tightly regulated in healthy cells

Protein misfolding within cells may cause disease by creating a deficiency of an essential
protein or by inducing apoptosis
Cell Injury Caused by Toxins Misfolded proteins often lose their activity and are rapidly degraded, both of which can
Toxins, including environmental chemicals and substances produced by infectious contribute to a loss of function.
pathogens, induce cell injury that culminates primarily in necrotic cell death.
If this function is essential, cellular injury ensues.
Different types of toxins induce cell injury by two general mechanisms:
One important disease in which this occurs is cystic fibrosis, which is caused by
Direct-acting toxins
inherited mutations in a membrane transport protein that prevent its normal folding.
Some toxins act directly by combining with a critical molecular component or cellular
Cell death as a result of protein misfolding is recognized as a feature of a number of diseases,
organelle.
including the neurodegenerative disorders Alzheimer disease,
In mercuric chloride poisoning (as may occur from ingestion of contaminated Huntington disease, and Parkinson disease, and may underlie type 2 diabetes as well
seafood), mercury binds to the sulfhydryl groups of various cell membrane proteins,
Improperly folded proteins can also accumulate in extracellular tissues, as in amyloidosis.
causing inhibition of ATP-dependent transport and increased membrane
permeability.
DNA Damage
Many anti-neoplastic chemotherapeutic agents also induce cell damage by direct Exposure of cells to radiation or chemotherapeutic agents, intracellular generation of ROS,
cytotoxic effects. and acquisition of mutations may all induce DNA damage, which if severe may trigger
Also included in this class are toxins made by microorganisms apoptotic death
These often cause damage by targeting host cell molecules that are needed for Damage to DNA is sensed by intracellular sentinel proteins, which transmit signals that lead
essential functions, such as protein synthesis and ion transport. to the accumulation of p53 protein. p53 first arrests the cell cycle (at the G1 phase) to allow
Latent toxins the DNA to be repaired before it is replicated
Many toxic chemicals are not intrinsically active but must first be converted to However, if the damage is too great to be repaired successfully, p53 triggers apoptosis, mainly
reactive metabolites, which then act on target cells. by stimulating BH3-only sensor proteins that ultimately activate Bax and Bak, proapoptotic
Understandably, such toxins typically affect the cells in which they are activated. members of the Bcl-2 family.
This is usually accomplished by cytochrome P-450 in the smooth ER of the liver and When p53 is mutated or absent (as it is in certain cancers), cells with damaged DNA that
other organs. would otherwise undergo apoptosis survive.
Although the metabolites might cause membrane damage and cell injury by direct In such cells, the DNA damage may result in mutations or DNA rearrangements (e.g.,
covalent binding to protein and lipids, the most important mechanism of cell injury translocations) that lead to neoplastic transformation
involves the formation of free radicals.
Carbon Tetrachloride (CCl4) Inflammation
Once widely used in the dry cleaning industry but now banned and the analgesic A common cause of injury to cells and tissues
acetaminophen belong in this category Elicited by pathogens, necrotic cells, and dysregulated immune responses, as in autoimmune
The effect of CCl4 is still instructive as an example of chemical injury diseases and allergies.
CCl4 is converted to a toxic free radical, principally in the liver, and this free radical is In all these situations, inflammatory cells, including neutrophils, macrophages,
the cause of cell injury, mainly by membrane phospholipid peroxidation lymphocytes, and other leukocytes, secrete products that evolved to destroy
In less than 30 minutes after exposure to CCl4, there is sufficient damage to the ER microbes but also may damage host tissues.
membranes of hepatocytes to cause a decline in the synthesis of enzymes and plasma These injurious immune reactions are classified under hypersensitivity
proteins within 2 hours, swelling of the smooth ER and dissociation of ribosomes from
the RER have occurred. Common Events in Cell Injury From Diverse Causes
There also is decreased synthesis of apoproteins that form complexes with In the previous discussion, we addressed the mechanisms of cell injury according to the
triglycerides and thereby facilitate triglyceride secretion; this defect results in the initiating cause, and highlighted the principal pathways of injury that are triggered in
accumulation of lipids in hepatocytes and other cells and the fatty liver of CCl4 different pathophysiologic situations.
poisoning. Some abnormalities characterize cell injury regardless of the cause, and are thus seen in a
Mitochondrial injury follows, and subsequently diminished ATP stores result in variety of pathologic situations.
defective ion transport and progressive cell swelling the plasma membranes are
further damaged by fatty aldehydes produced by lipid peroxidation in the ER.
The end result can be cell death.

Role of mitochondria in cell injury and death

Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis

Mitochondrial Dysfunction
Mitochondria may be viewed as mini-factories that produce life-sustaining energy in the
The unfolded protein response and endoplasmic reticulum (ER) stress. The presence of misfolded proteins in the ER is detected by sensors in the ER form of ATP
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 misfolde d proteins. When the
Mitochondria are sensitive to many types of injurious stimuli, including hypoxia, chemical
amount of misfolded proteins is too great to be corrected, excessive activation of ER sensors activates the mitochondrial pathway of apoptosis and the toxins, and radiation
irreparably damaged cell dies; this is also called the terminal unfolded protein response.
Mitochondrial changes occur in necrosis and apoptosis.
They may result in several biochemical abnormalities:
Endoplasmic Reticulum Stress
Failure of oxidative phosphorylation leads to progressive depletion of ATP,
The accumulation of misfolded proteins in a cell can stress compensatory pathways in the
culminating in necrosis of the cell
ER and lead to cell death by apoptosis
Abnormal oxidative phosphorylation also leads to the formation of ROS, which have
During normal protein synthesis, chaperones in the ER control the proper folding of newly
many deleterious effects.
synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for
Damage to mitochondria is often associated with the formation of a high-conductance
proteolysis.
channel in the mitochondrial membrane, called the mitochondrial permeability
If unfolded or misfolded proteins accumulate in the ER, they first induce a protective cellular
transition pore.
response that is called the Unfolded Protein Response
The opening of this channel leads to the loss of mitochondrial membrane
This adaptive response activates signaling pathways that increase the production of
potential and pH changes, further compromising oxidative phosphorylation
chaperones and decrease protein translation, thus reducing the levels of misfolded proteins
Mitochondria also contain proteins such as cytochrome c that, when released into the
in the cell. When a large amount of misfolded protein accumulates and cannot be handled by
cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis
the adaptive response, the signals that are generated result in activation of proapoptotic
1) Defects in Membrane Permeability
sensors of the BH3-only family as well as direct activation of caspases, leading to apoptosis by
Increased membrane permeability leading ultimately to overt membrane
the mitochondrial (intrinsic) pathway.
damage is a feature of most forms of cell injury that culminate in necrosis.
The most important sites of membrane damage during cell injury are the
Intracellular accumulation of misfolded proteins may be caused by abnormalities that
mitochondrial membrane, the plasma membrane, and membranes of
increase the production of misfolded proteins or reduce the ability to eliminate them
lysosomes.
This may result from gene mutations that lead to the production of proteins that cannot fold
properly

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 6 of 10
Increased permeability of the plasma membrane and lysosomal membranes is Myocardium subjected to a persistently increased workload, as in hypertension or
not a feature of apoptosis. with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to generate the
2) Mitochondrial membrane damage required higher contractile force.
Damage to mitochondrial membranes results in decreased production of ATP, If, on the other hand, the myocardium is subjected to reduced blood flow
with many deleterious effects culminating in necrosis. (ischemia) due to an occluded coronary artery, the muscle cells may undergo
3) Plasma membrane damage injury.
Plasma membrane damage leads to loss of osmotic balance and influx of fluids The mechanisms driving cardiac hypertrophy involve at least two types of
and ions, as well as loss of cellular contents signals: mechanical triggers, such as stretch, and soluble mediators that
The cells may also leak metabolites that are vital for the reconstitution of ATP, stimulate cell growth, such as growth factors and adrenergic hormones.
thus further depleting energy stores. These stimuli turn on signal transduction pathways that lead to the induction
4) Injury to lysosomal membranes of a number of genes, which in turn stimulate synthesis of many cellular
Results in leakage of their enzymes into the cytoplasm and activation of the proteins, including growth factors and structural proteins.
acid hydrolases in the acidic intracellular ph of the injured (e.g., ischemic) cell The result is the synthesis of more proteins and myofilaments per cell, which
Activation of these enzymes leads to enzymatic digestion of cell components, increases the force generated with each contraction, enabling the cell to meet
and the cells die by necrosis. increased work demands.
SUMMARY There may also be a switch of contractile proteins from adult to fetal or neonatal
Different initiating events cause cell injury and death by diverse mechanisms. forms during muscle hypertrophy, the -myosin heavy chain is replaced by the fetal
Hypoxia and ischemia lead to ATP depletion and failure of many energy-dependent form of the myosin heavy chain, which produces slower, more energetically
functions, resulting first in reversible injury and, if not corrected, in necrosis. economical contraction.
In ischemia-reperfusion injury, restoration of blood flow to an ischemic tissue An adaptation to stress such as hypertrophy can progress to functionally significant
exacerbates damage by increasing production of ROS and by inflammation. cell injury if the stress is not relieved.
Oxidative stress refers to accumulation of ROS, which can damage cellular lipids, Whatever the cause of hypertrophy, a limit is reached beyond which the enlargement
proteins, and DNA, and is associated with numerous initiating causes. of muscle mass can no longer compensate for the increased burden.
Protein misfolding depletes essential proteins and, if the misfolded proteins When this happens in the heart, several degenerative changes occur in the myocardial
accumulate within cells, results in apoptosis. fibers, of which the most important are fragmentation and loss of myofibrillar
DNA damage (e.g., by radiation) also can induce apoptosis if it is not repaired. contractile elements.
Inflammation is associated with cell injury because of the damaging actions of the Why hypertrophy progresses to these regressive changes is incompletely understood.
products of inflammatory leukocytes There may be finite limits on the abilities of the vasculature to adequately supply the
We have now concluded the discussion of cell injury and cell death. enlarged fibers, the mitochondria to supply ATP, or the biosynthetic machinery to
these processes are the root cause of many common diseases. provide sufficient contractile proteins or other cytoskeletal elements.
We end this chapter with brief considerations of three other processes: cellular The net result of these degenerative changes is ventricular dilation and ultimately
adaptations to stresses; intracellular accumulations of various substances and cardiac failure.
extracellular deposition of calcium, both of which are often associated with cell injury;
and aging. Hyperplasia
Hyperplasia is an increase in the number of cells in an organ that stems from
CELLULAR ADAPTATIONS TO STRESS
increased proliferation, either of differentiated cells or, in some instances, less
Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or differentiated progenitor cells.
functions of cells in response to changes in their environment
Hyperplasia takes place if the tissue contains cell populations capable of replication
Physiologic Adaptations usually represent responses of cells to normal stimulation by
It may occur concurrently with hypertrophy and often in response to the same stimuli.
hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the
Hyperplasia can be physiologic or pathologic; in both situations, cellular
breast and uterus during pregnancy), or to the demands of mechanical stress (in the case of
proliferation is stimulated by growth factors that are produced by a variety of cell
bones and muscles)
types.
Pathologic Adaptations are responses to stress that allow cells to modulate their structure
The two types of Physiologic Hyperplasia a
and function and thus escape injury, but at the expense of normal function, such as
1) hormonal hyperplasia, exemplified by the proliferation of the glandular
squamous metaplasia of bronchial epithelium in smokers.
epithelium of the female breast at puberty and during pregnancy
2) Compensatory Hyperplasia, in which residual tissue grows after removal or loss
of part of an organ.
For example, when part of a liver is resected, mitotic activity in the
remaining cells begins as early as 12 hours later, eventually restoring the
liver to its normal size.
The stimuli for hyperplasia in this setting are polypeptide growth factors
produced by uninjured hepatocytes as well as non-parenchymal cells in
the liver
After restoration of the liver mass, various growth inhibitors turn off cell
proliferation.
Most forms of pathologic hyperplasia are caused by excessive hormonal or growth factor
stimulation.
After a normal menstrual period there is a burst of uterine epithelial proliferation that
is normally tightly regulated by the stimulatory effects of pituitary hormones and
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 ovarian estrogen and the inhibitory effects of progesterone.
B. Small spindle-shaped uterine smooth muscle cells from a normal uterus A disturbance in this balance leading to increased estrogenic stimulation
C. Large, plump hypertrophied smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.)
causes endometrial hyperplasia, which is a common cause of abnormal
menstrual bleeding.
Benign prostatic hyperplasia is another common example of pathologic hyperplasia
induced in responses to hormonal stimulation by androgens.
Stimulation by growth factors also is involved in the hyperplasia that is associated with
certain viral infections
Papillomaviruses cause skin warts and mucosal lesions that are composed of masses of
hyperplastic epithelium.
Here the growth factors may be encoded by viral genes or by the genes of the infected
host cells.
An important point is that in all of these situations, the hyperplastic process remains
controlled if the signals that initiate it abate, the hyperplasia disappears
It is this responsiveness to normal regulatory control mechanisms that distinguishes
pathologic hyperplasias from cancer, in which the growth control mechanisms
become permanently dysregulated or ineffective
Nevertheless, in many cases, pathologic hyperplasia constitutes a fertile soil in which
cancers may eventually arise.
Patients with hyperplasia of the endometrium are at increased risk of developing
endometrial cancer

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, 11.5 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 triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium
magenta.
Failure to stain is due to enzyme loss after cell death.

Hypertrophy
Hypertrophy is an increase in the size of cells resulting in an increase in the size of
the organ
In contrast, hyperplasia is an increase in cell number. Atrophy as seen in the brain
In pure hypertrophy there are no new cells, just bigger cells containing increased A. Normal brain of a young adult
B. Atrophy of the brain in an 82-year-old man with atherosclerotic disease
amounts of structural proteins and organelles. Atrophy of the brain is caused by aging and reduced blood supply
Hyperplasia is an adaptive response in cells capable of replication, whereas 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.
hypertrophy occurs when cells have a limited capacity to divide.
Hypertrophy and hyperplasia also can occur together, and obviously both result in an Atrophy
enlarged organ. Shrinkage in the size of cells by the loss of cell substance
Hypertrophy can be physiologic or pathologic and is caused either by increased When a sufficient number of cells are involved, the entire tissue or organ is reduced in size,
functional demand or by growth factor or hormonal stimulation. or atrophic
The massive physiologic enlargement of the uterus during pregnancy occurs as a Although atrophic cells may have diminished function, they are not dead.
consequence of estrogen stimulated smooth muscle hypertrophy and smooth muscle Causes of atrophy include
hyperplasia Decreased workload (e.g., immobilization of a limb to permit healing of a fracture)
In contrast, in response to increased workload the striated muscle cells in both the Loss of innervation
skeletal muscle and the heart undergo only hypertrophy because adult muscle cells Diminished blood supply
have a limited capacity to divide. Inadequate nutrition
Therefore, the chiseled physique of the avid weightlifter stems solely from the Loss of endocrine stimulation, and aging (Senile Atrophy)
hypertrophy of individual skeletal muscles. Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in
An example of pathologic hypertrophy is the cardiac enlargement that occurs with menopause) and others are pathologic (e.g., denervation), the fundamental cellular changes
hypertension or aortic valve disease are similar.
The differences between normal, adapted, and irreversibly injured cells are illustrated They represent a retreat by the cell to a smaller size at which survival is still possible
by the responses of the heart to different types of stress. A new equilibrium is achieved between cell size and diminished blood supply,
nutrition, or trophic stimulation.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 7 of 10
Cellular atrophy results from a combination of decreased protein synthesis and The main pathways of abnormal intracellular accumulations are inadequate removal and
increased protein degradation degradation or excessive production of an endogenous substance, or deposition of an
Protein synthesis decreases because of reduced metabolic activity. abnormal exogenous material
The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome Selected examples of each are described as follows.
pathway. 1) Fatty Change
Nutrient deficiency and disuse may activate ubiquitin ligases, which attach multiple Fatty change, also called steatosis, refers to any accumulation of triglycerides
copies of the small peptide ubiquitin to cellular proteins and target them for within parenchymal cells.
degradation in proteasomes. It is most often seen in the liver, since this is the major organ involved in fat
This pathway is also thought to be responsible for the accelerated proteolysis metabolism, but also may occur in heart, skeletal muscle, kidney, and other
seen in a variety of catabolic conditions, including the cachexia associated with organs.
cancer. Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus,
In many situations, atrophy also is associated with autophagy, with resulting increases obesity, or anoxia. Alcohol abuse and diabetes associated with obesity are the
in the number of autophagic vacuoles. most common causes of fatty change in the liver (fatty liver) in industrialized
Autophagy is the process in which the starved cell eats its own organelles in an nations
attempt to survive. 2) Cholesterol and Cholesteryl Esters
Cellular cholesterol metabolism is tightly regulated to ensure normal
generation of cell membranes (in which cholesterol is a key component)
without significant intracellular accumulation.
However, phagocytic cells may become overloaded with lipid (triglycerides,
cholesterol, and cholesteryl esters) in several different pathologic processes,
mostly characterized by increased intake or decreased catabolism of lipids.
Of these, atherosclerosis is the most important. .
3) Proteins
Morphologically visible protein accumulations are less common than lipid
accumulations
They may occur when excesses are presented to the cells or if the cells
synthesize excessive amounts. In the kidney, trace amounts of albumin
filtered through the glomerulus is normally reabsorbed by pinocytosis in
the proximal convoluted tubules.
However, in disorders with heavy 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
histologic appearance of pink, hyaline cytoplasmic droplets.
Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus, shown schematically (A) and histologically (B) The process is reversible if the proteinuria abates, the protein droplets are
metabolized and disappear marked accumulation of newly synthesized
Metaplasia immunoglobulins that may occur in the RER of some plasma cells, forming
Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is rounded, eosinophilic Russell bodies.
replaced by another adult cell type Protein aggregation are alcoholic hyaline in the liver
In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by Neurofibrillary tangles in neurons
another cell type better able to withstand the adverse environment. 4) Glycogen
Metaplasia is thought to arise by the reprogramming of stem cells to differentiate along a Excessive intracellular deposits of glycogen are associated with abnormalities in
new pathway rather than a phenotypic change (transdifferentiation) of already the metabolism of either glucose or glycogen. In poorly controlled diabetes
differentiated cells. mellitus, the prime example of abnormal glucose metabolism
Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium Glycogen accumulates in renal tubular epithelium, cardiac myocytes, and
of habitual cigarette smokers, in whom the normal ciliated columnar epithelial cells of the cells of the islets of Langerhans.
trachea and bronchi often are replaced by stratified squamous epithelial cells
Glycogen also accumulates within cells in a group of related genetic disorders
The rugged stratified squamous epithelium may be able to survive the noxious collectively referred to as glycogen storage diseases, or glycogenoses
chemicals in cigarette smoke that the more fragile specialized epithelium would not
tolerate.
Although the metaplastic squamous epithelium has survival advantages, important
protective mechanisms are lost, such as mucus secretion and ciliary clearance of
particulate matter.
Because vitamin A is essential for normal epithelial differentiation, its deficiency also
may induce squamous metaplasia in the respiratory epithelium.
Metaplasia need not always occur in the direction of columnar to squamous epithelium
In chronic gastric reflux, the normal stratified squamous epithelium of the lower
esophagus may undergo metaplastic transformation to gastric or intestinal-type
columnar epithelium.
Metaplasia also may occur in mesenchymal cells, but in these situations it is generally a Lipofuscin granules in cardiac myocytes (deposits indicated by arrows)

reaction to some pathologic alteration and not an adaptive response to stress.

Bone is occasionally formed in soft tissues, particularly in foci of injury.
The influences that induce metaplastic change in an epithelium, if persistent, may
predispose to malignant transformation.
Squamous metaplasia of the respiratory epithelium often coexists with lung cancers
composed of malignant squamous cells.
It is thought that cigarette smoking initially causes squamous metaplasia, and cancers
arise later in some of these altered foci.

SUMMARY: Cellular Adaption to Stress

Hypertrophy
Increased cell and organ size, often in response to increased workload; induced
Hemosiderin granules in liver cells
by growth factors produced in response to mechanical stress or other stimuli (A) Hematoxylin-eosinstained section showing golden-brown, finely granular pigment.
Occurs in tissues incapable of cell division (B) Iron deposits shown by a special staining process called the Prussian blue reaction.

Hyperplasia
5) Pigments
Increased cell numbers in response to hormones and other growth factors
Pigments are colored substances that are either exogenous, coming from
Occurs in tissues whose cells are able to divide or contain abundant tissue stem
outside the body, such as carbon, or are endogenous, synthesized within the
cells
body itself, such as lipofuscin, melanin, and certain derivatives of hemoglobin.
Atrophy
The most common exogenous pigment is carbon, a ubiquitous air pollutant of
Decreased cell and organ size, as a result of decreased nutrient supply or disuse
urban life.
Associated with decreased synthesis of cellular building blocks and increased
When inhaled, it is phagocytosed by alveolar macrophages and
breakdown of cellular organelles and autophagy
transported through lymphatic channels to the regional
Metaplasia
tracheobronchial lymph nodes.
Change in phenotype of differentiated cells, often in response to chronic
Aggregates of the pigment blacken the draining lymph nodes and pulmonary
irritation, that makes cells better able to withstand the stress
parenchyma (anthracosis)
Usually induced by altered differentiation pathway of tissue stem cells
May result in reduced functions or increased propensity for malignant Lipofuscin, or wear-and-tear pigment
transformation An insoluble brownish-yellow granular intracellular material that
accumulates in a variety of tissues (particularly the heart, liver, and
brain) with aging or atrophy.
Represents complexes of lipid and protein that are produced by the free
radicalcatalyzed peroxidation of polyunsaturated lipids of subcellular
membranes.
It is not injurious to the cell but is a marker of past free radical injury
Brown Pigment
When present in large amounts, imparts an appearance to the tissue
that is called brown atrophy.
Melanin
An endogenous, brown-black pigment that is synthesized by
melanocytes located in the epidermis
Acts as a screen against harmful uv radiation.
Although melanocytes are the only source of melanin, adjacent basal
keratinocytes in the skin can accumulate the pigment (e.g., in freckles),
as can dermal macrophages.
Hemosiderin
Hemoglobin-derived granular pigment that is golden yellow to brown
and accumulates in tissues when there is a local or systemic excess of
iron.
Mechanisms of intracellular accumulation
Iron is normally stored within cells in association with the protein
1) Abnormal metabolism, as in fatty change in the liver Apoferritin, forming ferritin micelles.
2) Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly Represents large aggregates of these ferritin micelles, readily visualized
3) A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in
lysosomal storage diseases. by light and electron microscopy
4) An inability to degrade phagocytosed particles, as in carbon pigment accumulation.
Iron can be unambiguously identified by the Prussian blue
INTRACELLULAR ACCUMULATIONS histochemical reaction
Under some circumstances, cells may accumulate abnormal amounts of various substances, Although hemosiderin accumulation is usually pathologic, small
which may be harmless or may cause varying degrees of injury. amounts of this pigment are normal in the mononuclear phagocytes of
The substance may be located in the cytoplasm, within organelles (typically the bone marrow, spleen, and liver, where aging red cells are normally
lysosomes), or in the nucleus, and it may be synthesized by the affected cells or it may degraded.
be produced elsewhere.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 8 of 10
Excessive deposition of hemosiderin, called Hemosiderosis, and more
Accumulation of mutations in nuclear and mitochondrial DNA ultimately
extensive accumulations of iron seen in Hereditary Hemochromatosis compromises the functional activities and survival of cells.
2) Decreased cellular replication
PATHOLOGIC CALCIFICATION Normal cells (other than stem cells) have a limited capacity for replication, and after a
Pathologic calcification, a common process in a wide variety of disease states, is the result fixed number of divisions, they become arrested in a terminally non-dividing state,
of an abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, known as Replicative Senescence.
and other minerals. Aging is associated with progressive replicative senescence of cells.
It can occur in two ways. Cells from children have the capacity to undergo more rounds of replication than do
1) Dystrophic Calcification cells from older people.
In this form, calcium metabolism is normal but it deposits in injured or dead tissue, Cells from patients with Werner syndrome, a rare disease characterized by premature
such as areas of necrosis of any type aging, have a markedly reduced in vitro life span.
It is virtually ubiquitous in the arterial lesions of advanced atherosclerosis
Although dystrophic calcification may be an incidental finding indicating insignificant
past cell injury, it also may be a cause of organ dysfunction 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
Initiated by the extracellular 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 phosphates accumulate as a result of the action of
membrane bound phosphatases.
The crystals are then propagated, forming larger deposits.
2) Metastatic Calcification
This form is associated with hypercalcemia and can occur in normal tissues.
The major causes of hypercalcemia
a) Increased secretion of parathyroid hormone, due to either primary parathyroid
tumors or production of parathyroid hormonerelated protein by other
malignant tumors
b) Destruction of bone due to the effects of accelerated turnover (e.g., Paget
disease), immobilization, or tumors (increased bone catabolism associated with
multiple myeloma, leukemia, or diffuse skeletal metastases)
c) Vitamin Drelated disorders including vitamin D intoxication and sarcoidosis
(in which macrophages activate a vitamin D precursor)
d) Renal failure, in which phosphate retention leads to secondary
hyperparathyroidism.
The role of telomeres and telomerase in replicative senescence of cells
MORPHOLOGY Mechanisms and consequences of telomere attrition
Repeated cell division associated with aging leads to progressive shortening of telomeres, which triggers senescence and loss of stem cell pools
Regardless of the site, calcium salts are seen on gross examination as fine white Telomere attrition is characteristic of somatic cells. Stem cells maintain their telomeres and are, therefore, capable of mor e cycles of replication.
granules or clumps, often felt as gritty deposits. Cancer cells frequently activate telomerase and are thus able to maintain telomeres.

Dystrophic calcification is common in areas of caseous necrosis in tuberculosis.

Sometimes a tuberculous lymph node is essentially converted to radiopaque Replicative senescence occurs in aging cells because of progressive shortening of telomeres,
stone. which ultimately results in cell cycle arrest
On histologic examination, calcification appears as intracellular and/or extracellular Telomeres are short repeated sequences of DNA present at the ends of chromosomes that
basophilic deposits. are important for ensuring the complete replication of chromosome ends and for protecting
With time, heterotopic bone may form in foci of calcification. the ends from fusion and degradation
Metastatic calcification can occur widely throughout the body but principally affects Telomeric DNA also binds proteins that shield it, preventing activation of a DNA damage
the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa. response.
The calcium deposits morphologically resemble those in dystrophic calcification. When somatic cells replicate, a small section of the telomere is not duplicated, and
Although they generally do not cause clinical dysfunction, extensive telomeres become progressively shortened.
calcifications in the lungs may be evident on radiographs and may produce As they shorten, the ends of chromosomes cannot be protected and are sensed in cells
respiratory deficits, and massive deposits in the kidney (nephrocalcinosis) can as broken DNA, which signals cell cycle arrest.
lead to renal damage. Telomere length is maintained by nucleotide addition mediated by an enzyme called
Telomerase.
SUMMARY: Abnormal Intracellular Depositions and Calcifications A specialized RNA-protein complex that uses its own RNA as a template for adding
Abnormal deposits of materials in cells and tissues are the result of excessive intake or nucleotides to the ends of chromosomes.
defective transport or catabolism. Expressed in germ cells and is present at low levels in stem cells, but absent in most
Depositions of lipids somatic cells
Fatty Change Therefore, as mature somatic cells age, their telomeres become shorter and they exit
Accumulation of free triglycerides in cells, resulting from excessive intake or the cell cycle, resulting in an inability to generate new cells to replace damaged ones.
defective transport (often because of defects in synthesis of transport proteins) In immortalized cancer cells, telomerase is usually reactivated and telomere length is
Manifestation of reversible cell injury stabilized, allowing the cells to proliferate indefinitely.
Cholesterol deposition Telomere shortening also may decrease the regenerative capacity of stem cells, further
Result of defective catabolism and excessive intake; seen in macrophages and contributing to cellular aging.
smooth muscle cells of vessel walls in atherosclerosis Abnormalities in telomere maintenance have been implicated in many diseases, such as
Deposition of proteins: reabsorbed proteins in kidney tubules aplastic anemia and other cytopenias (thought to be caused by a failure of hematopoietic
Immunoglobulins in plasma cells stem cells), premature greying of hair, skin pigment and nail abnormalities, pulmonary and
Deposition of glycogen liver fibrosis, and others.
In macrophages of patients with defects in lysosomal enzymes that break down These disorders are sometimes considered the prototypic telomeropathies.
glycogen (Glycogen Storage Diseases) Defective Protein Homeostasis
Deposition of pigments With the passage of time, cells are unable to maintain normal protein homeostasis,
Typically indigestible pigments, such as carbon, lipofuscin (breakdown product because of increased turnover and decreased synthesis caused by reduced translation
of lipid peroxidation), or iron (usually resulting from overload, as in of proteins and defective activity of chaperones (which promote normal protein
Hemosiderosis) folding) and proteasomes (which destroy misfolded proteins).
Pathologic calcifications The resultant decrease in intracellular proteins can have many deleterious effects on
Dystrophic Calcification: deposition of calcium at sites of cell injury and necrosis cell survival, replication, and functions.
Metastatic Calcification: deposition of calcium in normal tissues, caused by The concomitant accumulation of misfolded proteins exacerbates the loss of
hypercalcemia (usually a consequence of parathyroid hormone excess) functional proteins and can trigger apoptosis.
Calorie restriction has been found to slow down aging and prolong life in every species tested
from flies to mice.
It is now thought that calorie restriction alters signaling pathways that influence aging
Among the biochemical alterations associated with calorie restriction that have been
described as playing a role in counteracting the aging process is reduced activation of
insulin-like growth factor receptor signaling, which involves a downstream network of
kinases and transcription factors.
Reduced IGF-1 signaling leads to lower rates of cell growth and metabolism and
possibly reduced errors in DNA replication, better DNA repair and improve protein
homeostasis.
Calorie restriction also serves to improve immunity.
All of these inhibit aging.
Persistent inflammation
As individuals age, the accumulation of damaged cells, lipids, and other endogenous
substances may activate the inflammasome pathway, resulting in persistent low-level
Mechanisms that cause and counteract cellular aging inflammation.
DNA damage, replicative senescence, and decreased and misfolded proteins are among the best-described mechanisms of cellular aging. Some Inflammation in turn induces chronic diseases, such as atherosclerosis and type 2
environmental influences, such as calorie restriction, counteract aging by activating various signaling pathways and transcription factors.
diabetes.
Cytokines produced during inflammatory reactions may themselves induce cellular
CELLULAR AGING alterations that exacerbate aging, and chronic metabolic disorders may accelerate the
Individuals age because their cells age. aging process.
Aging has important health consequences, because age is one of the strongest independent Clinical observations and epidemiologic studies have shown that physical activity and, as
risk factors for many chronic diseases, such as cancer, Alzheimer disease and ischemic heart mentioned previously, calorie restriction slow the aging process, whereas stresses, perhaps
disease. acting via increased production of glucocorticoids, accelerate aging.
Not simply a consequence of cells running out of steam, but in fact is regulated by a The precise mechanisms underlying these effects remain to be defined, and for now we all
limited number of genes and signaling pathways that are evolutionarily conserved from yeast remain vulnerable to the ravages of age.
to mammals.
SUMMARY: Cellular Aging
Cellular aging is the result of a progressive decline in the life span and functional activity of Results from a combination of multiple, progressive cellular alterations, including:
cells. Accumulation of DNA damage and mutations
Several abnormalities contribute to the aging of cells: Replicative senescence: reduced capacity of cells to divide secondary to
1) Accumulation of mutations in DNA progressive shortening of chromosomal ends (telomeres)
A variety of metabolic insults over time may result in damage to nuclear and Defective protein homeostasis: loss of normal proteins and accumulation of
mitochondrial DNA. misfolded proteins
ROS induced by toxins and radiation exposure contribute to DNA damage associated Aging is exacerbated by chronic diseases, especially those associated with prolonged
with aging. inflammation, and by stress, and is slowed down by calorie restriction and exercise.
Although most DNA damage is repaired by DNA repair enzymes, some persists and
accumulates as cells age, especially if repair mechanisms become inefficient over time.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 9 of 10
Various forms of cellular derangements and adaptations cover a wide spectrum,
ranging from reversible and irreversible forms of acute cell injury, to adaptations in
cell size, growth, and function, to largely unavoidable consequences of aging.
Reference is made to these many different alterations throughout this book, because all
instances of organ injury and ultimately all cases of clinical disease arise from
derangements in cell structure and function.

Remelou G. Alfelor, M.D. PLE Pathology Review: Chapter 2 Cell Injury, Cell Death, and Adaptations Page 10 of 10