CELL ADAPTATIONS

CELL INJURY
CELL DEATH

Lecture-2

Dr. M. Masoom Akhtar

 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 environment of cells is
normally tightly regulated such that it remains fairly constant, a state
referred to as homeostasis.
• Cells can alter their functional state in response to modest stress to
maintain the steady state. More excessive physiologic stresses, or
adverse pathologic stimuli (injury), result in
(1) adaption,
(2) reversible injury, or
(3) irreversible injury and cell death (Table 1-1).
ADOPTATION
• 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.
OR
• Adaptation occurs when physiologic or pathologic stressors induce a
new state that changes the cell but otherwise preserves its viability in
the face of the exogenous stimuli. These changes include:
• Hypertrophy (increased cell mass)
• Hyperplasia (increased cell number)
• Atrophy (decreased cell mass)
• Metaplasia (change from one mature cell type to another)
• 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;
however, if the stress is severe, persistent, or rapid in onset, it results in irreversible
injury and death of the affected cells.
CELLULAR ADAPTATIONS TO STRESS

Adaptations are reversible changes in the number, size, phenotype,

metabolic activity, or functions of cells in response to changes in their
environment. For example:
1. Physiologic adaptations usually represent responses of cells to
normal stimulation by hormones or endogenous chemical
mediators (e.g., the hormone-induced enlargement of the breast
and uterus during pregnancy), or to the demands of mechanical
stress (in the case of bones and muscles).
2. Pathologic adaptations are responses to stress that allow cells to
modulate their structure and function and thus escape injury, but at
the expense of normal function, such as squamous metaplasia of
bronchial epithelium in smokers.
Hypertrophy
• Hypertrophy is an increase in the size of cells resulting in an increase
in the size of the organ. Stated another way, that in pure hypertrophy
there are no new cells, just bigger cells containing increased amounts
of structural proteins and organelles.
• Hypertrophy can be physiologic or pathologic and is caused either
by increased functional demand or by growth factor or hormonal
stimulation.
• The massive physiologic enlargement of the uterus during pregnancy
occurs as a consequence of estrogen-stimulated smooth muscle
hypertrophy and smooth muscle hyperplasia.
• Another example of pathologic hypertrophy is the cardiac
enlargement that occurs with hypertension or aortic valve disease.
• The differences between normal, adapted, and irreversibly
injured cells are illustrated by the responses of the heart to
different types of stress. Myocardium subjected to a
persistently increased workload, as in hypertension or with a
narrowed (stenotic) valve, adapts by undergoing hypertrophy
to generate the required higher contractile force. If, on the
other hand, the myocardium is subjected to reduced blood
flow (ischemia) due to an occluded coronary artery, the
muscle cells may undergo injury.
• The mechanisms driving cardiac hypertrophy involve at least
two types of signals: mechanical triggers, such as stretch,
and soluble mediators that stimulate cell growth, such as
growth factors and adrenergic hormones. These stimuli turn
on signal transduction pathways that lead to the induction of
a number of genes, which in turn stimulate synthesis of
many cellular proteins, including growth factors and
structural proteins. The result is the synthesis of more
proteins and myofilaments per cell, which increases the force
generated with each contraction, enabling the cell to meet
increased work demands.
Hyperplasia
•  Hyperplasia is an increase in the number of cells in an organ that
stems from increased proliferation, either of differentiated cells or,
in some instances, less differentiated progenitor cells.
• Hyperplasia takes place if the tissue contains cell populations capable
of replication; it may occur concurrently with hypertrophy and often
in response to the same stimuli.
• Hyperplasia can be physiologic or pathologic; in both situations,
cellular proliferation is stimulated by growth factors that are
produced by a variety of cell types.
• The two types of physiologic hyperplasia are:
• (1) Hormonal hyperplasia, exemplified by the proliferation of the glandular
epithelium of the female breast at puberty and during pregnancy, and
• (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 nonparenchymal 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. For example, 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 ovarian estrogen and the inhibitory effects of progesterone.
• A disturbance in this balance leading to increased estrogenic
stimulation 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.
• While in 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.
Atrophy
• Atrophy is shrinkage in the size of cells by the loss of cell substance.
• When a sufficient number of cells are involved, the entire tissue or
organ is reduced in size, or atrophic. Although atrophic cells may have
diminished function, they are not dead.
• Causes of atrophy include a decreased workload (e.g., immobilization
of a limb to permit healing of a fracture), loss of innervation,
diminished blood supply, inadequate nutrition, loss of endocrine
stimulation, and aging (senile atrophy).
• Although some of these stimuli are physiologic (e.g., the loss of
hormone stimulation in menopause) and others are pathologic (e.g.,
denervation), the fundamental cellular changes are similar.
Autophagy
• Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own
components.
• It is a survival mechanism in times of nutrient deprivation, so that the
starved cell can live by eating its own contents and recycling these
contents to provide nutrients and energy.
• In this process, intracellular organelles and portions of cytosol are first
sequestered within an ER-derived autophagic vacuole, whose formation
is initiated by cytosolic proteins that sense nutrient deprivation.
• The vacuole fuses with lysosomes to form an autophagolysosome, in
which lysosomal enzymes digest the cellular components.
• In some circumstances, autophagy may be associated with atrophy of
tissues (previously discussed) and may represent an adaptation that
helps cells survive lean times.
Metaplasia

Metaplasia is a change in which one adult cell type (epithelial or

mesenchymal) is replaced by another adult cell type.
• In this type of cellular adaptation, a cell type sensitive to a particular
stress is replaced by another cell type better able to withstand the
adverse environment. Metaplasia is thought to arise by the
reprogramming of stem cells to differentiate along a new pathway
rather than a phenotypic change (transdifferentiation) of already
differentiated cells.
• Epithelial metaplasia is exemplified by the change that occurs in the
respiratory epithelium of habitual cigarette smokers, in whom the
normal ciliated columnar epithelial cells of the trachea and bronchi
often are replaced by stratified squamous epithelial cells.
• The influences that induce metaplastic change in an epithelium, if
persistent, may predispose to malignant transformation.
DYSPLASIA.

A. Disordered cellular growth

B. Most often refers to proliferation of precancerous cells
For example, cervical intraepithelial neoplasia (CIN) represents
dysplasia and is a precursor to cervical cancer.
C. Often arises from longstanding pathologic hyperplasia
(e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett
esophagus)
D. Dysplasia is reversible, in theory, with alleviation of inciting stress.
If stress persists, dysplasia progresses to carcinoma (irreversible).
APLASIA AND HYPOPLASIA
• A. Aplasia is failure of cell production during embryogenesis
(e.g., unilateral renal agenesis).
• B. Hypoplasia is a decrease in cell production during embryogenesis,
resulting in a relatively small organ (e.g., streak ovary in Turner
syndrome).
CELLULAR INJURY
1. BASIC PRINCIPLES
• A. Cellular injury occurs when a stress exceeds the cell's ability to adapt.
• B. The likelihood of injury depends on the type of stress, its severity, and the
type of cell affected.
1. Neurons are highly susceptible to ischemic injury; whereas, skeletal
muscle is relatively more resistant.
2. Slowly developing ischemia (e.g., renal artery atherosclerosis) results
in atrophy;
whereas, acute ischemia (e.g., renal artery embolus) results in injury.
• C. Common causes of cellular injury include inflammation, nutritional
deficiency or excess, hypoxia, trauma, and genetic mutations.
2. HYPOXIA
A. Low oxygen delivery to tissue; important cause of cellular injury
1. Oxygen is the final electron acceptor in the electron transport
chain o f oxidative phosphorylation.
2. Decreased oxygen impairs oxidative phosphorylation,
resulting in decreased ATP production.
3. Lack of ATP (essential energy source) leads to cellular injury.
B. Causes of hypoxia include ischemia, hypoxemia, and decreased O2-
carrying capacity of blood.
Ischemia is decreased blood flow through an organ. Arises with
1. Decreased arterial perfusion (e.g., atherosclerosis)
2. Decreased venous drainage (e.g., Budd-Chiari syndrome)
3. Shock - generalized hypotension resulting in poor tissue perfusion
• D. Hypoxemia is a low partial pressure of oxygen in the blood (Pao2 <
60 mm Hg, Sao2 < 90%). Arises with:
1. High altitude - Decreased barometric pressure results in
decreased PAO2
2. Hypoventilation - Increased PACO2 results in decreased PAO2
3. Diffusion defect - PAO2 not able to push as much O2 into the
blood due to a thicker diffusion barrier (e.g., interstitial
pulmonary fibrosis)
4. V/Q mismatch - Blood bypasses oxygenated lung (circulation
problem, e.g., right- to-left shunt), or oxygenated air cannot reach
blood (ventilation problem, e.g., atelectasis).
E. Decreased O2-carrying capacity arises with hemoglobin (Hb) loss or
dysfunction.
Examples include
1. Anemia (decrease in RBC mass ) - Pao2 normal; Sao2 normal
2. Carbon monoxide poisoning
i. CO binds hemoglobin more avidly than oxygen-Pao normal; Sao
2 2

decreased
ii. Exposures include smoke from fires and exhaust from cars or gas
heaters.
iii. Classic finding is cherry-red appearance o f skin.
iv. Early sign o f exposure is headache; significant exposure leads to
coma and death.
3. Methemoglobinemia
i. Iron in heme is oxidized to Fe3+, which cannot bind oxygen-
Pao2 normal; Sao2 decreased
ii. Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in
newborns
iii. Classic finding is cyanosis with chocolate-colored blood.
iv. Treatment is intravenous methylene blue, which helps reduce
Fe3+ back to Fe2+ state.
• Physical agents, including trauma, heat, cold, radiation, and
electric shock.
• Chemical agents and drugs, including therapeutic drugs, poisons,
environmental pollutants, and “social stimuli” (alcohol and
narcotics).
• Infectious agents, including viruses, bacteria, fungi, and parasites.
• Immunologic reactions, including autoimmune diseases and cell
injury following responses to infection.
• Genetic derangements, such as chromosomal alterations and
specific gene mutations.
• Nutritional imbalances, including protein–calorie deficiency or lack of
specific vitamins, as well as nutritional excesses.
Morphologic Alternations in Cell Injury
• Injury leads to loss of cell function long before damage is
morphologically recognizable.
• Morphologic changes become apparent only some time after
a critical biochemical system within the cell has been
deranged; the interval between injury and morphologic
change depends on the method of detection. However, once
developed, reversible injury and irreversible injury (necrosis)
have characteristic features.
 REVERSIBLE AND IRREVERSIBLE
CELLULAR INJURY
A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP.
B. Low ATP disrupts key cellular functions including
1. Na+-K+pump, resulting in sodium and water buildup in the cell
2. Ca2+pump, resulting in Ca2+ buildup in the cytosol of the cell
3. Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid
buildup results in low pH, which denatures proteins and precipitates DNA.
C. The initial phase of injury is reversible. The hallmark of reversible injury is
cellular swelling.
1. Cytosol swelling results in loss o f microvilli and membrane blebbing.
2. Swelling of the rough endoplasmic reticulum (RER) results in
dissociation of ribosomes and decreased protein synthesis.
D. Eventually, the damage becomes irreversible. The hallmark o f
irreversible injury is membrane damage.
1. Plasma membrane damage results in
i. Cytosolic enzymes leaking into the serum (e.g., cardiac
troponin)
ii. Additional calcium entering into the cell
2. Mitochondrial membrane damage results in
i. Loss o f the electron transport chain (inner mitochondrial
membrane)
ii. Cytochrome ‘c’ leaking into cytosol (activates apoptosis)
3. Lysosome membrane damage results in hydrolytic enzymes leaking
into the cytosol, which, in turn, are activated by the high intracellular
calcium.
E. The end result of irreversible injury is cell death.
Necrosis
• Necrosis is a form of cell death in which cellular membranes fall
apart, and cellular enzymes leak out and ultimately digest the cell
(fig)
• Necrosis is the sum of the morphologic changes that follow cell death
in living tissue or organs.
• Two processes underlie the basic morphologic changes:
• Denaturation of proteins
• Enzymatic digestion of organelles and other cytosolic
components
• There are several distinctive features of necrosis:
- necrotic cells are more eosinophilic (pink) than viable cells by
standard hematoxylin and eosin (H&E) staining.
- They appear “glassy” owing to glycogen loss and may be
vacuolated;
- cell membranes are fragmented.
- Necrotic cells may attract calcium salts; this is particularly true
of necrotic fat cells (forming fatty soaps).
- Nuclear changes include pyknosis (small, dense nucleus),
karyolysis (faint, dissolved nucleus), and karyorrhexis
(fragmented nucleus).
NECROSIS is divided into several types based on gross features
1. Coagulative necrosis is the most common pattern, predominated by
protein denaturation with preservation of the cell and tissue framework.
This pattern is characteristic of hypoxic death in all tissues except the
brain. Necrotic tissue undergoes either heterolysis (digestion by lysosomal
enzymes of invading leukocytes) or autolysis (digestion by its own lysosomal
enzymes).
In coagulative necrosis
1. Necrotic tissue that remains firm (Fig. 1.5A); cell shape and organ
structure are preserved by coagulation of proteins, but the nucleus
disappears (Fig. 1.5B).
2. Characteristic of ischemic infarction of any organ except the brain
3. Area of infarcted tissue is often wedge-shaped (pointing to focus of
vascular occlusion) and pale.
4. Red infarction arises if blood re-enters a loosely organized tissue
(e.g., pulmonary or testicular infarction, Fig. 1.6).
2. Liquefactive necrosis:
1. Necrotic tissue that becomes liquefied; enzymatic lysis of cells and
protein results in liquefaction.
2. Characteristic of
i. Brain infarction - Proteolytic enzymes from microglial cells
liquefy the brain.
ii. Abscess - Proteolytic enzymes from neutrophils liquefy tissue.
iii. Pancreatitis - Proteolytic enzymes from pancreas liquefy
parenchyma
3. Gangrenous necrosis
1. Coagulative necrosis that resembles mummified tissue (dry
gangrene, Fig. 1.7)
2. Characteristic of ischemia of lower limb and GI tract
3. If superimposed infection of dead tissues occurs, then
liquefactive necrosis ensues (wet gangrene).
4. Caseous necrosis
1. Soft and friable necrotic tissue with "cottage cheese-like"
appearance (Fig. 1.8)
2. Combination of coagulative and liquefactive necrosis
3. Characteristic of granulomatous inflammation due to
tuberculous or fungal infection
5. Fat necrosis
1. Necrotic adipose tissue with chalky-white appearance due to
deposition of calcium (Fig. 1.9)
2. Characteristic of trauma to fat (e.g., breast) and pancreatitis-
mediated damage of peripancreatic fat
3. Fatty acids released by trauma (e.g., to breast) or lipase (e.g.,
pancreatitis) join with calcium via a process called saponification.
i. Saponification is an example of dystrophic calcification in which
calcium deposits on dead tissues. In dystrophic calcification, the
necrotic tissue acts as a nidus for calcification in the setting of normal
serum calcium and phosphate.
ii. Metastatic calcification, as opposed to dystrophic calcification,
occurs when high serum calcium or phosphate levels lead to calcium
deposition in normal tissues (e.g., hyperparathyroidism leading to
nephrocalcinosis).
6. Fibrinoid necrosis
1. Necrotic damage to blood vessel wall
2. Leaking of proteins (including fibrin) into vessel wall results in
bright pink staining o f the wall microscopically (Fig. 2.10).
3. Characteristic of malignant hypertension and vasculitis
APOPTOSIS
Programmed cell death (apoptosis) occurs when a cell dies through
activation of a tightly regulated internal suicide program.
• The function of apoptosis is to eliminate unwanted cells selectively,
with minimal disturbance to surrounding cells and the host. The cell’s
plasma membrane remains intact, but its structure is altered so that
the apoptotic cell fragments and becomes an avid target for
phagocytosis.
• The dead cell is rapidly cleared before its contents have leaked out;
therefore cell death by this pathway does not elicit an inflammatory
reaction in the host.
• Thus, apoptosis is fundamentally different from necrosis, which is
characterized by loss of membrane integrity, enzymatic digestion of
cells, and frequently a host reaction.
• Nevertheless, apoptosis and necrosis sometimes coexist and may
share some common features and mechanisms.
Causes of Apoptosis
Apoptosis can be physiologic or pathologic.
Physiologic Causes of Apoptosis
• Programmed destruction of cells during embryogenesis
• Hormone-dependent involution of tissues (e.g., endometrium,
prostate) in the adult
• Cell deletion in proliferating cell populations (e.g., intestinal
epithelium) to maintain a constant cell number
• Death of cells that have served their useful purpose (e.g.,
neutrophils following an acute inflammatory response)
• Deletion of potentially harmful self-reactive lymphocytes
• Pathologic Causes
• DNA damage (e.g., due to hypoxia, radiation, or cytotoxic drugs). If repair
mechanisms cannot cope with the damage caused, cells will undergo apoptosis
rather than risk mutations that could result in malignant transformation. Relatively
mild injury may induce apoptosis, whereas larger doses of the same stimuli result in
necrosis.
• Accumulation of misfolded proteins (e.g., due to inherited defects or due to
free radical damage). This may be the basis of cell loss in a number of
neurodegenerative disorders.
• Cell death in certain viral infections (e.g., hepatitis), either caused directly by
the infection or by cytotoxic T cells.
• Cytotoxic T cells may also be a cause of apoptotic cell death in tumors and in
the rejection of transplanted tissues.
• Pathologic atrophy in parenchymal organs after duct obstruction (e.g., pancreas).
Morphologic and Biochemical Changes in Apoptosis
• Morphologic features of apoptosis (see Table 1-2) include cell
shrinkage, chromatin condensation and fragmentation, cellular
blebbing and fragmentation into apoptotic bodies, and phagocytosis of
apoptotic bodies by adjacent healthy cells or macrophages.
• Protein breakdown occurs through a family of proteases called
caspases (so named because they have an active site cysteine and
cleave at aspartate residues).
• Internucleosomal cleavage of DNA into fragments 180 to 200 base
pairs in size gives rise to a characteristic ladder pattern of DNA bands on
agarose gel electrophoresis.
• Plasma membrane alterations (e.g., flipping of phosphatidylserine
from the inner to the outer leaf of the plasma membrane) allow
recognition of apoptotic cells for phagocytosis.
• Therefore morphologically:
1. Dying cell shrinks, leading cytoplasm to become more
eosinophilic (pink, Fig. l.ll).
2. Nucleus condenses and fragments in an organized manner.
3. Apoptotic bodies fall from the cell and are removed by
macrophages; apoptosis is not followed by inflammation.
 Mechanism of Apoptosis
• Apoptosis is regulated by biochemical pathways that control the
balance of death- and survival–inducing signals mediated caspases
that activate proteases and endo nucleases.
• Caspases were so named because they are cysteine proteases that
cleave proteins after aspartic acid residues.
The process of apoptosis is divided into an initiation phase, when
caspases become active, and an execution phase, when the enzymes
cause cell death.
INITIATION PHASE

• Initiation of apoptosis occurs through two distinct but convergent

pathways:
1. The intrinsic mitochondrial pathway
2. The extrinsic death receptor-mediated pathway.
Intrinsic (Mitochondrial) Pathway
• When mitochondrial permeability is increased, cytochrome c, as well as
other pro-apoptotic molecules, is released into the cytoplasm; death
receptors are not involved.
• Mitochondrial permeability is regulated by more than 20 proteins of the Bcl
family. Bcl-2 and Bcl-x are the two predominant antiapoptotic proteins
responsible for reducing mitochondrial leakiness.
• On the other hand, cellular stress (e.g., misfolded proteins, DNA damage) or
loss of survival signals is sensed by other Bcl members (e.g., Bim, Bid, and
Bad).
• These molecules then activate two critical pro-apoptotic proteins—Bax and
Bak—that form oligomers that insert into the mitochondrial membrane and
create permeability channels.
• With concomitantly decreasing Bcl-2/Bcl-x levels, mitochondrial membrane
permeability increases, leaking out several proteins that can activate caspases
• Thus, released cytochrome c binds to apoptosis activating factor-1
(Apaf-1) to form a large multimeric apoptosome complex that
triggers caspase-9 (an initiator caspase) activation.
• The essence of the intrinsic pathway is a balance between pro-
apoptotic and anti-apoptotic molecules that regulate mitochondrial
permeability.
• Extrinsic (Death Receptor–Initiated) Pathway
• Death receptors are members of the tumor necrosis factor (TNF)
receptor family (e.g., type 1 TNF receptor and Fas). They have a
cytoplasmic death domain involved in protein-protein interactions.
• Cross-linking these receptors by external ligands, such as TNF or
Fas ligand (FasL), causes them to trimerize to form binding sites for
adapter proteins that serve to bring multi- ple inactive caspase-8
molecules into close proximity.
• Low-level enzymatic activity of these pro-caspases eventually cleaves
and activates one of the assembled group, rapidly leading to a down-
stream cascade of caspase activation.
• This enzymatic pathway can be inhibited by a blocking protein called
FLIP; viruses and normal cells can produce FLIP to protect themselves
against Fas-mediated death.
• Execution Phase  
• Caspases occur as inactive pro-enzymes that are activated through
proteolytic cleavage; the cleavage sites can be hydrolyzed by other
caspases or autocatalytically.
• Initiator caspases (e.g., caspase-8 and -9) are activated early in the
sequence and induce the cleavage of the executioner caspases (e.g.,
caspase-3 and -6) that do the bulk of the intracellular proteolytic
degradation.
• Once an initiator caspase is activated, the death program is set in
motion by rapid and sequential activation of other caspases.
• Executioner caspases act on many cell components; they cleave
cytoskeletal and nuclear matrix proteins, disrupting the cytoskeleton
and leading to nuclear breakdown.
• In the nucleus, caspases cleave proteins involved in transcription,
DNA replication, and DNA repair; in particular, caspase-3 activates a
cytoplasmic DNAase resulting in the characteristic internucleosomal
cleavage.
Apoptosis in Health and Disease
1. Growth Factor Deprivation
• Examples include hormone-sensitive cells deprived of the relevant
hormone, lymphocytes not stimulated by antigens or cytokines, and
neurons deprived of nerve growth factor. Apoptosis is triggered by the
intrinsic (mitochondrial) pathway due to a relative excess of pro-
apoptotic versus antiapoptotic members of the Bcl family.
2. DNA Damage
• DNA damage by any means (e.g., radiation or chemotherapeutic agents)
induces apoptosis through accumulation of the tumor- suppressor
protein p53. This results in cell cycle arrest at G1 putatively to allow
time for DNA repair. If repair cannot take place, p53 then induces
apoptosis by increasing the transcription of several pro-apoptotic
members of the Bcl family.
3. Protein Misfolding
Accumulation of misfolded proteins—due to oxidative stress, hypoxia,
or genetic mutations—leads to the unfolded protein response,
increasingly recognized as a feature of several neurodegenerative
disorders.
This response induces increased production of chaperones and
increased proteasomal degradation with decreased protein synthesis. If
the adaptive responses cannot keep pace with the accumulating
misfolded proteins, caspases are activated and apoptosis results (Fig. 1-
5).
4. TNF Family Receptors
Apoptosis induced by Fas-FasL interactions (see preceding discussion)
are important for eliminating lymphocytes that recognize self-antigens;
mutations in Fas or FasL result in autoimmune diseases.
TNF is an important mediator of the inflammatory reaction, but can
also induce apoptosis (see preceding discussion).
5. Cytotoxic T Lymphocytes
Cytotoxic T lymphocytes (CTLs) recognize foreign antigens on the surface
of infected host cells and secrete perforin, a transmembrane pore-
forming molecule.
This allows entry of the CTL-derived serine protease granzyme B that in
turn activates multiple caspases, thereby directly inducing the effector
phase of apoptosis. CTLs also express FasL on their surfaces and can kill
target cells by Fas ligation (via FasL).
 FREE RADICAL INJURY
1. BASIC PRINCIPLES
A. Free radicals are chemical species with an unpaired electron in their
outer orbit.
B. Physiologic generation of free radicals occurs during oxidative
phosphorylation.
1. Cytochrome c oxidase (complex IV) transfers electrons to oxygen.
2. Partial reduction of O2 yields superoxide (O2ꜙ), hydrogen
peroxide (H2O2 ), and hydroxyl radicals (˙ OH ).
C. Pathologic generation of free radicals arises with
1. Ionizing radiation - water hydrolyzed to hydroxyl free radical
2. Inflammation - NADPH oxidase generates superoxide ions
during oxygen- dependent killing by neutrophils.
3. Metals (e.g., copper and iron ) – Fe2+ generates hydroxyl free
radicals (Fenton reaction).
4. Drugs and chemicals - P450 system of liver metabolizes drugs
(e.g., acetaminophen), generating free radicals.
D. Free radicals cause cellular injury via peroxidation of lipids and
oxidation of DNA and proteins; DNA damage is implicated in aging and
oncogenesis.
• E. Elimination of free radicals occurs via multiple mechanisms.
1. Antioxidants (e.g., glutathione and vitamins A , C, and E)
2. Enzymes
I) Superoxide dismutase (in mitochondria) - Superoxide
(O2ꜙ) → H2O2
II) Glutathione peroxidase (in mitochondria) - 2GSH + free
radical → GS-SG and H2O
III) Catalase (in peroxisomes) - H2O2 → O2ꜙ and H2O
3. Metal carrier proteins (e.g., transferrin and ceruloplasmin
EXAMPLES OF FREE RADICAL
INJURY
A. Carbon tetrachloride (CCl4)
1. Organic solvent used in the dry cleaning industry
2. Converted to CCl3 free radical by P450 system of hepatocytes
3. Results in cell injury with swelling of RER; consequently,
ribosomes detach, impairing protein synthesis.
4. Decreased apolipoproteins lead to fatty change in the liver
(Fig. 1.12).
B. Reperfusion injury
1. Return of blood to ischemic tissue results in production of
O2- derived free radicals, which further damage tissue.
2. Leads to a continued rise in cardiac enzymes (e.g., troponin)
after reperfusion of infarcted myocardial tissue.
Thankyou