Cellular Responses to Stress

and Toxic Insults: Adaptation,

Injury and Cell Death

Margie s. gayapa, m.d., dpsp

 Pathology
• devoted to the study of • General pathology -
the structural, concerned with the
biochemical and common reactions of
functional changes in cells and tissues to
cells, tissues and organs injurious stimuli
that underlie disease • Systemic pathology -
alterations and
underlying mechanisms
in organ specific
diseases
 4 Aspects of the Disease Process
 Etiology – genetic or  Morphologic changes -
acquired refer to the structural
alterations in cells or
 Pathogenesis - refers to tissues that are either
the sequence of cellular, characteristic of a
biochemical and disease or diagnostic of
molecular events that an etiologic process
follow the exposure of
cells or tissues to an  Functional
injurious agent Derangements and
Clinical Manifestations
Stages of Cellular Response to
Stress or Injurious Stimuli
Cellular Responses to Injury
 Adaptations

• Reversible changes in • Hypertrophy

the size, number, • Hyperplasia
phenotype, metabolic • Atrophy
activity, or functions of
cells in response to • Metaplasia
changes in their
environment.
 Hypertrophy
• Due to the synthesis of
Increase in the size of cells more structural
components of the cells
• Dividing cells may
undergo hyperplasia
and hypertrophy
• In non-dividing cells
Increase in the size of the (e.g. myocardial fibers),
organ increased tissue mass is
due to hypertrophy
 Hypertrophy

 Increased workload
• Physiologic
 Massive physiologic
• Pathologic growth of the uterus
during pregnancy
 Mechanisms of Hypertrophy

• Hypertrophy: result of
increased production of
cellular proteins
• Hypertrophy can be
induced by linked actions
of mechanical sensors,
growth factors (TGF-β,
IGF-1, fibroblast GF), and
vasoactive agents (i.e. α-
adrenergic agonists)
 Hyperplasia
• Hyperplasia and
hypertrophy frequently
Increase in the number of occur together triggered
cells in an organ or tissue by the same external
stimulus
• Result of growth factor-
driven proliferation of
mature cells andby
increased output of new
Increased mass of the organ cells from tissue stem
or tissue cells
• Physiologic or pathologic
 Physiologic Hyperplasia
Hormonal hyperplasia: Compensatory
increases the functional hyperplasia; increases
capacity of tissue tissue mass after damage
(epithelial proliferation of or partial resection
female breast at puberty
and during pregnancy

Hormonal hyperplasia is well illustrated by the proliferation of the glandular

epithelium of the female breast at puberty and during pregnancy, usually
accompanied by enlargement (hypertrophy) of the glandular epithelial
cells. The classical illustration of compensatory hyperplasia comes from the
myth of Prometheus, which shows that the ancient Greeks recognized the
capacity of the liver to regenerate.
 Pathologic Hyperplasia
• Caused by excesses of
hormones or growth
factors acting on target
cells e.g. goiter,
endometrial hyperplasia,
benign prostatic hyperplasia
• Constitutes a fertile soil in
which cancerous
proliferation may eventually
rise
 Thyroid gland, hypertrophy and hyperplasia
Thyroid gland, normal
 Atrophy
• Reduced size of an organ • Common causes of
or tissue resulting from a
decrease in cell size
(autophagy) and number
(apoptosis)
• Physiologic
• Pathologic (local or
generalized)
pathologic atrophy:
– Decreased workload
(atrophy of disuse)
– Loss of innervation
(denervation atrophy)
– Diminished blood supply
– Inadequate nutrition
– Loss of endocrine
stimulation
– Pressure
 Mechanisms of Atrophy
• Results from decreased • Increased autophagy:
protein synthesis and starved cells eat its
increased protein components to reduce
degradation in cells nutrient demand and
– Degradation of cellular match the supply
proteins occur mainly by
ubiquitin-proteasome
pathway -- responsible for
the accelerated proteolysis
seen in catabolic
conditions, including
cancer cachexia
Atrophy
 Metaplasia
• Reversible change in which
one differentiated cell type (
epithelial or mesenchymal)
is replaced by another cell
type
• Result of a reprogramming
of stem cells known to exist
in normal tissues, or of
undifferentiated
mesenchymal cells present
in connective tissue
Cell Injury and
Death
 Causes of Cell Injury
• Oxygen deprivation
• Physical agents (i.e. mechanical trauma)
• Chemical agents and drugs
• Infectious agents
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances
 Reversible Cell Injury
• Hallmarks:
– reduced oxidative
phosphorylation with
resultant depletion of
energy stores in the form
of ATP
– cellular swelling caused by
changes in ion
concentrations and water
influx
• Features
– Cellular swelling -incapable
of maintaining ionic and
fluid homeostasis and is
the result of failure of
energy-dependent ion
pumps in the plasma
membrane
– Fatty change - cells
involved in and dependent
in fat metabolism e.g.
hepatocytes and
myocardial cells
 Cellular Swelling
• First manifestation of cell
injury to cells
• Grossly, it causes some
pallor, increased turgor,
and increase in weight of
the organ
• Microscopically,
cytoplasmic vacuoles
(distended and pinched-
off segments of the ER --
hydropic change or
vacuolar degeneration)
• Ultrastructurally,
– Plasma membrane alterations
i.e. blebbing, blunting and loss of
microvilli
– Mitochondrial changes i.e.
swelling, + small amorphous
densities
– Dilation of ER i.e. detachment of
polysomes, myelin figures
– Nuclear alterations,
disaggregation of granular and
fibrillar elements
 Cell Death
• Irreversible
• 2 principal types:
– Necrosis
– Apoptosis
Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)

Nucleus Pyknosis  karyorrhexis Fragmentation into

karyolysis nucleosome-size fragments

Plasma membrane Disrupted Intact; altered structure,

especially orientation of lipids

Cellular contents Enzymatic digestion; may leak Intact; may be released in

out of cell apoptotic bodies

Adjacent inflammation Frequent No

Physologic or pathologic role Invariably pathologic Often physiologic, means of

(culmination of irreversible eliminating unwanted cells;
cell injury) may be pathologic after some
forms of cell injury, especially
DNA damage
Cell Death and
Necrosis
 Necrosis
• Result of denaturation – More glassy
of intracellular proteins homogenous
appearance, result of
and enzymatic digestion loss of glycogen particles
of the injured cell
– Cytoplasm becomes
vacuolated and appears
• Microscopically, moth-eaten – enzymatic
digestion
– Increased eosinophilia,
due to loss of – Myelin figures - large,
cytoplasmic RNA and whorled phospholipid
denaturation of masses derived from
cytoplasmic proteins damaged cell
membranes
 Necrosis
• Nuclear changes
– Karyorrhexis: pyknotic
– Due to nonspecific
nucleus undergoes
breakdown of DNA
fragmentation
– Pyknosis - nuclear
shrinkage and increased
basophilia; chromatin – Karyolysis: basophilia of
condenses into a solid, the chromatin fade
shrunken basophilic which reflects loss of
mass DNA because of
enzymatic degradation
by endonucleases
Morphologic changes in reversible cell injury and necrosis

Downloaded from: StudentConsult (on 10 October 2009 04:10 PM)

© 2005 Elsevier
 Morphologic
Patterns of Cell
Death
 Coagulative Necrosis
• Architecture of dead tissues • Ischemia caused by
is preserved obstruction in a vessel
may lead to coagulative
• Affected tissues exhibit necrosis of the supplied
firm texture tissue in all organs
except the brain

• Infarct – localized area

of coagulative necrosis
Gangrenous Necrosis
gangrenous necrosis is not a
specific pattern of cell death, but the
term is commonly used in clinical
practice. It is usually applied to a
limb, generally the lower leg, that
has lost its blood supply and has
undergone necrosis (typically
coagulative necrosis) involving
multiple tissue planes.
18. Gangrenous necrosis usually
implies coagulative necrosis and is
commonly seen in a limb that has
lost its blood supply. Wet gangrene
is necrosis combined with bacterial
infection.
 Liquefactive Necrosis

• Characterized by
digestion of the dead
cells resulting in
transformation of the
tissue into a liquid
viscous mass
• Seen in focal bacterial
or fungal infections or
hypoxia in CNS
 Caseous Necrosis
• Most often in foci of
tuberculous infection
• “caseous” – cheeselike;
derived from the friable
white appearance of the
area of necrosis
• Collection of fragmented or
lysed cells and amorphous
granular debris enclosed
within a distinctive
inflammatory border
(granuloma)
Caseous Necrosis
 Fat Necrosis

• Focal areas of fat

destruction, resulting
from release of
activated pancreatic
lipases into the
substance of the
pancreas and the
peritoneal cavity
 Fibrinoid Necrosis

• Special form of necrosis

usually seen in immune
reactions involving
blood vessels.
• Occurs when complexes
of antigens and
antibodies are
deposited in the walls
of arteries.
 Mechanisms of Cell Injury
• ATP depletion
• Mitochondrial damage
• Influx of intracellular calcium and loss of
calcium homeostasis
• Accumulation of oxygen-derived free radicals
• Defects in membrane permeability
• Damage to DNA and Proteins
Mechanisms of Cell Injury
 ATP Depletion
• Reduction in ATP is the
fundamental cause of cell
death
• ATP depletion and
decreased ATP synthesis
are frequently associated
with both hypoxic and
chemical (toxic) injury
• Ischemia, mitochondrial
damage, actions of toxins
e.g. cyanide
 Mitochondrial Damage

• Formation of a high
conductance channel in
the mitochondrial
membrane
(mitochondrial
permeability transition
pore – loss of
mitochondrial
membrane potential –
failure of oxidative
phosphorylation)
 Mitochondrial Damage

• Abnormal oxidative
phosphorylation –
formation of ROS
• Mitochondria sequester
between their outer
and inner membranes
several proteins e.g.
protein c and caspases
that are capable of
activating apoptotic
pathways
 Influx of Calcium and Loss of Calcium Homeostasis

• Accumulation of Ca2+
results in opening of
mitochondrial
permeability transition
pore and activation of
cellular enzymes
• Increases cellular Ca2+
levels result in the
induction of apoptosis
 Accumulation of Oxygen-Derived Free Radicals

Free radicals are generated • Reduction-oxidation

in the following reactions that occur
conditions: during normal metabolic
• Absorption of radiant reaction
energy • Transition metals such as
• Enzymatic metabolism of iron and copper donate
exogenous chemicals or or accept free electrons
drugs (e.g., carbon during intracellular
tetrachloride [CCl4] can reactions and catalyze
generate CCl3) free radical formation
• Nitric oxide (NO)
Accumulation of Oxygen-Derived Free Radicals
Defects in Membrane Permeability
Mechanisms:
• Reactive oxygen species
• Decreased phospholipid
synthesis
• Increased phospholipid
breakdown
• Cytoskeletal abnormalities

Consequences:
• Mitochondrial,
lysosomal and plasma
membrane damage
 Damage to DNA and Proteins

2 phenomena characterize • Accumulation of

irreversibility: damaged DNA and
• Inability to reverse misfolded proteins trigger
mitochondrial apoptosis
dysfunction
• Profound disturbances in • Leakage of intracellular
membrane function proteins through
damaged cell membranes
and into the circulation –
means of detecting
tissue-specific cellular
injury
 Ischemic and Hypoxic Injury

• Hypoxia – reduced oxygen • Ischemia tends to cause

availability where energy more rapid and severe
production by anaerobic cell and tissue injury than
glycolysis can continue does hypoxia
• Ischemia – result from
hypoxia most commonly • Mild ischemia – reversible
due to a mechanical injury
arterial obstruction • Severe or prolonged
ischemia – necrosis or
apoptosis
 Ischemia Reperfusion Injury

– Inflammation – result of
• New damaging production of cytokines
processes are set to and increased
motion during expression of adhesion
reperfusion: molecules
– Generation of reactive – Activation of
oxygen and nitrogen complement system
species
 Chemical Injury
• Some chemicals can act • Other chemicals are not
directly by combining biologically active but
with some critical must be converted to
molecular component reactive toxic
or cellular organelle metabolites
– mercuric chloride – CCl4 is converted to CCl3
– cyanide by cytochrome P450
 APOPTOSIS

• Pathway of cell death

that is induced by a
tightly regulated
intracellular program in
which cells destined to
die activate enzymes
that degrade the cells'
own nuclear DNA and
nuclear and cytoplasmic
proteins
 Apoptosis
Physiologic:
• Embryogenesis
Pathologic condition
• Hormone-dependent • DNA damage
involution in the adult • Accumulation of
• Cell deletion in proliferating misfolded proteins
cell populations
• Cell death in certain
• Death of host cells that infections
have served their useful
purpose • Pathologic atrophy after
• Elimination of potentially duct obstruction
harmful self-reactive
lymphocytes
 Apoptosis

Morphologic features:
• Cell shrinkage
• Chromatin condensation
• Formation of cytoplasmic
blebs and apoptotic
bodies
• Phagocytosis of apoptotic
cells or cell bodies,
usually by macrophages
 Apoptosis – Biochemical Features
Biochemical features:
• Caspases
– Initiator – caspase 8,
caspase 9
– Executioner – caspase 3,
caspase 6
• DNA breakdown
– Breakdown of DNA into
large 50- to 300- kilobase
pieces
– Endonuclease activity –
basis of detecting cell
death
• Membrane alteration
recognition by
phagocytes
– Movement of
phospholipids from inner
leaflet to outer leaflet of
the membrane –
recognized by receptors on
phagocytes also detectable
by binding of annexin V
 Apoptosis
Mechanisms:
• Initiation phase, during
which caspases become
catalytically active
– intrinsic – mitochondrial
– extrinsic – death
receptor initiated
• Execution phase, during
which these enzymes
act to cause cell death
Apoptosis
 Apoptosis
Examples: Disorders associated with
• Growth Factor dysregulated apoptosis:
deprivation • Defective apoptosis and
• DNA damage increased cell survival
• Protein misfolding – Autoimmune diseases

• Apoptosis Induced by • Increased apoptosis and

Tumor Necrosis Factor excessive cell death
Family of Receptors – Neurodegenerative
diseases
• Cytotoxic T-Lymphocyte- – Ischemic injury
Mediated Apoptosis
 Necroptosis
• Programmed cell death
which is a hybrid of
necrosis and apoptosis
• Pyroptosis – occurs in
cells infected by
microbes, involving
activation of caspase 1
– generates biologically
active IL-1
– along with caspase 11
cause cell death
 Autophagy
• Process in which a cell • 3 types:
eats its own contents – Chaperone-mediated
• Adaptive response – Microautophagy
– Macroautophagy
 Intracellular
Accumulations

• Categories:
– Normal cellular
constituents
– Abnormal substance
– Pigment.
Lipids

• Steatosis (fatty change) –

abnormal accumulation
of triglycerides, most
commonly seen in
alcoholic liver disease and
NAFLD (diabetes and
obesity)
• Cholesterol and
cholesterol esters
– atherosclerosis
Lipids

• Cholesterol and
cholesterol esters
– Xanthomas (acquired or
hereditary hyperlipidemia)
– Cholesterolosis
– Neiman Pick disease, type
C – lysosomal storage
disease; mutations in
enzyme affecting
cholesterol trafficking
Proteins

• Reabsorption droplets in
renal proximal tubules
• Russell bodies
• Defective intracellular
transport and secretion of
critical proteins (α1 AT
deficiency – slow protein
folding – partially folded
intermediates in ER)
 Proteins

• Accumulation of
cytoskeletal proteins
(alcoholic hyaline –
intermediate
filaments;
neurofibrillary tangle
in Alzheimer’s disease
• Accumulation of
abnormal proteins
e.g. amyloidosis
Hyaline Change

• Alteration within cells

or in the extracellular
space that give a
homogenous, glassy
pink appearance on
routine HE
Glycogen

• Abnormality in glucose
or glycogen metabolism
• Glycogen storage
disease or glycogenoses
Pigments
• Exogenous
– Carbon or coal dust –
anthracosis
– Tattooing

• Endogenous
– Lipofuscin (wear and tear
pigment, associated with
free radical injury and lipid
peroxidation)
– Melanin
– Homogentisic acid
– Hemosiderin
 Pathologic Calcification
• Abnormal deposition of • Metastatic Calcification:
Ca salts with smaller – occur in normal tissues
amounts of Fe, Mg and whenever there is
other mineral salts hypercalcemia
– e.g. increased
parathyroid hormone,
• Forms: destruction of bone
– Dystrophic tissue, vitamin D related
– Metastatic disorders and renal
failure
 Pathologic Calcification

• Dystrophic Calcification
– occurs in foci of necrosis
– formation of crystalline
calcium phosphate
mineral (apatite)
– grossly, fine white
granules or clumps
(gritty deposits)
 Cellular Aging
• Result of a progressive • Factors:
decline in cellular – Genetic
function and viability – Diet
caused by genetic – Social conditions
abnormalities and the – Age-related diseases
accumulation of cellular
and molecular damage
due to the effects of
exposure to exogenous
influences
Cellular Aging