Cellular adaptation, cell

injury & cell death

Dr Kricha Pande
Dept of
Pathology
Pathology
• Pathology is the study (logos) of suffering
(pathos).

• Paraclinical discipline.

• involves both basic science and clinical

practice and is devoted to the study of the
structural and functional changes in cells,
tissues, and organs that underlie disease.
Some definitions
• Incidence: is a measure of the risk of developing
some new condition within a specified period of time.

• Etiology: is the study of causation.

▫ deals with the causes or origin of disease.

• Pathogenesis: The development of a disease. The

origin of a disease and the chain of events leading to
that disease.

• A lesion: is any abnormal tissue found on or in an

organism, usually damaged by disease or trauma.
Lesion is derived from the Latin word laesio which
means injury.
Some definitions
▫ A medical sign is an indication of some
medical fact or quality that is detected by a
physician during a physical examination of a
patient.

▫ A symptom is a departure from normal

function or feeling which is noticed by a
patient, indicating the presence of disease or
abnormality.

▫ Prognosis is a medical term denoting the

doctor's prediction of how a patient's disease
will progress, and whether there is a chance of
Some definitions
• Pathogenesis: Sequence of events from
the initial stimulus to the ultimate
expression of the disease.

• Morphology (Abnormal Anatomy):

Gross,
Microscopic,
Radiologic,
Molecular.
Classification of Diseases
• Congenital

• Acquired
- inflammatory
- vascular
- growth disorder
- metabolic
- degenerative
- drug induced
- infective
 Rudolph
Virchow
1821-1902
The Father of
Modern
Pathology
CELLULAR RESPONSES TO
INJURY
• Cellular Adaptations
• Atrophy, hypertrophy, hyperplasia,
metaplasia

• Acute Cell Injury

• Reversible Injury
• Cell death
• Necrosis
• Apoptosis

• Intracellular Accumulations

• Pathologic Calcification
Growth Disturbances
• Cellular adaptations

• Cells are capable of adjusting their

structure and functions in response to
various physiological and pathological
conditions.

• This capability is called cellular

adaptation.
Adaptive responses
• Hypertrophy • Altered demand
▫ hyper = above, more (muscle activity)
▫ trophe = nourishment, food
• Hyperplasia • Altered stimulation
▫ plastein = to form, to shape; (growth factors,
growth, development hormones)
• Dysplasia
▫ dys = bad or disordered • Altered nutrition
• Metaplasia (including gas
▫ meta = change or beyond exchange)
• Hypoplasia
▫ hypo = below, less
• Atrophy, Aplasia, Agenesis
▫ a = without
▫ nourishment, form, begining
Atrophy
• Shrinkage in the size of the cell by loss of cell
substance.

• Causes of atrophy
Decreased workload (atrophy of disuse).
Loss of innervation (denervation atrophy).
Diminished blood supply.
Inadequate nutrition.
Loss of endocrine stimulation.
Aging (senile atrophy).
Pressure.

• Although atrophic cells may have diminished function,

they are not dead. However, atrophy may progress to
the point at which cells are injured and die.
The testis at the right has undergone
atrophy and is much smaller than the
normal testis at the left.

L R
Kidney atrophy shrinkage of cells;
classified as:
Physiologic--due to
decreased work
load (e.g.,
decreased size of
uterus following
child birth, or
disease)

Pathologic--primarily
due to denervation
of muscle,
diminished blood
supply, nutritional
deficiency
Hypertrophy
• Hypertrophy refers to an increase in the size of cells,
resulting in an increase in the size of the organ.

• can be physiologic or pathologic.

• prolactin and estrogen cause hypertrophy of the breasts
during lactation.

• bulging muscles of bodybuilders result from an increase in

size of the individual muscle fibers in response to
increased demand.

• Hypertrophy of cardiac muscles in hypertension.

• These changes usually revert to normal if the cause is

removed.
Physiological hypertrophy
Microscopic physiological hypertrophy
Mechanisms of muscle hypertrophy
• Increased protein synthesis
increased cell size 
increased organ size.

• Nondividing cells produce

more protein and membrane
without division.

• Mechanosensors, PI3K /Akt

signaling pathway important
in exercise-induced growth.

• Growth factors, vasoactive

agents, hormones mediate
stress-induced response.

• Unrelieved stress eventually

results in irreversible injury
Hypertrophy
• This is cardiac hypertrophy
involving the left ventricle.

• The number of myocardial

fibres does not increase, but
their size can increase in
response to an increased
workload, leading to the
marked thickening of the
left ventricle in this patient
with systemic hypertension.
Hyperplasia
• Hyperplasia is an increase in the number of
cells in an organ or tissue, usually resulting in
increased volume of the organ or tissue.

• Hyperplasia can be classified as:

▫ physiologic--hormonal (e.g., breast and uterus during
pregnancy)
▫ compensatory--regeneration of liver following partial
hepatectomy. Various growth factors and interluekins
are important in such hyperplasia.
▫ pathologic--excessive hormonal stimulation, viral
infection (papilloma viruses); neoplasms

• Eg. Endometrial hyperplasia, prostatic

hyperplasia.
Hyperplasia
• The prominent folds of
endometrium in this uterus
opened to reveal the endometrial
cavity are an example of
hyperplasia.

• Cells forming both the

endometrial glands and the
stroma have increased in number.

• As a result, the size of the

endometrium has increased.

• This increase is physiologic with

a normal menstrual cycle.
Pathological hormomal hyperplasias

• Hyperplasias reversible with appropriate

treatment

• Benign Prostate Hyperplasia

▫ BPH from accumulation of stable DHT-AR complexes
▫ Androgen-driven upregulation of Fibroblast Growth
Factors and TGFb
▫ FGF stimulates proliferation of stroma
Prostate normal vs. hyperplasia
Metaplasia
• Transformation or replacement of one adult cell type
to another adult cell type
▫ (e.g., the change from columnar to squamous cells in
respiratory tract, from squamous to columnar in Barrett
esophagitis).
▫ Metaplasia also occurs in mesenchymal tissue (e.g.,
formation of bone in skeletal muscle).
• Metaplastic changes usually result from chronic
irritation.

• Metaplastic changes seem to precede the development

of cancer, in some instances.

• Metaplasia is thought to arise from reprogramming of

stem or undifferentiated cells that are present in adult
tissue.
Metaplasia
• Metaplasia is a reversible change in which one adult
cell type (epithelial or mesenchymal) is replaced by
another adult cell type.

• Metaplasia is not a normal physiologic process and

may be the first step toward neoplasia.

• Columnar to squamous: occurs in the respiratory tract

in response to chronic irritation (smoker).

• Metaplasia from squamous to columnar type may also

occur, as in Barrett esophagus.

• Connective tissue metaplasia.

Metaplasia respiratory epithelium

Metaplasia of laryngeal respiratory epithelium has occurred here in a

smoker. The chronic irritation has led to an exchanging of one type of
epithelium (the normal respiratory epithelium at the right) for another
(the more resilient squamous epithelium at the left).
Metaplasia of esophageal epithelium

Glandular, or Barrett’s,metaplasia of the normal esophageal

squamous mucosa has occurred here, with the appearance of gastric
type columnar mucosa, secondary to gastric reflux.
This is dysplasia. The normal cervical squamous epithelium
(Short Arrow) has become transformed to a more
disorderly growth pattern, or dysplastic epithelium (Long
Arrow). This is farther down the road toward neoplasia, but
dysplasia is still a potentially reversible process.
Cellular Injury
• cellular injury as reversible or
irreversible conditions which occur
after the limits of adaptive response
to a stimulus are exceeded.

• Include degeneration and necrosis.

• Degeneration = reversible cell injury

• Necrosis = irreversible cell injury
Cell Injury
• If the cells fail to adapt under stress, they
undergo certain changes called cell injury. The
affected cells may recover from the injury
(reversible) or may die (irreversible).

• Causes of Cell Injury

▫ oxygen deprivation (anoxia)
▫ physical agents
▫ chemical agents
▫ infections agents
▫ immunologic reactions
▫ genetic defects
▫ nutritional imbalances
IMPORTANT TARGETS OF CELL INJURY

• Aerobic respiration –
▫ ATP depletion or decreased synthesis.

• Cell membranes - plasma membranes,

mitochondrial, lysosomal and other organelle
membranes.

• Protein synthesis.

• Cytoskeleton.

• Genetic apparatus.
Mechanisms of cell injury

• Energy depletion (ATP)

• Mitochondrial permeability
• Cytosolic calcium increase
• Free radicals, reactive (activated) oxygen
species (ROS)
• Membrane damage and permeability
changes
• DNA and protein structural damage
Principle structural targets for cell
damage
• Cell membranes
▫ Plasma membrane
▫ Organelle membranes
• DNA
• Proteins
▫ Structural
▫ Enzymes
• Mitochondria
▫ oxidative phosphorylation
Pathogenesis of cell injury -
hypoxia
• Reversible
▫ Loss of ATP
 Failure of Na/K pump

▫ Anaerobic
metabolism
 Increased lactic acid
and phosphate

▫ Reduced protein
synthesis
Pathogenesis of cell injury -
hypoxia

• Irreversible
▫ Massive intra-
cytoplasmic calcium
accumulation

▫ Enzyme activation
Pathogenesis of cell injury -
general

• Reduced ATP synthesis/mitochondrial

damage
• Loss of calcium homeostasis
• Disrupted membrane permeability
• Free radicals
Free radicals
• Highly reactive, unstable chemicals.

• Free radicals have a single unpaired electron in

the outer orbit.

• Are usually derived from oxygen to produce

reactive oxygen species, superoxide, hydroxyl
radicals,H2O2,etc.

• Associated with cell injury

▫ Chemicals/drugs, reperfusion injury, inflammation,
irradiation, oxygen toxicity, carcinogenesis
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 April 2005 06:11 PM)
© 2005 Elsevier
Free radicals
• Free radical generation occurs by….
▫ Absorption of irradiation
 E.g. OH•, and H•
▫ Endogenous normal metabolic reactions
 E.g. O2-•, and H2O2
▫ Transition metals
 E.g. Fe+++
▫ nitrous oxide
 an important paracrine-type mediator that
helps regulate vascular pressure
▫ Toxins
 e.g. carbon tetrachloride
Free radicals
• Free radicals are removed by….
▫ Spontaneous decay
▫ Anti-oxidants
 E.g. Vitamin E, vitamin A, ascorbic acid,
glutathione
▫ Storage proteins
 E.g. transferrin, ferritin, ceruloplasmin
▫ Enzymes
 Catalase, SOD, glutathione peroxidase
Free radicals
• Injure cells by…..
▫ Membrane lipid peroxidation
 Autocatalytic chain reaction
▫ Interaction with proteins
 Protein fragmentation and protein-protein
cross-linkage
▫ DNA damage
 Single strand breaks (genomic and
mitochondrial)
Cell Death

• Death of cells occurs in two ways:

▫ Necrosis--(irreversible injury) changes
produced by enzymatic digestion of dead
cellular elements.

▫ Apoptosis--vital process that helps

eliminate unwanted cells--an internally
programmed series of events effected by
dedicated gene products
Cell injury - morphology

• Reversible

• Irreversible
Morphology of Cell Injury
• Irreversible/Necrosis
▫ The changes are produced by enzymatic
digestion of dead cellular elements,
denatunation of proteins and autolysis (by
lysosomal enzymes).

▫ Cytoplasm - increased eosinophilia

▫ Nucleus - nonspecific breakdown of DNA
leading to
 pyknosis (shrinkage),
 karyolysis (fading) and
 karyorrhexis (fragmentation).
Mechanisms of Cell Death
• Mechanisms of cell death caused by different
agents may vary. However, certain biochemical
events are seen in the process of cell necrosis:
▫ ATP depletion
▫ Loss of calcium homeostasis and free cytosolic calcium
▫ Free radicals: superoxide anions, Hydroxyl radicals,
hydrogen peroxide
▫ Defective membrane permeability
▫ Mitochondrial damage
▫ Cytoskeletal damage
Cell injury - morphology

• Light microscopy

▫ Cytoplasmic
changes

▫ Nuclear changes
Cell Death

• Death of cells occurs in two ways:

▫ Necrosis--(irreversible injury) changes
produced by enzymatic digestion of dead
cellular elements.

▫ Apoptosis--vital process that helps

eliminate unwanted cells--an internally
programmed series of events effected by
dedicated gene products
Necrosis
• Definition
refers to a spectrum of morphologic changes that
follow cell death in living tissue, largely resulting from
the progressive degradative action of enzymes on the
lethally injured cell.
▫ Death of groups of contiguous cells in tissue or organ
• Patterns
▫ Coagulative
▫ Liquefactive
▫ Caseous
▫ Fat necrosis
▫ (gangrene)
▫ (Infarct)
 Red/haemorrhagic
 White
Patterns of Necrosis In Tissues or
Organs
• As a result of cell death the tissues or organs display
certain macroscopic changes:
▫ Coagulative necrosis:
 typically seen in hypoxic environments
 the outline of the dead cells are maintained and the tissue is
somewhat firm.
 Example: myocardial infarction

▫ Liquifactive necrosis: the dead cells undergo disintegration

and affected tissue is liquified.
 Example: cerebral infarction.
 usually associated with cellular destruction and pus formation (e.g.
pneumonia).
 ischemia (restriction of blood supply) in the brain produces
liquefactive rather than coagulative necrosis.
Coagulative necrosis
• Cells have died but the basic shape
and architecture of the tissue
endures
• Most common manifestation of
ischaemic necrosis in tissues.
• Affected tissue maintains solid
consistency.
• In most cases the necrotic cells are
ultimately removed by inflammatory
cells.
• The dead cells may be replaced by
regeneration from neighboring cells,
or by scar (fibrosis).
Coagulative necrosis
Liquefactive necrosis
 This is liquefactive
necrosis in the brain
in a patient who
suffered a "stroke"
with focal loss of
blood supply to a
portion of cerebrum.
This type of infarction
is marked by loss of
neurons and
neuroglial cells and
the formation of a
clear space at the
centre left.
Liquefactive necrosis
• Complete dissolution of
necrotic tissue.
• Most commonly due to
massive infiltration by
neutrophils (abscess
formation).
▫ Release of reactive oxygen
species and proteases
• Liquefaction is also
characteristic of
ischaemic necrosis in
the brain.
Patterns of Necrosis In Tissues or
Organs
• Caseous necrosis:
▫ specific form of coagulation necrosis typically caused by mycobacteria
(e.g. tuberculosis).
▫ a form of coagulative necrosis (cheese-like).
▫ Example: tuberculosis lesions.

• Fat necrosis:
▫ enzymatic digestion of fat.
▫ Example: necrosis of fat by pancreatic enzymes.

• Gangrenous necrosis:
▫ Necrosis (secondary to ischemia)
▫ usually with superimposed infection.
▫ Example: necrosis of distal limbs, usually foot and toes in diabetes.
Caseous necrosis
• a distinctive form of coagulative
necrosis.
• Accumulation of amorphous (no
structure) debris within an area
of necrosis.
• Tissue architecture is abolished
and viable cells are no longer
recognizable.
• Characteristically associated with
the granulomatous inflammation
of tuberculosis. Also seen in some
fungal infections.
Caseous Necrosis
• Microscopically,
caseous necrosis is
characterized by
acellular pink areas
of necrosis, as seen
here at the upper
right, surrounded
by a granulomatous
inflammatory
process.
A granuloma with caseous necrosis in
tuberculosis
• Caseous necrosis hilar
lymph node lung.

• Term caseous is
derived from the
cheesy white gross
appearance of the area
of necrosis
Fat necrosis
• Results from the action of lipases released
into adipose tissue.
▫ pancreatitis, trauma.
• Free fatty acids accumulate and precipitate
as calcium soaps (saponification).
▫ These precipitates are grossly visible as pale
yellow/white nodules
• Microscopically, the digested fat loses its
cellular outlines. There is often local
inflammation
Fat Necrosis
• This is fat necrosis of
the pancreas. Cellular
injury to the
pancreatic acini leads
to release of powerful
enzymes which
damage fat by the
production of soaps,
and these appear
grossly as the soft,
chalky white areas
seen here on the cut
surfaces.
Microscopically, fat necrosis adjacent to pancreas is seen here.
There are some remaining steatocytes at the left (S) which are not
necrotic. The necrotic fat cells at the right (Arrow) have vague
cellular outlines, have lost their peripheral nuclei, and their
cytoplasm has become a pink amorphous mass of necrotic material.

S
 Gangrene ("gangrenous
necrosis")
• Not a separate kind of necrosis at all, but
a term for necrosis that is advanced and
visible grossly.
▫ If there's mostly coagulation necrosis, (i.e., the
typical blackening, desiccating foot which
dried up before the bacteria could overgrow),
we call it dry gangrene.
▫ If there's mostly liquefactive necrosis (i.e., the
typical foul-smelling, oozing foot infected with
several different kinds of bacteria), or if it's in
a wet body cavity, we call it wet gangrene.
Gangrenous Necrosis
• In this case, the
toes were involved
in a frostbite injury.
This is an example
of "dry" gangrene in
which there is
mainly coagulative
necrosis from the
anoxic injury.
Other types of necrosis
▫ Gummatous necrosis is restricted to necrosis
involving spirochaetal infections (e.g. syphilis).
▫ Haemorrhagic necrosis is due to blockage of
the venous drainage of an organ or tissue (e.g.
in testicular torsion).
▫ Fibrinoid necrosis is caused by immune-
mediated vascular damage. It is marked by
deposition of fibrin-like proteinaceous material
in arterial walls, which appears smudgy and
eosinophilic on light microscopy.
Infarction
• An area of ischaemic necrosis in a tissue
or organ
▫ White
 Arterial occlusion in most solid tissues
▫ Red/haemorrhagic
 Venous occlusion
 Loose tissues
 Dual blood supply
 Previously congested
Red infarct White infarct
Apoptosis
• is a distinct reaction pattern which
represents programmed single-cell suicide.

• Cells actually expend energy in order to

die.

• Derived from Greek "falling off" (as for

autumn leaves)

• Apoptosis is "the physiological way for a

cell to die", seen in a variety of normal
situations.
Apoptosis

• This process helps to eliminate unwanted cells by an

internally programmed series of events effected by
dedicated gene products. It serves several vital functions
and is seen under various settings.

▫ During development for removal of excess cells during

embryogenesis
▫ To maintain cell population in tissues with high turnover of
cells, such as skin, bowels.
▫ To eliminate immune cells after cytokine depletion, and
autoreactive T-cells in developing thymus.
▫ To remove damaged cells by virus
▫ To eliminate cells with DNA damage by radiation, cytotoxic
agents etc.
▫ Hormone-dependent involution - Endometrium, ovary, breasts
etc.
▫ Cell death in tumours.
Apoptosis - morphology
• Necrosis:
▫ pathological response to cellular injury.
▫ Chromatin clumps, mitochondria swell
and rupture, membrane lyses, cell
contents spill, inflammatory response
triggered

• Apoptosis
▫ DNA cleaved at specific sites - 200 bp
fragments.
▫ Cytoplasm shrinks without membrane
rupture
▫ Blebbing of plasma and nuclear
membranes
▫ Cell contents in membrane bounded
bodies, no inflammation
Apoptosis vs Necrosis
Apoptosis trigger

• Withdrawal of growth stimuli

▫ E.g. growth factors
• Death signals
▫ E.g. TNF and Fas
• DNA damage
▫ p53 plays an important role
Apoptosis - mechanisms
• Extrinsic
factors
▫ E.g. by
members of the
TNF family

• Intrinsic
mechanisms
▫ E.g. hormone
withdrawal
Morphology of Apoptosis
• Shrinkage of cells.

• Condensation of nuclear chromatin peripherally under

nuclear membrane.

• Formation of apoptotic bodies by fragmentation of the

cells and nuclei. The fragments remain membrane-bound
and contain cell organelles with or without nuclear
fragments.

• Phagocytosis of apoptotic bodies by adjacent healthy cells

or phagocytes.

• Unlike necrosis, apoptosis is not accompanied by

inflammatory reaction
Intracellular accumulations

• (1) a normal cellular constituent accumulated

in excess, such as water, lipids, proteins, and
carbohydrates;

• (2) an abnormal substance, either exogenous,

such as a mineral or products of infectious
agents, or endogenous, such as a product of
abnormal synthesis or metabolism.

• (3) a pigment.
Intracellular accumulations

• Lipids
▫ Neutral Fat
▫ Cholesterol

• “Hyaline” = any “proteinaceous” pink “glassy”

substance

• Glycogen

• Pigments (EX-ogenous, END-ogenous)

• Calcium
FATTY LIVER
TATTOO, MICROSCOPIC
Hemosiderin/Melanin
CALCIFICATION
• DYSTROPHIC (LOCAL CAUSES) (often with FIBROSIS)
• Occurs in dead and degenerated tissues.
Calcium level is normal in this case.
Seen in areas of necrosis, whether they are of coagulative,
caseous, or liquefactive type, and in foci of enzymatic
necrosis of fat.
Eg. In tuberculous lymph node.

• METASTATIC (SYSTEMIC CAUSES)

Seen in normal tissues whenever there is hypercalcemia.
Occur widely throughout the body put principally affects
the interstitial tissues of the gastric mucosa, kidneys, lungs,
systemic arteries, and pulmonary veins.
Eg. Hyperparathyroidism, metastatic disease.
Calcification
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