CELL INJURY,

ADAPTATION & DEATH

dr. Rena Normasari

 Cellular Injury & Adaptation:

 Normal cell is in a steady state “Homeostasis”

 External stimuli bringing changes in cell
physiology and or anatomy - Injury
 Reversible / Irreversible
 Adaptation / Injury / cell death
 Causes of cell Injury:

 Reduced oxygen - Ishemia, infarction

 Physical agents
 Chemical
 Biological agents - Viruses, Bacteria etc.
 Immune reaction - Hypersensitivity
 Nutritional deficiencies.
 Genetic abnormalitiy - Sickle, Hemophilia
 Cell Injury

 Cell responses to injurious stimuli depend upon:

 Type of injury
 Duration
 Severity

 Consequences of injurious stimulus depend upon:

 Type of cell,
 Cell status,
 Cell adaptability
 Genetic makeup of the injured cell
 Targets of cell Injury:

 Respiration
 Integrity of cell membrane
 Synthesis of proteins
 Cytoskeleton
 Integrity of genetic apparatus
 General Biochemical Mechanisms

1. Loss of energy (ATP depletion, O2 depletion)

2. Mitochondrial damage
3. Loss of calcium homeostasis
4. Defects in plasma membrane permeability
5. Generation of reactive oxygen species (O2•,H2O2,
OH•) and other free radicals
 Hypoxia

Decreased oxidative phosphorilation

in mitochondria, fall in ATP production

Depletion of Cellular ATP

 Depletion of Cellular ATP

Failure of membrane Failure of membrane

Na/K pump Ca pump

K leaves the cell

Ca inters the cell
Na& water inter the cell

Cell Swelling
Loss of microvilli
Blebs
Endoplasmic reticulum swelling
Myelin figures
 Increased Cytosolic Calcium

 Activation of Protein Kinase

Phosphorylation of proteins
 Activation of ATPase
Decrease ATP
 Activation of Phospolipases
Membrane damage
 Activation of Endonuclease
Nuclear chromatin damage
 Activation of Proteases
Cytoskeleton/membrane damage
 Stimulate
Depletion of Cellular ATP
phospofructokinase

Increase lactic acid

Increase glycolysis
Decrease pH

Clumping of nuclear chromatin

&
Activation/release of
lysosomal enzymes
Activation / release of Lysosomal
enzymes

Detachment of ribosomes from RER

Decreased protein synthesis

Lysosomal enzymes degrade cytoplasmic

and nuclear components
 Free Radicals

 Free radicals are chemical species with a single

unpaired electron in an outer orbital
 Free radicals are chemically unstable and therefore
readily react with other molecules, resulting in
chemical damage
 Free radicals initiate autocatalytic reactions;
molecules that react with free radicals are in turn
converted to free radicals
 Free Radicals

Intracellular Sources of Free Radicals

 Normal redox reactions generate free radicals
 Nitric oxide (NO) can act as a free radical
 Ionizing radiation (UV, X-rays) can hydrolyze water
into hydroxyl (OH•) and hydrogen (H•) free radicals
 Metabolism of exogenous chemicals such as CCl4can
generate free radicals
 Free radical generation is a “physiological”
antimicrobial reaction
 Free Radicals

Neutralization of Free Radicals

1. Spontaneous decay
2. Superoxidedismutase(SOD):
2O2•+ 2H →O2+ H2O2
3. Glutathione (GSH):
2OH•+ 2GSH →2H2O + GSSG
4. Catalase:
2H2O2→O2+ H2O
5. Endogenous and exogenous antioxidants (Vitamins
E, A, C and β-carotene)
 Free Radicals

If not adequately neutralized, free radicals can damage

cells by three basic mechanisms:

1. Lipid peroxidation of membranes

2. DNA fragmentation
3. Protein cross-linking
 Response to Injury:

 Adaptations (reversible)
 Hydropic degeneration
 Hypertrophy
 Hyperplasia
 Atrophy
 Metaplasia
 Dysplasia
 Accumulations - hyaline, fat, etc.
 Necrosis (irreversible)
 Cellular swelling

Cellular swelling is the first change

to be recognized in almost all types
of cell injury
Cellular swelling occurs when
there is membrane damage and
a loss of ability to maintain ionic
and fluid homeostasis
Cellular swelling

Normal Liver cells

Swollen Liver cells

 Fatty Change
This is a result of metabolic
derangement of injured cells which
have a high thoughput of lipid as
part of their normal metabolic
requirements
Such change is usually seen in the
liver, but occurs less commonly in
the myocardium and kidney
Fatty Change

“Fatty Liver”
 Cellular adaptation to injury
Atrophy

 A shrinkage in cell size

due to decreased
synthesis or increased
catabolism
 The cells are still alive
and may return to
original size if
stimulated by correct
signals
 Cerebral atrophy -
Alzheimers
Muscle ischemic atrophy:
 Atrophy

 The main event in atrophy is the degradation of the

proteins. There are two major systems for this:
1. Lysosomes
2. The ubiquitin-proteasome pathway
 Often there is an increase of autophagic vacuoles in
the atrophic cell
 Cellular adaptation…
Hypertrophy
 An increase of cell size due to an increase of
protein synthesis and of organelle numbers
Left ventricle hypertrophy
 Cellular adaptation…
Hyperplasia
 An increase of number
of cells.
 The hyperplasia can
be physiological,
hormonal or
compensatory, or
pathologic (most often
due to an increase of
hormones or growth
factors)
BPH - Benign Prostatic Hyperplasia.
 Cellular adaptation…
Metaplasia

 One cell type is

reversed by another
type, due to
reprogramming of
stem cells in epithelia
or mesenchyma.
 If the influences are
persistent - cancer
may arise
 Cellular adaptation…
displasia
 E.g. Cervical dysplasia
 Dysplasia is a step
toward cancer.
 Dysplasias may
progress to malignant
neoplasms
Cervical dysplasia
 Cellular adaptation…
Intracellular Accumulations
 Normal constituents:
 Fatty change: Alcoholic hepatitis, Obesity.
 Glycogen, protein storage – enzyme deficiency.

 Abnormal constituents:
 Hemosiderin in Iron over load
 Copper in Wilsons disease

 Exogenous constituents
 Carbon pigment in lungs
 Silicosis

 Lipofuscin:
 Wear and tear pigment in ageing – Brown Atrophy
 Irreversible cell injury

If the cause of cell injury persist the cell reach the

threshold where it is no longer reversible.
 Membrane damage
 Influx of extracellular Ca++ and release of intracellular Ca++
 Lysosomal swelling
 Mitochondrial vacuolization
 Pyknosis, caryolysis or karyorrhexis of nucleus
Irreversible…
 Irreversible cell injury - necrosis
 Necrosis refers to a sequence of morphologic
changes that follow cell death
 Types of necrosis
 Coagulative - Infarction
 Liquifactive - Brain, abscess
 Caseous - Bacterial / Tuberculosis
 Fat Necrosis
 Gangrene - With infection
 Fibrinoid
 Gummatous
 Haemorrhagic
 Morphologic appearance
Result of two processes:
 Enzymatic digestion of the cell
 Denaturation of proteins
Dead cells are more eosinophilic, and the color is more
homogenic. The cytoplasm becomes vacuolated, and
the cell may be calcified.
The nucleus becomes either pycnotic, karyorrhexis or
karyolytic
 Necrosis

The digestion or dissolution of

cells through the activity of
intrinsic enzymes is termed
autolysis, dissolution from
enzymes from other cells is
termed heterolysis
 Necrosis

Autolysis brings about changes

in both the cytoplasm and
nucleus during the evolution of a
necrotic cell
Necrosis

Normal cell has an intact

nucleus with visible
nucleolus

Cytoplasm is pale
pink,with purple from
RNA of the rER

Sublethal damage may

produce cytoplasmic
vaculation
Necrosis

Early necrotic cell

shows increased
cytoplasmic eosinophilia
due to loss of
cytoplasmic RNA

Nucleus becomes
small,basophilic termed
pyknosis, indication
cessation of DNA
transcription
Necrosis

Process continues with

releases of nucleases
causing fragmentation
of the nucleus in to
pieces, termed
karyorrhexis
 Necrosis

Process continues with

complete dissolution of
the nucleus termed
? karyolysis
?
?
 Necrosis

Pyknosis Karyolysis

Normal Karyorrhexis
 Coagulative necrosis

Coagulative necrosis describes

dead tissue that appears firm and
pale
 Coagulative necrosis

• Protein denaturation
because increased acidosis
predominates vs
enzymatic digestion
• The general architecture is
preserved because
denaturation of enzymes -
blocking proteolysis Renal Infarction - Coagulative

• Due to hypoxia
Renal Infarction - Coagulative necrosis
 Liquefactive necrosis

Liquefactive or colliquative necrosis

describes dead tissue that appears
semiliquid as a result of dissolution of
tissue by the action of hydrolytic
enzymes.
 Liquefactive necrosis

• The most common types of damage

leading to the liquefactive pattern are
necrosis in the brain owing to arterial
occlusion (cerebral infarction and
necrosis caused by bacterial infections).
 Liquefactive necrosis

• Characteristic to
bacterial or fungal
infection
• Results of white cell
accumulation
• Completely digests
dead cells
Stroke- Liquifactive necrosis
Liquefactive necrosis

Liquefaction necrosis
of a cerebral infarct

Semi-fluid mass of
protein and no
cellular structure
 Gangrenous necrosis

• Is not a distinct pattern, but a

combination
• It refers to coagulative necrosis with a
superimposed infection with a
liquefactive component, the lesion is
called “wet gangrene”
Gangrenous necrosis
 Caseous Necrosis

• Describes dead tissue that is soft and

white, resembling cream cheese

• This pattern is invariably associated

with tuberculosis
 Caseous Necrosis

With this type of necrosis, dead

cells form an amorphous
proteinaceous mass but, in contrast
to coagulative necrosis, no original
architecture can be seen
histologically
Caseous Necrosis

Caseous necrosis of
a kidney infected with
Mycobacterium
tubelculosis

The necrotic area is

homogenously pink
and no renal
architecture
Caseous necrosis Tuberculosis
 Gummatous Necrosis

• Describes dead tissue when it is firm

and rubbery
• As in caseous necrosis the dead cells
form an amorphous proteinaceous
mass in which no original architecture
can be seen histologically
Gummatous Necrosis

Gummatous necrosis
of the liver with
infection of Treponema
pallidum

Area of necrosis,
without any underlying
cellular architecture
 Hemmorrhagic necrosis
Describes dead tissues that
are suffused with extravasated red cells

This pattern is seen particularly when cell

death is due to blockage of the venous
drainage of a tissue, leading to massive
congestion by blood and to subsequent
arterial failure of perfusion
Hemmorrhagic necrosis

An area of testicular
hemmorrhagic
necrosis

Caused by twisting of
the testis on the end of
the spermatic
chord,cutting of venus
return, leading to
ischemia & massively
infused with RBC
 Fat Necrosis

• Not a specific pattern, but rather a

description of fat destruction

• Fat necrosis most often is associated with

the release of activated pancreatic enzymes
into the adjacent parenchyma or peritoneal
cavity during acute pancreatitis
 Fat Necrosis

• Activated pancreatic enzymes liquefy fat

cell membranes and hydrolyze the
triglyceride esters contained within them
• Fat necrosis may also be seen after trauma
to fat, for example in the breast
Fat Necrosis

Gross
appearance
of acute
pancreatitis

Visible white
areas of fat
necrosis
Fat Necrosis

Microscopic
appearance
of acute
pancreatitis

Area of fat
necrosis
 Fibrinoid necrosis

Describes the appearance of arteries

in cases of vasculitis and
hypertension, when fibrin is
deposited in the damaged necrotic
vessel wall
Fibrinoid necrosis

Blood vessel damaged

by severe hypertension
showing deposition of
fibrin in the damaged
wall
 Gummatous
Patterns of necrosis necrosis
seen in
Syhpilis

Most common pattern is coagulative

necrosis caused by ischemia

Liquefactive
necrosis Fibrinoid necrosis Caseous
is seen in seen in blood necrosis
brain vessel walls is seen in
and tuberculosis
infections
Fat necrosis seen in
Pancreatitis and
Breast trauma
 Subcellular responses to injury

 Lysosomal catabolism by:

– Heterophagy
– Autophagy
 Mitochondrial alterations
 Hypertrophy of SER
 Cytoskeleton abnormalities
 Heterophagy

 External materials are engulfed by cell by

endocytosis.
 After fusing with a lysosome the engulfed material is
degraded.
 This process is used mainly by neutrophils and
macrophages.
 Autophagy

 Lysosomes may fuse with vacuoles from ribosome

free ER. This is involved in removal of damaged
organelles, and are most common in atrophic cells.
 Autophagy is also present in cells undergoing
differentiation
 If the material is not degraded it will be deposited
as residual bodies within the cell
 Hypertrophy of SER

When exposed to specific compounds the cell may

adapt by producing an increased amount of proteins
and SER.
This will render the cell to respond more efficiently. It
will however respond more efficiently to other
stimuli as well.
 Mitochondrial alterations

Mitochondria may alter in number

(hypertrophy/atrophy) in shape (megamitochondria)
or in function (hypoxia)

Megamitochondria
 Cytoskeletal abnormalities

For a cell to reshape the cytoskeleton needs to undergo

changes (hypertrophy/atrophy).
Abnormalities may lead to:
 atypical cell shape
 decreased motility
 aberrant organelle movement
 Apoptosis

• A programmed and energy -dependent

process designed specifically to switch-
off cells and eliminate them
• This controlled pattern of cell death is
very different than that which occurs as
a result of a damaging stimuli
 Apoptosis

A suicidal mechanism in several processes

- Destruction of cells in organogenesis
- Hormone-dependent physiological involution
- Cell death in proliferating tissue – including
tumors
- Deletion of autoreactive T-cells in thymus,
cytokine-starved lymphocytes or cell death induced
by cytotoxic T-cells
- Injury that cause irreparable DNA damage
 Apoptosis

Destruction of cells during

embryogensis:
• implantation
• organogenesis
• developmental involution
 Apoptosis

Hormonal-dependent physiological
involution:

• Endometrium during the

menstrual cycle
• Lactating breast after weaning
• Prostrate after castration
 Apoptosis

Cell depletion in proliferating

populations:
• Intestional crypt epithelium
• Cell death in tumors
 Apoptosis

Depletion of immune-cell
populations:

• T-cell in the thymus

• Cytokine deprived T-cells
• Cytotoxic T-cell induced death
 Apoptosis

Normal cells are arranged in close contact and united

by cell junctions. Early in the process of apoptosis there
is synthesis of enzymes needed to cause cell
dissolution. This is termed priming.

In development cells are

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primed for apoptosis
and survive only if
rescued by a specific
trophic factor ie bcl-2
gene product
 Apoptosis

The apoptotic cells lose surface specializations

and junctions, shrinking in size. The nuclear chromatin
condenses beneth the nuclear membrane. In contrast
to necrosis,cell organells remain normal

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Endonuclease enzyme
cleave chromosomes
into individual
necleosome fragments
 Apoptosis

There is splitting of the cell into several fragments,

apoptotic bodies. Nuclear fragmentation also
occurs,with each fragment containig viable
mitochondria and organells

This process takes

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 Apoptosis

Apoptotic fragments are recognized by adjacent

cells, which ingest them by phagocytosis for
destruction. Some fragments degenerate
extracellulary , while others are ingested by local
phagocytic cells

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 Necrosis and 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 Intact; may be released in

leak out of cell apoptotic bodies
Adjacent inflammation Frequent No

Physiologic or Invariably pathologic Often physiologic, means of

pathologic role (culmination of irreversible eliminating unwanted cells;
cell injury) may be pathologic after some
forms of cell injury, especially
DNA damage