CELL
INJURY
Dr. Saumya Jindal
Topic Outline
• Normal cell
• Causes and Types of Injury
• Reversible and Irreversible Injury
• Cell adaptations
• Cell death
NORMAL HUMAN CELL
•
A normal cell is always in a steady state.
•
“Homeostasis” - ability of a cell to maintain internal equilibrium
by adjusting its physiological processes.
Cells are constantly exposed to stress:
• Normal physiologic stress
• Severe stress, which causes injury and alters the normal steady
state of the cell, consequently,
• It can survive in a damaged state and adapt to the injury
(reversible injury or adaptation)
• It can die (irreversible injury or cell death).
Causes of Cell Injury
• Hypoxia and ischemia
• Free radicals
• Chemical agents
• Physical agents
• Infections
• Immunological reactions
• Nutritional defects
• Aging
Hypoxia & Ischemia
• Causes:
• Low levels of oxygen in the air
• Low hemoglobin
• Decreased or diseased RBCs
• Respiratory or cardiovascular diseases
• Ischemia (reduced supply of blood)
Free Radicals
Molecules with a single unpaired electron in an outer orbital.
 Chemically unstable.
 To gain stability, the radical gives up or steals an electron.
 Readily react with other molecules, proteins, carbohydrates, and
lipids, resulting in chemical damage.

Sources of Free
Radicals
• Chemical injury
• Physical injury
• Inflammation
• Infections
• Oxygen toxicity
• Reperfusion injury
• Malignant transformation
• Aging
Examples:
• Reactive Oxygen Species (ROS) generated by mitochondrial
respiration :
• Oxygen Superoxide
• H2O2 (Hydrogen peroxide)
• OH (hydroxyl group)
• Inflammation :
• Accumulation of leucocytes
• NO (Nitric oxide) reactive nitrite
Mechanism
of Injury
by Free
Radicals
Chemical Agents
• Chemical agents can cause cellular injury by:
• Direct contact of the chemical with molecular components of
the cell.
• Indirect injury by :
Formation of free radicals or lipid peroxidation
Examples of injurious
chemicals
• Cyanide
• Mercuric chloride
• Chemotherapeutic agents & antibiotics
• Carbon Monoxide (CO)
• Ethanol
• Lead
Physical agents
• Mechanical injury resulting in tearing or crushing of tissues, eg.
blunt injuries, car accidents, trauma
• Extreme temperatures
• Hypothermia
• Hyperthermia
• Atmospheric Pressure
• Blast injuries
• Water pressure – increased or decreased
Infectious Agents
• Bacteria: produce toxins
• Endotoxin
• Exotoxin
• Viruses :
• Decrease the ability to synthesise proteins
• Change host cell’s antigenic properties
Types of reversible cell injury include:
• Hydropic swelling, where cells swell due to an influx of
water
• Fatty change (steatosis), the accumulation of fat in the
cytoplasm
• Glycogen depletion, which impairs cellular function
• DNA and protein damage, which can be repaired if the injury
is minor and temporary.
These injuries occur when a stressor, like ischemia or hypoxia
is removed before the cell sustains irreversible damage
Morphology of reversible
cell injury:
•Generalized swelling of the cell and its
organelles - Hydropic change
• Blebbing of the plasma membrane
• Detachment of ribosomes from the endoplasmic
reticulum
• Clumping of nuclear chromatin.
Transition to irreversible
cell injury :
•Increasing swelling of the cell
•Swelling and disruption of lysosomes
•Severe swelling & dysfunction of mitochondria
with the presence of large calcium-rich
densities in swollen mitochondria
•Disruption membranes→ phospholipase
•Irreversible nuclear changes: Pyknosis,
karyorrhexis and karyolysis
Cellular Adaptations
• Cells change to
• Adapt to a new environment
• Escape from injury
• Protect themselves
• Growth adaptations:
• Hyperplasia, Hypoplasia
• Hypertrophy, Atrophy
• Metaplasia, Dysplasia
• Degenerations: (Accumulations)
• Hydropic change (water collection in cell /edema)
• Fatty Change
• Hyaline Change
• Pigment storage – wear & tear..
Cellular Adaptation to
Injury
• The most common morphologically apparent
adaptive changes are
– Atrophy (decrease in cell size)
– Hypertrophy (increase in cell size)
– Hyperplasia (increase in cell number)
– Metaplasia (change in cell type)
Atrophy
• Decrease in cell size due to loss of cell substance (protein
degradation & lysosomal proteases digest extracellular endocytosed
molecules)
• Often hormone dependent (insulin, TSH, etc).
• Atrophic cells have diminished function.
Atrophy Examples
• Physiologic:
Uterus following parturition
• Pathologic:
• Decreased workload (Disuse atrophy)
• Loss of innervation (Denervation atrophy)
• Decreased blood supply (Brain atrophy)
• Malnutrition (Marasmus).
• Lack of hormonal stimulation.
• Ageing:
• Senile atrophy
Atrophy of frontal lobe
Atrophy: Undescended
testes
Hypertrophy
• Increase in cell
cellular substance
size
• Hypertrophy
is
caused
increased functional
by
gain
of
either
by
Hypertrophy examples
• Physiological & Pathological
• Skeletal muscles in manual workers &
athletes
• Smooth muscles in pregnant uterus
(Hyperplasia accompanies hypertrophy
here)
• Cardiac muscles in hypertension
• Remaining kidney after nephrectomy
Left ventricle hypertrophy HPTN
Compare normal & pregnant
uterus
Hyperplasia
• An increase in the number of cells of a tissue or organ, from an
increased rate of cell division.
• Hyperplasia may be a predisposing condition to neoplasia
Cells differ in their capacity to divide :
• High capacity: Epidermis, intestinal epithelium,
hepatocytes, bone marrow, fibroblasts.
• Low capacity: Bone, cartilage, smooth muscles
• Nil capacity: Neurons, cardiac muscle, skeletal muscle
Examples of Hyperplasia
• Physiological Hyperplasia (hormonal or compensatory):
• Uterine enlargement during pregnancy
• Female breast in puberty & lactation
• Compensatory hyperplasia in the liver
• Pathological
• Hyperplasia of the endometrium (excessive hormone
stimulation).
• Wound healing (growth factors).
• Infection by papillomavirus
Endometrial Hyperplasia
Metaplasia
• A “reversible” change: one adult cell type is
replaced by another adult cell type that is
better suited to tolerate a specific abnormal
environment.
• It may occur in epithelial or mesenchymal
tissue.
• e.g. Bronchial, gastric, cervical epithelium,
bone in injured soft tissue
Disadvantages :
• Because of metaplasia, normal protective mechanisms may
be lost.
• Persistence of signals that result in metaplasia can lead to
progression from metaplasia to dysplasia and possibly to
cancer.
Example of Metaplasia
Replacement of ciliated columnar epithelium with stratified
squamous epithelium in the respiratory tract of a smoker.
Columnar (gastric) metaplasia in esophageal squamous
epithelium
Dysplasia
• Abnormal changes in size, shape, appearance, and organisational
structure of the cells
• Atypical hyperplasia can progress to neoplasia
• Caused by persistent injury or irritation
“Cells having disordered arrangement”
Cervical dysplasia
CELL DEATH
• Ultimate result of injury
• Physiological- embryogenesis, lymphoid tissue
development, hormonally induced involution
• Therapeuticchemotherapy.
cancer
radiotherapy
and
Types :

Necrosis: Morphologic changes seen in dead cells within
living tissue.

Autolysis: Dissolution of dead cells by the cells' own
digestive enzymes. (not seen)

Apoptosis: Programmed cell death
NECROSIS
• Irreversible
• Necrosis is local cell death and cellular dissolution in living
tissues.
• Necrosis involves the process of self/auto digestion and lysis.
• Morphologic appearance of necrosis is due to:
oEnzymic digestion of the cell
oDenaturation of proteins
Morphologic changes :
• Increased eosinophilia of cells
• Pyknosis of nuclei
• Karyorrhexis
• Karyolysis
• Release of catalytic enzymes from lysosomes cause either
autolysis or heterolysis
• Types:
1. Coagulative
2. Liquefactive
3. Caseous
4. Fat
5. Fibrinoid
• Sequels of Necrosis:
• Autolysis
• Phagocytosis
• Organisation & fibrous repair
• Dystrophic calcification
1- Coagulative necrosis
• The commonest type of necrosis, usually ischemic
• Eg. Infarction in heart (MI), kidney, adrenals
• Results from the denaturation of all proteins including enzymes.
Renal Infarction: Coagulative
Necrosis
• Histology:
• Preservation of the tissue architecture &
cellular outlines.
• The necrotic area stains more
eosinophilic, often devoid of nuclei.
2- Liquefactive Necrosis
• Autolysis predominates and results in liquefied mass.
• Examples:
1. Hypoxia in the brain- Brain cells have a large amount of
hydrolytic digestive enzymes (hydrolases). These enzymes
cause the neural tissue to become soft and liquefy.
2. Bacterial infections (abscess) - Hydrolytic enzymes are
released from neutrophils to fight an invading pathogen.
Stroke
Lung
abscess
Liver abscess: Liquefactive
necrosis
3- Caseous Necrosis
• Typical of tuberculosis, it may be seen in others
• Grossly “cheese-like” appearance
• Histology:
• Central cheesy material, rimmed by chronic inflammatory
cells, epitheloid cells & Langhans giant cells
(GRANULOMA)
Caseous necrosis in Tuberculosis
Caseous necrosis - Tuberculosis
4- Fat Necrosis
• Examples:
• Traumatic fat necrosis → foreign body giant cells →
calcification → hard lump
• Enzymatic fat necrosis due to acute pancreatitis-
d/t pancreatic lipases breaking Adipose tissues →
triglycerides & fatty acids → saponification & calcification
Foci of fat necrosis with
saponification
in the mesentery
Fat Necrosis - Peritoneum
APOPTOSIS
• Programmed cell death by suicide.
• Death of a single cell or cluster of cells resulting in cell
shrinkage, not lysis and swelling without an inflammatory
reaction.
(Unlike necrosis where there is death of large amounts of the
tissue and an associated inflammatory reaction)
• Apoptosis depends on cellular signals which cause protein
cleavage (proteases) within the cell causing cell death.
Two main pathways of Apoptosis
• Intrinsic ‘mitochondrial’ pathway:
Increased
permeability
of
mitochondrial
membrane results in release of pro-apoptotic
factors (cytochrome c and AIF) that activate
downstream caspases  death .
• Extrinsic ‘death receptor’ pathway:
FAS and TNF1 receptor families
domain.
with
death
INTRACELLULAR ACCUMULATIONS
AND DEPOSITS
• Excessive production of a normal substance
• Normal production but a genetic or acquired defective
mechanism for removal of the substance.
• Abnormal exogenous substance
Accumulations include:
• Water
• Fat
• Cholestrol
• Proteins
• Glycogen
• Pigments
• Calcium
• Amyloid deposition
1- Fatty change
• Accumulation of excessive lipid in cells
• The liver is the main organ involved, to lesser
extent heart and kidney
Causes of fatty change :
• Toxins including alcohol
• Starvation and protein malnutrition
• Diabetes mellitus
• Oxygen lack (anemia & ischemia )
• Drugs, Complicate pregnancy & Obesity
2- Cholestrol & Cholestrol esters
• Accumulate in macrophages ( foam cells ) & in foreign body
giant cells.
• Examples:
• Atherosclerosis- Heart
• Hereditary & Acquired hyperlipidemia → Xanthomas (a
yellow nodule or plaque - skin.
3- Protein accumulation:
• Kidney in the nephrotic syndrome
• Plasma cells as immunoglobulins
• Mallory Bodies: Alcoholic liver disease as (Eosinophilic
intracellular hyaline body)
• Glycogen accumulation in Glycogen Storage Diseases.
Liver - Mallory hyaline Alcoholism
4- Pathologic Calcification
A- Dystrophic calcification :
• Abnormal deposition of calcium phosphate in dead or dying
tissue.
• Dystrophic calcification is an important component of the
pathogenesis of atherosclerotic disease and valvular heart
disease.
• Areas of caseous, coaggulative or fat necrosis.
• Dead parasites & their ova
• B- Metastatic calcification :
• Calcium deposition in normal tissues due to hypercalcemia:
 Increased PTH causing bone resorption
 Bone destruction: METASTATIC BONE CANCERS
 Vitamin D disorders Renal failure
• Organs affected:
 Kidney, stomach, lungs
5-Pigments
Pigments
ENDOGENOUS
EXOGENOUS
Anthracosis
Hb-derived
Non Hb -derived
Tattooing
Iron
Melanin
Bilirubin
Lipofuscin
Exogenous pigment : Anthracosis- Accumulation of carbon,
black pigment in Smokers, Tattoos
Lipofuscin - “wear and tear”pigment
accumulates as a part of the aging
process
Bile pigment (Bilirubin )- Derived from heme of Hb from
destroyed RBC, Hyperbilirubinemia may present clinically as
jaundice
Hemosiderin/ iron granules in liver cells
A- H&E section showing golden-brown, finely
granular pigment.
B- Prussian blue reaction, specific for iron.
1. In dystrophic
calcification, calcium levels
are?
1. Decreased
2. Increased
3. Highly increased
4. Normal
Q. Fat necrosis is seen in?
1. Bacterial lung abscess
2. Acute pancreatitis
3. Fungal infection
4. Tubecurlosis
Q. Example of caseous
necrosis?
1. Brain abscess
2. Renal infarct
3. Tubercular infection
4. All of the above
Q. Metaplasia is :
1. Irreversible cell injury
2. Reversible cell adaptation
3. Irreversible cell adaptation
4. None of the above
Q. Extrinsic and Intrinsic
pathways are types of?
1. Necropstosis
2. Autolysis
3. Necrosis
4. Apoptosis
Q. Pregnancy causes ______ of
the uterus ?
1. Atrophy
2. Hypertrophy
3. Hyperplasioa
4. Both 2 and 3
Q. Cholesterol accumulates in
which cells of the body?
1. Lymphocytes
2. Neutrophils
3. Macrophages
4. Fibroblasts
Q. Which is true about
necrosis?
1. It is an active process
2. There is no inflammation
3. It is always pathological
4. Involves a single cell or small clusters of
cell only
Q. Which of the following can
progress to neoplasia?
1. Hypertrophy
2. Hyperplasia
3. Dysplasia
4. Both 2 and 3