PATHOPHYSIOLOGY

CELL INJURY AND DEATH

Nazia kanwal
CNI
CON, UCHS. LAHORE
TRAUMA:
Injury to the body, or an event that causes long-lasting mental or emotional
damage.
Examples of trauma:
• Physical abuse.
• Sexual Abuse.
• Bullying.
• Family / Intimate Partner Violence (“domestic” violence)
• Community violence.
• Traumatic Grief.
• Medical Trauma.
• Terrorism.
CELL INURY:
When the limits of adaptive capacity exceeded or when no adaptive response is
possible,a consequence of events follows, termed as cell injury.
MECHANISM OF CELL INJURY
There are several pathogenic mechanisms through which cell injury can takes
place:
• Impaired cell membrane function.
• Decreased ATP production.
• Genetic alteration.
• Metabolic dearrangement
 • IMPAIRED CELL MEMBRANE FUNCTION:
Following mechanism impair the function of cell membrane
• Production of free radical:
Oxygen derived free radicals are chemical species with single unpaired
electron in outer orbit .When generated incells,they rapidly attack and
degrade nucleic acid and membrane molecules.
• Generation of free radical:
By oxygen toxicity, by drugs andchemicals,by cellular aging.
• Mechanism of injury:
Lipid peroxidation of membrane resulting in cellular and mitochondrial damage.
• Free radical degradation:
Free radicals are degraded by intracellular protective enzymes e.gCatalase .And
also by antioxidants e.g Vitamin E and C.
• DECREASED ATP PRODUCTION:
Hypoxia deprived of cell oxygen and interrupt oxidative metabolism and
generation of ATP.During hypoxic conditions ,hypoxic –inducible factors(HIF)
causes expression of genes that stimulate red blood cells formation ,produce ATP
in the absence of oxygen and increase angiogenesis(formation of new blood
vessels).
• Hypoxia result from inadequate amount of oxygen in air, anemia,
edema ,WhileIshcemia characterized by impaired oxygen delivery and
removal of waste.
Following conditions occur during that phase:
1)As oxygen tension falls ,oxidative metabolism ceases,cell reverts to anaerobc
metabolism using glycogen stores. Cellular Ph falls as lactic acid accumulates in
cell that has adverse effects on functioning.
2)Acute cell swelling caused by failure of sodium/potassium pump which
extrudes sodium from and returns potassium to cell .With impaired
function,potassium levels decrease and sodium ,water accumulate in cell, which
increase membrane permeability .
3)If oxygen supply is not restored there is loss of enzymes,protiensetc through
membrane and decrease protein synthesis occur which results in lipid deposition.
3) IMPAIRED CALCIUM HOMEOSTASIS:
Calcium function as second messenger and cytosolic signal .Normally intracellular
calcium ions levels are kept low compared with extracellular levels.The ischemia
and certain toxin lead to increase in cytosolic calcium because of increased influx
across cell membrane and release of calcium from intracellular stores.this lead to
increase of enzymes e.g phospholipases that cause damage to membrane.
4) GENETIC ALTERATION:
DNA abnormalities may be inherited from generation to generation by ionizing
radiations, viruses etc.
EFFECTS:
Failure to synthesis of intracellular protiens.
Failure of growth regulating protiens leads to cancer formation.
5) METABOLIC DEARRANGEMENT:
Exposure to any exogenous agents such as Alcohol, Drugs ,Heavy Metals and some
endogenous substance damage the cell.

Reversible and Irreversible cell injury

Reversible cell injury:
Reversible cell injury, also known as RCI, is a cellular injury in which the changes
can be reversed if the injurious stimulus is removed.
When the oxygen supply is reduced then there is decrease in synthesis of ATP. As
a consequence of reduced ATP availability, following changes develop in cellular
structure which is reversible if oxygen is restored.
• Cellular swelling.
• Desegregation of ribosome and failure of protein synthesis.
• Reduced intracellular pH resulting in clumping of nuclear chromatin.
• Appearance of myelin figures and cell blebs due to membrane damage.
• Reversible cell injury, although impairing cell functions, does not result in
cell death.
• Fatty changes.
Cellular swelling
Cellular swelling or cloudy swelling or hydropic change is characterized by the
presence of large vacuoles in the cytoplasm. It is the result of failure of cell
membrane pump which maintains Na, K balance across the cell membrane. It is
due to the deficiency of ATP and results in accumulation of Na inside and K
outside the cell. Excess Na inside the cell exerts osmotic pressure and pulls water
inside, resulting in cellular swelling.
The cytoplasm shows:
• Swelling of endoplasmic reticulum.
• Swelling mitochondria.’
• Swelling of the whole cell.
Desegregation of ribosome and failure of protein synthesis:
Ribosome become detached from the rough ER due to its swelling and therefore
protein synthesis is reduced.
Reduced intracellular pH:
Decease ATP synthesis stimulates the enzyme phosphofructokinase activity
resulting in increased rate of anaerobic glycolysis that leads to production of lactic
acids.
This decreases the pH and results in clumping of cytoplasmic organelles.
Lysosomal membrane also damage which results in release of enzyme and destroy
vital intacellular molecules.
Appearance of myelin figures abd cell belbs:
Myelin figures; Intracellular whorl like structure originating from damaged
membrane.
Cell blebs; a cell membrane deformity most likely caused by disorderly function of
the cellular cytoskeleton.
Fatty changes:
They are linked to intracellular accumulation of fat. When this occurs, small
vacuoles of fat disperse throughout the cytoplasm. These changes may occur
because normal cells are presented with an increased fat load or injured cells are
unable to metabolize the fat properly.
In obese people, fatty infiltrates often occurs within and between the cells of liver
and heart. The liver, where mostly fats are synthesized and metabolized is
particularly susceptible to fatty changes but it also occurs in kidney and other
organs.

Irreversible cell injury:

It refers to changes that lead to a new equilibrium with the environment. It causes
more permanent changes.
There are following changes occurs in this type of cell injury:
• Nuclear changes
• Cytoplasmic changes
Nuclear change:
Nuclear may show these types of changes like karyorrhexis and karyolysis.
Karyorrhexis: The pyknotic nucleus may break into numerios small particles.
Karyolysis: when the nucleus undergoes lysis without pyknosis, the process is
called karyolysis.
Cytoplasmic changes:
• Irreversible damage to mitochondria manifested by severe vacuolization.
• Extensive damage to the plasma membrane.
• Massive calcium influx acting as a poison for mitochondria.
• Loss of enzymes and protein due to the increased membrane permeability.
• Lysosomal swelling and leakage of enzymes.

Hypoxic cell injury:

Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and
generation of ATP.
Time required:
Time required for irreversible damage to cell depends on
*Degree of oxygen deprivation
*Metabolic needs of the cell
EXAMPLE: Cells i.e in heart,brain,and kidney require large amount of oxygen to
perform their functions.
*Brain cells begin to undergo permanent damage after 4 to 6 minutes of oxygen
deprivation.
MECHANISM:
During hypoxic condition
*Hypoxia induced factors(HIFs)can cause the expression of genes that stimulate
red blood formation, produce ATP in the absence of oxygen and increase
angiogenesis I.e. formation of new blood vessels.
CAUSES:
*Inadequate amount of oxygen in the air, *Respiratory disease, *Ischemia,
*Anemia, *Edema, *Inability of cell to use oxygen, *In some cases of edema, the
distance for diffusion of oxygen may be limiting factor in delivery of oxygen.

DIFFERENCE BETWEEN HYPOXIA AND ISCHEMIA

*Hypoxia: It depends upon oxygen contents of blood and affects all cells in the
body. Hypoxia causes a power failure in the cell, with widespread effects on cell's
structure and functional components.
As oxygen tension in the cell falls, oxidative metabolism ceases and the cell reverts
to anaerobic metabolism, using its limited glycogen stores in an attempt to
maintain vital function.
*Ischemia: It is characterized by impaired oxygen delivery and impaired removal
of metabolic products i.e lactic acid. It commonly affects blood flow through
limited numbers of blood blood vessels and produce local tissue injury.
EFFECT OF REDUCED ATP:
One important effect of reduced ATP is acute cell swelling caused by failure if
energy dependent sodium/potassium ATPase membrane pump, which extrudes
sodium from and returns potassium to cell. With impaired function of this
pump,intrace intracellular potassium level decrease and sodium and water
accumulate in the cell.
IMPAIRED CALCIUM HOMEOSTASIS: *Calcium functions as an important second
messenger and cytosolic signal for many responses.
*Various calcium binding protein, such as troponin and calmodulin,act as
transducers for the cytosolic calcium signal.
INTRACELLULAR CALCIUM ION LEVEL: Intracellular calcium ions level are kept low
as compared to extracellular level and maintained by membrane associated
calcium/magnesium ATPase exchange system. Ischemia and certain toxins lead to
an increase in cytosolic calcium because of increased influx across cell membrane
and release of calcium from intracellular store . Increased calcium level may
inappropriately activate a number of damaging the cell membrane.
EXAMPLE: Phospholipases: damage cell membrane
Proteases: damage cytoskeleton and membrane proteins
ATPase: breake down ATP and hasten it's depletion.
Injured cell accumulate calcium and is an ultimate cause of irreversible cell injury.

Radiation injury:
Definition: Radiation is damage to injury caused by exposure to ionizing radiation
large doses of ionizing radiation cause acute illness by reducing the production of
blood cells and damaging the digestive tract.
Types: There are three types of radiation injury.
• Ionizing radiation
• Non ionizing radiation
• Ultraviolet radiation.
• Ionizing radiation : A photon is a particle of radiation energy and
radiation energy above the Ultraviolet range is called ionizing radiation because
photon have enough energy to knock the electrons of atom and molecules.
• Ionization radiation impact cells causing Ionization of molecules and atoms
in the cells.
• It can immediately kill the cell interrupt the cell replication or cause a
variety of genetic mutations which may or may not be lethal.
• Radiation injury is caused by irradiation that is used in treatment of cancer.
Injurious Effects: The Injurious effect of ioninzing radiation varies with dose rate
and differential sensitivity of exposed tissue to radiation injury.
Because of effect on DNA synthesis and interference with mitosis rapidly dividing
cells of bone marrow and intestine are more vulnerable than tissues such as bone
and skeletal muscles.
Risk factors: Skin cancer, Leukemia, Osteogenic sarcomas , Lungs cancer
Chemical manifestation: Chemical manifestation of radiation injury result from
acute cell injury dose dependent changes in blood vessels that supply the
irradiated tissue and fibrotic tissue replacement.
Cell initial response: Cell initial response to radiation injury involves.
• Swelling, Disruption of mitochondria and other organelles.
 • Alternation in cell membrane and changes in nucleus.
Acute and chronic effects:
Acute affects: Acute reversible necrosis is represented by disorders such as
radiation cystitis dermatitis and diarrhea.
Chronic effects: Chronic effects of radiation are characterized by fibrosis and
scarring of tissues and organs.
• Non ionizing radiation : It refers to radiation energy at frequencies
below that visible light. Non ionizing radiation involves.
• Infrared radiation
• Microwaves
• Ultrasound
• Laser energy
Unlike Ionization radiation which can directly break the chemical bonds Non
ionizing exert it effect by causing vibration and rotation of molecules and atoms.
Uses:
Non ionizing low frequency radiations are used widely in:
• Rader
• Television
• Industrial operations
E. g heating, welding, melting of metals, processing of wood and plastics
• Household appliances.
E. g, microwave oven
• Medical appliances
• E. g, Diathermy
Injury from these sources in mainly thermal because of deep penetration of
infrared and microwave rays tends to involve dermal and subcutaneous injury.
UV radiation: Represent the portion of spectrum of electromagnetic radiation just
above the visible range.
It contains energetic rays that are powerful to disrupt intercellular bonds and
cause sunburn and increase the risk of skin cancer.
Degree of risk: It depends upon
• Type of Ultraviolet rays, Intensity of exposure
 • Amount of protective melanin pigment in skin.
Skin damage produce by Ultraviolet radiation is thought caused by reactive
oxygen species and by damage to meaning producing process in skin.
UV damage DNA resulting in the formation of pyrimidine dimer.
Pyrimidine Dimer: The insertion of two pyrimidine bases into replicating DNA
instead one.
• The importance of DNA repair in producing against Ultraviolet radiation
injury is evidenced of vulnerability of people who lack enzyme needed to
rapair UV induced DNA damage.
Xeroderma pigmemtosum : It is genetic disorder an enzyme needed to repair
sunlight induced DNA damage is lacking. The autosomal recessive disorder is
characterized by extreme photosensitivity and an increased risk of skin cancer in
sun exposed skin.
Chemical mechanism of cell injury: Chemicals induced cell injury by one of the
two general mechanisms:
• Some chemicals act directly by combining with a critical molecular
component or cellular organelle.
• Mostly chemicals cause injury by aiding in the formation of free radicals.
• Chemical agents can injure the cell membrane and other cell
structures block enzyme pathways coagulate cell Protein and disrupt the osmotic
and ionic balance of cell.
• Corrosive substances such as strong acid and bases destroy cells
when they come in contact with the body.
Other chemicals may injure cells in the process of metabolism or elimination.
For example: carbon tetrachloride (CCL4),cause little damage until it is
metabolized to a highly reactive free radical (CCl4) by liver enzyme , CCl4 is toxic
to liver cell. Many drugs and chemicals cause tissue injury.
Drugs: Drugs alcohol, prescription drugs, OTC drugs and street drugs are capable
of directly or indirectly damaging tissue.
• Ethyl alcohol can harm the gastric mucosa, liver developing fetus, and other
organs.
• Antineoplastic and immunosupressant drugs can directly injure cells.
• Acetaminophen, a commonly used OTC analgesic drug is detoxified in a liver
where small amount are converted into highly toxic metabolite when large
amount of the drug are ingested it cause massive liver necrosis due to
accumulation of toxic metabolite.
Lead toxicity: Lead is a toxic metaleven its small amount reach to toxic level.
Sources: The sources of lead in the environment are flakingpaint, lead
contaminated dust, lead contaminated root vegetables,lead water pipes and
newsprint and toys.
• Children are exposed to lead through ingestion of peeling paints by
Breathing dust from lead paint or playing in lead contaminated soil.
• High lead blood levels continue to be a problem among
Children ,Research has found that low lead level in the blood can have
devastating cognitive and intellectual deficits as well as neurobehavioral
problems in children.
• in the nervous system lead toxicity cause demyelination of cerebellar
white matter and death of cortical cell
• in childhood it effect neurobehavioral development and result in low IQ
level. Peripheral demyelination neuropathy may occur in adults.
• The most serious manifestation of lead poisoning is acute
encephalopathy, persistent vomiting, ataxia, seizures, papilledema and
coma.
Cardinal sign of lead toxicity: Anemia is a cardinal sign of lead toxicity
lead compete with the enzymes required for hemoglobin synthesis and
with the membrane associated enzymes that prevent hemolysis of red
blood cell , due to iron deficiency the life span of RBCs decreased,
• In gastrointestinal tract, it is characterized by lead colic a form of acute
abdominal pain.
• Lead toxicity leads to hypertension.
Absorption of lead: Lead is absorbed through the gastrointestinal tract
or the lungs into the blood.
• Deficiency of calcium, iron or zinc increase lead absorption.
• In children lead is absorbed through the lungs if Absorption in infants
and children is greater they are more vulnerable to lead toxicity.
• The major targets of lead toxicity are the red blood cells, the GIT , the
kidneys and the nervous system.
Screening for lead toxicity: Screening for lead toxicity involves the use of
capillary blood obtained from finger stick to measure free erythrocyte
protoporphyrin (EP).
• Elevated level of EP result from the inhibition of the enzyme required for
hemoglobin synthesis in the RBCs by lead.
• The test is useful in detecting high lead level nut does not detect level
below 20 to 25 ug/dl.
Mercury toxicity: Mercury is toxic on four forms: mercury vapour, inorganic
divalent mercury, methyl mercury and ethyl mercury.
• Mercury toxicity affects the central nervous system and kidney.
• In case of dental feeling the concern involves mercury vapors released into
the mouth .However; the amount of vapors released from feeling is very
small.
• Thimerosak,is an ethyl mercury ‫۔‬containing preservative that prevent
microorganisms growth in vaccines.
Sources: The main source of methyl mercury exposure is from consumption of
fish such as swordfish.
• The developing brain is more susceptible to mercury induced damage it
is recommended that children and pregnant avoid consumption of fish.
Injury from physical agent
Physical agent includes
• Mechanical forces
• Extremes of temperature
• Electrical injuries
Mechanical forces
Trauma or injury due to mechanical forces occurs as the result of body
impact with another object, can be in motion resulting in
• Laceration, Fractures, Burns, Injury to blood vessels and
• Disruption in blood flow
Extremes of temperature
Heat and cold cause damage to cell, its organelles, and its enzyme system
Heat: Exposure to low intensity heat: cause burns, heat stroke, cell injury by
inducing vascular injury, accelerating cell metabolism, inactivating temperature
sensitive enzymes and disrupting cell membrane. Exposure to high intensity heat:
cause coagulation of blood vessels and tissue protein occur as in fried egg
Cold: Increase blood viscosity induces vasoconstriction through reflex activity of
sympathetic system may cause tissue hypoxia, decrease blood flow lead to
capillary thrombosis and stasis
Electrical injuries
• Cause extensive tissue injury and disruption of neural and cardiac impulses
 • Body act as conductor of electrical current
• Can cause seizures or cardiac arrhythmias
• Most severe tissue injury at skin, thick, dry skin is resistant to flow of
current than thin, wet skin degeneration of vessels and thrombi forms .
.Effect of electricity determines by voltage, current, resistance of tissue as AC is
more dangerous than DC.
Injury from biological agents
Biological agents are able to replicate and thus continue to cause injury to
cells
• Viruses incorporate themselves into the DNA of the cell
• Bacteria secrete exotoxins or endotoxins that interfere with cellular
reproduction of ATP,or release antitoxins that cause injury
• Parasites can cause direct injury to cell
Injury from Nutritional imbalances
• Nutritional excesses such as obesity and diets high in fats can predispose to
atherosclerosis leading ischemia
The body needs minerals, vitamins, certain fatty acids, and specific amino acids
• Nutritional and vitamins deficiencies interfere with cell metabolism and
delay wound healing
Free radical injury: Many injurious agents exert damaging effects through reactive
chemical species known as free radicals
• Free radicals are highly reactive chemical species with an unpaired electron
in the outer orbit of the molecule in the literature the unpaired electron is
denoted by a dot
• The unpaired electron causes free radicals to be unstable and highly
reactive so they react nonspecifically with molecule in the vicinity,
moreover free radicals can establish their chain of reaction consisting of
many events that generate new free radicals .in cells and tissues free
radicals react with protein, lipid and carbohydrates thereby damage cell
membrane, inactivate enzymes and damage nucleic acid that make up
DNA, the action of free radical may dispute and damage cell and tissue.
Reactive oxygen species
It’s oxygen containing molecules that include free radical such as superoxide and
hydroxyl radical and non-radicals such as hydrogen peroxide. These molecules are
produced endogenously by normal metabolic processes or cell activities such as
the metabolic burst that accompanies phagocytosis.
Exogenous causes
Including ionizing and UV radiation can cause ROS (Reactive oxygen species)
production in the body
Oxidative stress
It’s a condition that occurs when the generation of ROS exceeds the ability of the
body to neutralize and eliminate ROS. It leads to
• Oxidation of cell components, Activation of signal transduction pathway
• Change in gene, Protein expression
• DNA modification and damage can occur as a result of oxidative stress
• It is associated with cell and tissue damage
• Oxidative stress is important role in the development of cancer
Endothelial dysfunction: That contribute to the development of progression and
prognosis of cardiovascular disease is thought to be caused in part by oxidative
stress
Anti-oxidant: Antioxidants are natural and synthetic molecules that inhibit the
reaction of ROS with biological structure or prevent the uncontrolled formation of
ROS
• It includes enzymes
• Non enzymatic compound
• Catalase
NECROSIS: Necrosis refers to cell death in an organ or tissue that is still part of a
living organism. Or Necrosis refers to sequence of morphological changes that
follow cell death in living tissue. Types
• Basic types
• Coagulative necrosis
• Liquefactive necrosis
• caseous necrosis
• In special sites
• Fat necrosis
• Fibrinoid necrosis
• Gangrenous necrosis
• Coagulative necrosis
In this type of necrosis, it can be transformed into a grey firm mass.
Example: myocardial infarction
Necrosis due to hypoxia in all cells except brain
Mechanism: During coagulation necrosis acidosis develops and denature the
enzymatic and structural proteins of cell.
• Liquefactive necrosis
Transformation of cell into liquid.
Mechanism; It occurs due to autolytic and heterolytic action of enzyme convert
the cell proteins into liquid.
Example; supporative inflammation (pus formation by bacterial action), ischemic
necrosis of brain
• Caseous necrosis:
It is the combination of coagulative and liquefactive necrosis and characterized by
the presence of soft cheesymaterial. It is the distinctive form of necrosis in which
dead cell persist indefinitely.
Example: It is most common in the Centre of tuberculosis granuloma
Morphology: necrotic focus is composed of structurless amorphous granular
debris enclosed within a ring of granulomatous inflammation.
NECROSIS IN SPECIAL SITES
Fat Necrosis
It occurs in two forms
• Traumatic
• Enzymatic
Traumatic: It occurs following severe injury to the tissue with high fat content
such as in breast subcutaneous tissue and abdomen.
Enzymatic: This refers to the necrosis in adipose tissue, induced by the action of
pancreatic enzyme which is liberated due to trauma to pancreas.
Fibrinoid Necrosis: It is the type of connective tissue necrosis especially affecting
arterial walls. This type of necrosis particularly seen in two conditions
• Auto immune disease e.g.:
• Rheumatic fever
• Polyarthritis
 • SLE
• Malignant hypertension
Morphology
It is characterized by the loss of normal structure and replacement by the bright
pink-staining necrotic material that resembles the fibrin microscopically.
Gangrene Necrosis
Gangrene necrosis refers to the death of tissue due to lack of blood supply or
infection.
Causes of Gangrene
• Arterial obstruction due to
• Thrombosis
• Embolus
• Diabetes
• Buergers’s disease and Reynaud’s disease
• Infection( boils, gas gangrene, gangrene of scrotum)
• Trauma(crush injuries, pressure sore)
• Physical agents(burns,chemicals,frostbite)
Clinical types: Wet gangrene, Dry gangrene, gas gangrene
• Wet gangrene
• Found on exposed parts
• Line of demarcation between ling and dead cells
• Arterial blood supply blocked while venous not affected
• No smell, no gas bubbles, tissue black
• Minimal infection
• Dry gangrene
• Found on internal organs
• No line of demarcation
• Sudden arterial and venous obstruction
 • Foul smell,edema,black coloration
• Severe infection and putrefaction
• Gas gangrene
• Found on exposed parts
• Swelling due to edema
• Crepitus
• No line of demarcation
• Caused by contamination of deep wound with spore of clostridia
Mechanism of necrosis
Two processes cause the basic morphology changes of necrosis.
• Enzymatic degradation of cell
• Denaturation of protein
Enzymatic degradation of cell
In this process, hydrolytic enzymes are derived from liposome’s of invading
inflammatory cells (WBS). The enzymatic degradation by this method is
heterolysis. The mechanism leads to liquefaction pattern of necrosis.
In the liquefaction, it can be transformed to a gray, firm mass( i.e., liquefaction
necrosis) or it can be converted into cheesy material by infiltration of fat like
substance( i.e., caseous necrosis)
Denaturation of protein: This mechanism leads to coagulative pattern of necrosis.
During coagulation necrosis, acidosis develops and denatures the enzymatic and
structural protein of the cell. This type of necrosis is done by hypoxic injury and is
seen in infracted areas
Mechanism and significance of apoptosis?
Definition: It is a selective process that eliminates injured and aged cells,thereby
controlling tissue regeneration .The programmed cell death is called apoptosis.
It differs from necrosis population of healthy cell and represents a physiological
process by which abnormal and unsuitable cell die and eliminated.
Morphological changes in cell: The shrinkage and condensation of nucleus and
cytoplasm. The chromatin aggregate at the nuclear envelop and DNA
fragmentation occur. Then the cell becomes fragmented into multiple apoptotic
bodies in a mummer that maintain the integrity of the plasma membrane and
does not initiate the inflammation.
Changes in plasma membrane induce phagocytosis of the apoptotic bodies by
macrophages and other cell, thereby completing the degradation process.
Mechanism of apoptosis: It is linked to many pathologic processes and diseases.
For example, interference with apoptosis is known to be a mechanism that
contributes to carcinogenesis, it may be implicated in neurodegenerative disorder
such as Alzheimer, Parkinson disease.
There are two main pathway for apoptosis: Extrinsic pathway & Intrinsic pathway
Extrinsic pathway:
It is the death receptor dependent and it involves the activation of receptors such
as tumor necrosis factor (TNF) receptors and Fas ligand receptor.Fas receptor may
be expressed on the surface of certain cell such as cytotoxic T cell or appear in a
soluble form .when Fas ligand bind to its receptors protein congregate at the
cytoplasmic end of the Fas receptor to form a death initiating complex.The
complex then convert procaspases -8 to caspase -8 in case of apoptosis .The end
result the activation of endonuclease that cause fragmentation of DNA and cell
death .
Intrinsic pathway:
It is a death receptor independent .It is also called mitochondrian pathway ,of
apoptosisis activated by condition such as DNA damage ,ROS,Hypoxia ,decreased
ATP level ,cellular senescence ,and activation of the p53 protein by DNA
damage .It involves the opening of the mitochondrial membrane permeability
pores with release of cytochrome c from mitochondria into the
cytoplasm .cytoplasmic cytochrome c activates caspases, including caspase -3 it is
the common step in both pathway. Furthmore, activation or increased level of pro
apoptotic proteins, such as Bid and Bax , after caspase-8 activation in the extrinsic
pathway lead to release of mitochondrial cytochrome c .
Significance of apoptosis:
This process is important physiologically in balancing cell proliferation and
elimination. It is associated with maintenance of the organ size in adult. Organ
development and remodeling in the embryo. Physiological atrophy breast after
weaning.