Apoptosis & Necrosis (MedLive by DR Priyanka)

CELL ADAPTATIONS
CELL INJURY
CELL DEATH
DR. PRIYANKA SACHDEV , MD
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Cell Adaptation & Injury Apoptosis & Necrosis Inflammation Haemodynamic Disorder
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TYPES OF CELLS
1. Labile cells
2. Stable cells
3. Permanent cells
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Dr. PRIYANKA SACHDEV

Labile
Continuous regeneration from stem cells (self-renewal)
a) Hematopoietic cells in bone marrow

b) Surface epithelia – skin, oral cavity, vagina, cervix
c) Duct epithelia – salivary glands, pancreas, biliary tract
d) Mucosas – GIT, uterus, fallopian tubes, urinary bladder

Stable
Regeneration as response to injury
a) Parenchyma – liver, pancreas, renal tubules

b) Mesenchymal cells, endothelium

Permanent
Nonproliferative in postnatal life
a) Neurons
b) Cardiomyocytes

INTRODUCTION
• Cells are the structural and functional units of

tissues and organs.
• Normal cells have a fairly narrow range of function or steady

state: Homeostasis

Normally cells in homeostasis
Physiological and pathological stress
Cellular adaptation (reversible on withdrawal of stimulus)
If the irritant stimulus persists for long time
Cell injury
Reversible cell injury
Irreversible cell injury (Cell death)

-Apoptosis
-Necrosis
• Cell injury results when cells are stressed so severly
that they are no longer able to adapt
• i.e., when the limits of adaptive response to a stimulus

are exceeded, cell injury occurs.

• Cell injury is reversible up to a certain point,
but if the stimulus persists or is severe
enough from the beginning, the cell reaches a
“point of no return” and suffers irreversible
injury and ultimate cell death.

• Adaptation, reversible injury and irrversible
injury & cell death are stages of progressive
impairment of the cell’s normal function and
structure.

CELL DEATH
DR. PRIYANKA SACHDEV, MD


CELL DEATH
• Apoptosis
• Necrosis

Apoptosis
OVERVIEW
• Definition
• Types
• Mechanisms
• Morophological changes in apoptosis
• Diagnosis of Apoptosis
• Differences from necrosis

Definition
CELL SUICIDE

Definition
• It is a pathway of cell death that is induced by a tightly
regulated intracellular program in which cells destined to
die activate enzymes (caspase) degrade the cells own
nuclear DNA and cytoplasmic proteins.
• The cell is phagoctosed

• There is no leakage outside
• So there is no inflammation
Definition
• It is a pathway of cell death that is induced by a tightly
regulated intracellular program in which cells destined to
die activate enzymes (caspase) degrade the cells own
nuclear DNA and cytoplasmic proteins.
• The cell is phagoctosed

• There is no leakage outside
• So there is no inflammation
• It is the way of elimination of unwanted cells and
those cells which are damaged beyond repair capacity
of cell.

• Apoptosis generally involves single cell in contrast to
necrosis that usually involve a group of cells.

• It is the ‘ programmed cell death’.
• It is genetically programmed.
• It is an energy dependent process.

POLLS 1
Central to apoptosis is the utilization of
• a) Nitrous oxide
• b) Adenyl cyclase
• c) Caspases
• d) c-AMP

Central to apoptosis is the utilization of -
• a) Nitrous oxide
• b) Adenyl cyclase
• c) Caspases
• d) c-AMP

OVERVIEW
• Definition
• Types
• Mechanisms

TYPES
Apoptosis may be of two types →
• A) Physiological → Programmed cell death

• B) Pathological → Unprogrammed cell death

APOPTOSIS
Physiological Pathological
Physiological causes
1.Embryogenesis
2.Elimination of potentially self reacting lymphocytes.
3.Hormone dependent involution of uterus and breast.
4.Death of cells that have completed their functions

APOPTOSIS
Physiological Pathological
Pathological Causes
• 1. Cell death in tumours exposed to chemotherapeutic

agents.
• 2. Progressive depletion of CD4+T cells in the pathogenesis
of AIDS.
• 3. Cell death in viral infections e.g. formation of Councilman
bodies in viral hepatitis.

OVERVIEW
• Definition
• Types
• Mechanisms

Mechanism
• Apoptosis can be induced through two distinct but
convergent pathways.
1. Extrinsic pathway – it is initiated by extracellular stimulus

with help of specific receptors called death receptors
2. Intrinsic pathway – it is result of increased mitochondrial

membrane permeability and release of proapoptotic
markers like cytochrome C into the cytoplasm.
Mechanism
Extrinsic pathway Intrinsic pathway
Initiation Execution Initiation Execution

Phases
Apoptosis can be divided into two phases:
1. Initiation phase : starts with stimulus ( either extrinsic or

intrinsic) and consist of catabolic activation of caspase like 8 or 9.
2. Execution phase: executioner caspases act to cause cell death.

Mechanism

Extrinsic pathway → Initiation phase
• It is initiated through specific receptors called death
receptors
1. Fas protein (CD95)

2. TNF receptors

Fas protein (CD95)
Fas receptor (Death receptor)
Multiple Fas proteins come together
Cytoplasmic death domains combine to form a death domain

FADD
Activate pro- caspsase 8 to active caspase 8

Extrinsic pathway → Initiation phase
• It is initiated through specific receptors called death
receptors
1. Fas protein (CD95)

2. TNF receptors

TNF
TNF receptor
Multiple Fas proteins come together
Cytoplasmic death domains combine to form a death domain

TRADD
Active pro- caspsase 8 to active caspase 8

Mechanism

Mechanism

Intrinsic pathway → Initiation phase
• The intrinsic signaling pathways that initiate apoptosis

involve a diverse array of non-receptor-mediated stimuli
that produce intracellular signals within the cell and are
mitochondrial-initiated events

Stimuli
DNA damage (beyod repair)
DNA damage can occur after exposure to agents like
radiation and chemotherapy (genotoxic stress)

Stimuli
Anti apoptotic molecules Bcl-2 and Bcl-x are lost
Replaced by pro-apoptotic molecules like Bak, Bax, Bim
Increased mitochondrial permeability (MPT)
Release to cytochrome C into cytoplasm
Activates Apaf-1 along with procaspase-9
Activated caspase-9 Dr. PRIYANKA SACHDEV

Antiapoptotic molecules
1. BCL-2
2. BCL-X
3. McI-1
4. FLIP

Proapoptotic molecules
1. Bax
2. Bim
3. Bad
4. Bak
5. P53 gene
6. Apaf-1
7. Cytochrome C
REMEMBER
• Mitochondria are the most important organelles
involved in initiation and regulation of apoptosis
• Mitochondrial membrane permealization is the

hallmark of apoptosis

Mechanism

Mechanism

Execution phase
• It is a convergence point for both extrinsic and intrinsic
pathways.


Caspase 8 Caspase 9
Activates caspase 3 and 7
Sequentially activates all other caspase
Caspases cleave cytoskeletal and nuclear matrix proteins
Cell degenerate/ apoptotic bodies formed

REMEMBER
• Initiation Caspase → CASPASE 8 and 9
• Execution Caspase → CASPASE 3 and 7

Mechanism

Phagocytosis


Phosphatidylserine is a phospholipid present on inner
surface membrane normally
During apoptosis
Flipped to outer surface
Externalization of phosphatidylserine causes its tagging
Phagocytes ingulf it
These alterations permit the early recognition of
apoptotic cells by macrophages
Phagocytosis without the release of proinflammatory

cellular components.

• The process of apoptotic cells is so efficient that
dead cells disappear without leaving a trace and
inflammation is virtually absent.

• Essential feature is immediate, specific and non-
inflammatory nature of phagocytosis

POLLS 2
CD 95 is a marker of -
a) Intrinsic pathway of apoptosis

b) Extrinsic pathway of apoptosis
c) Monocyte
d) Leucocyte

CD 95 is a marker of -
a) Intrinsic pathway of apoptosis

b) Extrinsic pathway of apoptosis
c) Monocyte
d) Leucocyte

In apoptosis, cytochrome C acts
through
a) Apaf 1
b) Bcl-2
c) FADD
d) TNF

In apoptosis, cytochrome C acts
through
a) Apaf 1
b) Bcl-2
c) FADD
d) TNF

The following is an antiapoptotic gene -
• a) Bax
• b) Bad
• c) Bcl-X
• d) Bim

The following is an antiapoptotic gene -
• a) Bax
• b) Bad
• c) Bcl-X
• d) Bim

A

A

OVERVIEW
• Definition
• Types
• Mechanisms

Morophological changes in
apoptosis

1. Cellular shrinkage is earliest change
• It is due to damage to cytoskeletal proteins.

2. Cellular organelles are tightly packed thus imparting
intense eosinophilic color to cytoplasm

3. Nuclear changes
• Pyknosis ie.Chromatin condensation or nuclear

compaction
• Karyorrhexis ie. nuclear fragmentation.It is due to

activity of endonuclease and caspases
• It is the most characteristic feature Dr. PRIYANKA SACHDEV

4. Cytoplasmic membrane shows multiple surface
blebs.
• It is the end stage of apoptosis.
• Cell membrane intact thus preventing leaking out of

cellular contents.
5. Nuclear fragments and cytoplasmic organelles form
membrane bound apoptotic bodies
• These are membrane bound round masses of

eosinophilic cytoplasm with tightly packed orgaelles
which may contain nuclear debries
• These apoptotic bodies are recognised by phagocytes
and destroyed
• Characteristically, unlike necrosis, there is no acute

inflammatory reaction around apoptosis.

POLLS 3
The earliest change seen in apoptosis is
• a) Cell shrinkage
• b) Pyknosis
• c) Formation of apoptotic bodies
• d) Fragmentation of cells

The earliest change seen in apoptosis is
• b) Pyknosis
• c) Formation of apoptotic bodies
• d) Fragmentation of cells

Characteristic feature of apoptosis
• a) Cell membrane intact

• b) Cytoplasmic Basophilia
• c) Nuclear moulding
• d) Cell swelling

Characteristic feature of apoptosis
• a) Cell membrane intact

• b) Cytoplasmic Basophilia
• c) Nuclear moulding
• d) Cell swelling

All of the following are features of
apoptosis EXCEPT
• a) Cellular swelling
• b) Nuclear compaction
• c) Intact cell membrane
• d) Cytoplasmic eosiophilia

All of the following are features of
apoptosis EXCEPT
• a) Cellular swelling
• b) Nuclear compaction
• c) Intact cell membrane
• d) Cytoplasmic eosiophilia

Apoptotic bodies are
• a) Clumped chromatin bodies

• b) Pyknotic nucleus without organelles
• c) Cell membrane bound with organelles
• d) No nucleus with organelles

Apoptotic bodies are
• a) Clumped chromatin bodies

• b) Pyknotic nucleus without organelles
• c) Cell membrane bound with organelles
• d) No nucleus with organelles

A

OVERVIEW
• Definition
• Types
• Mechanisms

DIAGNOSIS OF APOPTOSIS


1. Apoptosis markers
• Annexin-V is a recombinant protein with high affinity for

phospholipid like phosphatidylserine.
• Phosphatidylserine is a phospholipid present on inner surface

membrane normally but it is flipped to outer surface during
apoptosis thus become a marker of apoptosis.

2. Agarose gel electrophoresis:
• Fragmented DNA shows Step Ladder Pattern,which is due to

internucleosomal cleavage of DNA by endonuclease
• During karryorrhexis endonuclease activation leaves short

DNA fragments regularly spaced in size.
• This ladderd patteren is characteristic but not specific for

apoptosis.
POLLS 4
Ladder pattern of DNA electrophoresis in
apoptosis is caused by the action of the
following enzyme
• a) Endonuclease
• b) Transglutaminase
• c) DNAse
• d) Caspase

Ladder pattern of DNA electrophoresis in
apoptosis is caused by the action of the
following enzyme
• a) Endonuclease
• b) Transglutaminase
• c) DNAse
• d) Caspase

Annexin V is a marker of-
• a) Apoptosis
• b) Necrosis
• c) Artherosclerosis
• d) Inflammation

Annexin V is a marker of-
• a) Apoptosis
• b) Necrosis
• c) Artherosclerosis
• d) Inflammation

OVERVIEW
• Definition
• Types
• Mechanisms

Differences from necrosis


POLLS 5
What is the common change in cell death
associated with both apoptosis and
necrosis?
• b) Bleb formation
• c) Chromatin condensation
• d) Presence of inflammation

What is the common change in cell death
associated with both apoptosis and
necrosis?
• b) Bleb formation
• c) Chromatin condensation
• d) Presence of inflammation

Apoptosis is differentiated from necrosis
by presence of following feature
• a) Absence of inflammation
• b) Cell swelling
• c) Disruption of plasma membrane
• d) Passive process

Apoptosis is differentiated from necrosis
by presence of following feature
• a) Absence of inflammation
• b) Cell swelling
• c) Disruption of plasma membrane
• d) Passive process

CELL DEATH
• Apoptosis
• Necrosis

NECROSIS
Normally cells in homeostasis
Physiological and pathological stress
Cellular adaptation (reversible on withdrawal of stimulus)
If the irritant stimulus persists for long time
Cell injury
Reversible cell injury
Irreversible cell injury (Cell death)

-Apoptosis
-Necrosis
DEFINITION
• Necrosis is death of cells and tissues in the living animal
• Necrosis is defined as a localised area of death of tissue

followed later by degradation of tissue by hydrolytic
enzymes liberated from dead cells
• It is invariably accompanied by inflamatory reaction

REMEMBER
• Necrosis usually affects a group of contigous cells (in

contrast to apoptosis which involves a single cell).
• There are inflammatory changes in the surrounding

tissue (in contrast to apoptosis where there in no
inflammatory changes).

Types of Necrosis (CCCFF)
• 5 types→
• Coagulative necrosis (most common)

• Colliquative / Liquefactive necrosis
• Caseous
• Fat necrosis
• Fibrinoid necrosis
• Introduction
• Causes
• Gross
• Microscopy

Coagulative necrosis


• Introduction
• Causes
• Gross
• Microscopy

INTRODUCTION
• Most common type of necrosis
• Architectural outlines persist but cellular and nuclear details

are lost (Ghost cells)
• Type of tissue can be recognized
• Denaturation (coagulation) of structural and enzymic proteins

blocks proteolysis.
Causes:
1.Ischemia due to thrombosis/ embolism in all organs
except brain (Amongst solid organs brain is the only
exception, i.e., it is the only solid organ in which ischemia
leads to liquefactive necrosis and not coagulative necrosis)
2.Mild burns (thermal injury)
3.Zenker's degeneration necrosis

Grossly
• Focus in the early stage is pale, firm, and slightly
swollen
• With progression, the affected area becomes more

yellowish, softer, and shrunken.

Microscopically
• The hallmark of coagulative necrosis is the conversion
of normal cells into their ‘tomb stones’ i.e. outlines of
the cells are retained and the cell type can still be
recognised but their cytoplasmic and nuclear details
are lost

1. ‘Tomb stones’ i.e. outlines of the cells are retained and
the cell type can still be recognised but their cytoplasmic
and nuclear details are lost
2. The necrosed cells are swollen and have more
eosinophilic cytoplasm than the normal.
3. These cells show nuclear changes of pyknosis,
karyorrhexis and karyolysis
4. Eventually, the necrosed focus is infiltrated by
inflammatory cells
COAGULATIVE LIQUIFACTIVE CASSEOUS FIBRINOID FAT
INTRO
CAUSES
GROSS
MICRO

• 5 types→

• Caseous
• Fat necrosis
Liquefactive (COLLIQUATIVE)
necrosis

• Introduction
• Causes
• Gross
• Microscopy

INTRODUCTION
• Liquefaction or colliquative necrosis→ hydrolytic
enzymes in tissue degradation have a dominant role in
causing semi-fluid material
• Their architectural details as well as cytoplasmic and

nuclear details are lost

Causes:
1. Pyogenic bacterial infections attract neutrophils.

Bacterial and leukocytic enzymes liquefy dead cells
and tissues.
2. Ischemic necrosis of brain

Gross appearance
• Affected area is soft with liquefied centre containing
necrotic debris
• Later, a cyst wall is formed.

Microscopic appearance:
1. No architectural or cellular details are visible in the
area of necrosis.
2. The necrotic area usually appears as a cavity containing
a mass of necrotic neutrophils, bacteria and tissue
debris
3. The entire necrotic mass is surrounded by a fibrous
connective tissue capsule/cyst wall
4. The cyst wall is formed by proliferating
capillaries,inflammatory cells, and gliosis
INTRO
CAUSES
GROSS
MICRO

• 5 types→

• Caseous
• Fat necrosis
Caseous necrosis (cheese like)


• Introduction
• Causes
• Gross
• Microscopy

INTRODUCTION
• Dead tissue is converted into a homogenous, granular
mass resembling cottage cheese.
• Their architectural details as well as cytoplasmic and

nuclear details are lost
• Accumulation of amorphous (no structure) debris

within an area of necrosis
Cause:
• Associated with lesions of Mycobacterium tuberculosis,

syphilis and fungi (Histoplasma , Coccidioidomycosis)

Gross appearance
• Foci of caseous necrosis resemble dry cheese and are

soft, granular and yellowish.
• This appearance is partly attributed to the histotoxic

effects of lipopolysaccharides present in the capsule of
the tubercle bacilli, Mycobacterium tuberculosis

Microscopically
• Centre of the necrosed focus contain structureless,
eosinophilic material having scattered granular debris
of disintegrated nuclei
• The surrounding tissue shows characteristic

granulomatous inflammatory reaction consisting of
epithelioid cells (modified macrophages having slipper-
shaped vesicular nuclei), interspersed giant cells of
Langhans’ and foreign body type and peripheral mantle
of lymphocytes
INTRO
CAUSES
GROSS
MICRO

• 5 types→

• Caseous
• Fat necrosis
Fat necrosis

• Introduction
• Causes
• Gross
• Microscopy

INTRODUCTION
• Fat necrosis is a special form of cell death occurring at
mainly fat-rich anatomic locations in the body.
• Death of adipose tissue in a living animal

Causes
• Pancreatic (acute pacreatitis)

• Traumatic (breast)

Grossly
• Fat necrosis appears as yellowish-white and firm
deposits.
• Formation of calcium soaps imparts the necrosed foci

firmer and chalky white appearance

Microscopically
• The necrosed fat cells have cloudy appearance
• They are surrounded by an inflammatory reaction.
• Formation of calcium soaps is identified in the tissue
sections as amorphous, granular and basophilic material

• 5 types→

• Caseous
• Fat necrosis
Fibrinoid Necrosis
• Fibrinoid necrosis is characterized by deposition of fibrin-

like material which has the staining properties of fibrin
• The fibrin like material is deposited in wall of blood

vessels

Causes
• Immunologic injury of vessel wall (e.g. in immune

complex vasculitis, autoimmune diseases, Arthus
reaction etc), arterioles in hypertension, peptic ulcer
etc.

Microscopically
• Fibrinoid necrosis is identified by brightly eosinophilic,
hyaline-like deposition in the vessel wall.
• Necrotic focus is surrounded by nuclear debris of

neutrophils (leucocytoclasis)
• Local haemorrhage may occur due to rupture of the blood

vessel.
INTRO
CAUSES
GROSS
MICRO

REVISION
• 5 types→

• Caseous
• Fat necrosis
INTRO
CAUSES
GROSS
MICRO

POLLS 6
Necrosis with cell bodies retained as ghost cells is
• a) Coagulative necrosis
• b) Liquefactive
• c) Caseous
• d) None

Necrosis with cell bodies retained as ghost cells is
• a) Coagulative necrosis
• b) Liquefactive
• c) Caseous
• d) None

All the following organs likely
undergo coagulative necrosis except
• a) Spleen
• b) Heart
• c) Kidney
• d) Brain

All the following organs likely
undergo coagulative necrosis except
• a) Spleen
• b) Heart
• c) Kidney
• d) Brain

Liquefactive necrosis is seen in -
• a) Heart
• b) Brain
• c) Lungs
• d) Spleen

Liquefactive necrosis is seen in -
• a) Heart
• b) Brain
• c) Lungs
• d) Spleen

C

A

B

C


D

GANGRENE


Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

DEFINITION
• Gangrene is necrosis of tissue associated with superadded
putrefaction

• GANGRENE = Necrosis + Putrefaction

Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

TYPES
2 main types of gangrene—
1.Dry
2.Wet
3.A variant of wet gangrene called gas gangrene.

1.“Dry” gangrene – no bacterial superinfection; tissue
appears dry
2. “Wet” gangrene – bacterial superinfection has

occurred; tissue looks wet and liquefactive
• In all types of gangrene, necrosis undergoes

liquefaction by the action of putrefactive bacteria.
Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

Dry Gangrene
• Begins in the distal part of a limb (toes ,feet)
• Due to ischaemia ( blockage of artery).
• spreads slowly upwards until where the blood supply is

adequate to keep the tissue viable.
• A line of separation is formed at this point between the

gangrenous part and the viable part Dr. PRIYANKA SACHDEV
• It is a type of coagulative necrosis
• The extent of vascular occlusion is frequently global

in the lower limbs, which impedes or prevents the
migration of leukocytes in to the area of coagulative
necrosis
• It is called gangrenous necrosis because the dead
tissue is not digested and removed but remains
mummified. Dr. PRIYANKA SACHDEV
Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

Grossly
• Affected part is dry, shrunken and dark black,
resembling the foot of a mummy.
• It is black due to liberation of haemoglobin from

haemolysed red blood cells which is acted upon by
hydrogen disulfide (H2S) produced by bacteria resulting
in formation of black iron sulfide.
• Line of separation
Histologically
• There is coagulative necrosis with smudging of the
tissue.
• Line of separation consists of inflammatory

granulation tissue

Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

Wet Gangrene
• When overlying skin of dry gangrenous tissue is
devitalized, bacterial infection is superimposed
• The coagulative necrosis is modified by liquifactive

necrosis.

• Occurs in naturally moist tissues and organs such as the
bowel, lung, mouth, cervix, vulva
• Develops due to blockage of both venous as well as arterial

blood flow
• More rapid.
• NO clear-cut line of demarcation

• The classic example is gangrene of the bowel,
commonly due to strangulated hernia.
• Diabetic foot which is due to high glucose content

favours growth of bacteria.

Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

Grossly
the affected part is soft, swollen, putrid, rotten and
dark.

Histologically
• There is coagulative necrosis
• Mucosa is ulcerated and sloughed.
• Intense acute inflammatory exudates and
• Thrombosed vessel

REMEMBER
• Dry gangrene -> Variant of Coagulative necrosis
• Wet gangrene -> Liquifactive necrosis is

superimposed on coagulative necrosis

Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

GAS GANGRENE
• Special form of wet gangrene caused by gas-forming
clostridia (gram-positive anaerobic bacteria)
• It entres through open contaminated wounds or

complication of operation on colon which normally
contains clostridia.

Headings
• Definition
• Types—>
a) Introduction
b) Gross
c) Microscopy

Grossly
• Swollen, oedematous, painful and crepitant due to

accumulation of gas bubbles of carbon dioxide within
the tissues formed by fermentation of sugars by
bacterial toxins

Microscopically
• Coagulative necrosis with liquefaction.
• Large number of gram-positive bacilli can be identified.
• leucocytic infiltration, oedema
• Capillary and venous thrombi are common.

POLLS 7
A

B

B

Pathological calcification


CALCIUM
Insoluble inorganic calcium salts are a normal constituent of bones and teeth.

CALCIUM
• The great majority of the calcium in the body is stored in
bone and teeth
• The bulk of remaining calcium is bound to protein or forms

small ionic complexes.
• It is estimated that 1% or less of the calcium in the body is

present in ionic form, the active form of the element.
CALCIUM
• Furthermore, the calcium concentration outside of cells is

approximately 10,000 fold higher than inside cells.
• Within cells, calcium is 10,000 fold higher in the

endoplasmic reticulum and mitochondria than in the
cytosol.
CALCIUM HOMEOSTASIS
• Vitamin D (1,25-
dihydroxycholecalciferol)
• Parathormone
• Calcitonin

Vitamin D (1,25-dihydroxycholecalciferol):
Stimulus
• Low extracellular calcium
• Parathormone stimulates formation of 1,25-
dihydroxycloecalciferol by the kidney
Main Action – lead to increased extracellular calcium

• increase the absorption of calcium and phosphorus from
the intestine.
Parathormone
Stimulus
• Low extracellular calcium
• Elevated extracellular phosphorus
Main actions – lead to increased extracellular calcium

• Stimulates formation of vitamin D by the kidney
• Increased mobilization of calcium from bone
• Increasing absorption of calcium from the intestine
• Promotes resorption of calcium from the kidney
• Promotes excretion of phosphorus in the urine
Calcitonin
Stimulus
• Elevated extracellular calcium
Action – lowers extracellular calcium

• Inhibits the parathormone-induced release of calcium
from bone
• Promotes the urinary excretion of phosphorus

PATHOLOGICAL CALCIFICATION
• Deposition of calcium salts in tissues other than osteoid or

enamel is called pathologic or heterotopic calcification
• It is abnormal deposition of calcium salts, together with

smaller amounts of iron, magnesium and mineral salts in
cells and tissues that are not normally mineralized.
TYPES
2 forms:
1. Dystrophic
2. Metastatic

Dystrophic calcification:
• Calcification of dead and dying tissues.
• The level of calcium in blood is usually normal. (There is

no hypercalcemia).
• Calcification occurs in two phases-initiation and

propagation
• within the cells or extra-cellularly
1. Extracellular initiation occurs in small vesicles derived

from degenerating cells
2. Initiation of intra-cellular calcification occurs in the

mitochondria of dead or dying cells.

Membrane of dead and degenerated
cell damaged,
Phospholipid is released
Phosphatases within the phospholipid

generate phosphate ions
calcium binds to phosphate ions
forming calcium phosphate

Sites of calcification:
Dead tissues
• caseation eg. Tuberculosis
• Dead parasites like trichinosis, Onchocercosis.
• fat necrosis
• infarcts
• thrombi
• haematoma
Degenerative tissues
• – atherosclerosis- monckeberg sclerosis
• – damaged heart valves
• – infected lymph nodes
• – degenerating tumours

TYPES
2 forms:
1. Dystrophic
2. Metastatic

Metastatic calcification
It is deposition of calcium salts in many tissues which may
be normal.
It is associated with disorders of calcium metabolism and

there is hypercalcemia.
It may occur widely throughout the body, hence the term

“metastatic.”
Those organs that ‘lose’ acid
Have an underlying alkaline

compartment.
An alkaline internal
component is susceptible to
calcification.

Causes:
1. Hyperparathyroidism- A. Primary, due to neoplasm
B. Secondary-nutritional orrenal failure
(uremia)
2. Hypervitaminosis-D (Vit.D Toxicosis). Increased absorption of

Ca from intestine.
3. Neoplasms: Lymphosarcoma and apocrine adenocarcinoma

secrets parathyroid hormone- like peptides and cause
hypercalcemia.
TYPES
2 forms:
1. Dystrophic
2. Metastatic

• Gross and microscopic appearance is similar to
dystrophic and metastatic calcification.

Gross
• Calcification appears as pale chalky white areas in the

tissues.
• Even if not visible, calcification can sometimes be

detected by the coarse gritty feel of the tissues when
scraped or incised with a knife or scalpel blade.

Microscopic appearance:
• Calcium salts appear as blue granules (deep basophilic)

on H& E.
• Single necrotic cells act like little grains of sand around

which a “pearl” of calcium is deposited. This is called a
psammoma body
• Special stain Von Kossa gives a black color, Alizarin red S

that produces red staining
Significance and results
• Calcification is usually harmless.
• May cause hindrance to organs motility

and inelasticity.

Both types of calcification consist of calcium phosphate crystals
The big difference is that →

• Dystrophic calcification occurs in damaged tissue and normal
blood calcium level
• Metastatic calcification occurs in normal tissue in the setting

of hypercalcemia
POLLS 8
A

A

B

C

D

AGING


• Cellular aging is the result of a progressive decline in
cellular function and viability caused by genetic
abnormalities and the accumulation of cellular damage
due to the effects of exposure to exogenous influences
• Ageing is distinct from mortality and disease although aged

individuals are more vulnerable to disease.

• In India, due to improved health care, it has gone up
from an average of 26 years at the time of
independence in 1947 to 64 years at present.
• Survival is longer in women than men (3: 2).

• The maximum human lifespan has remained stable at
about 110 years.
Life expectancy of an individual depends
on
1. Intrinsic genetic process
• the genes controlling response to endogenous and exogenous factors.
• It has been seen that long life runs in families
• high concordance in lifespan of identical twins has been observed.
2. Environmental factors
3. Lifestyle of the individual such as diseases due to alcohol, smoking, drug

addiction.
4. Age-related diseases e.g. atherosclerosis and IHD, DM, hypertension,

osteoporosis, Alzheimer’s disease, Parkinson’s disease etc. Dr. PRIYANKA SACHDEV
PATHOGENESIS OF AGING
• 1. TELOMERE THEORY
• 2. Genetic control in invertebrates
• 3. Diseases of accelerated ageing
• 4. Oxidative stress hypothesis (free radical-mediated
injury)
• 5. Hormonal decline
• 6. Defective host defenses
• 7. Failure to renew

1. TELOMERE THEORY
• After a fixed number of divisions all somatic cells become
arrested in a terminally nondividing state, known as
senescence.

• Telomeres are short repeated sequences of DNA (TTAGGG) present at the
linear ends of chromosomes that are important for protecting DNA
• With every cell division,there is progressive shortening of telomere present

at the tips of chromosomes
• Telomere length is normally maintained by an enzyme called telomerase.
• Telomerase is a specialized RNA-protein complex that uses its own RNA as a

template for adding nucleotides to the ends of chromosomes

• The activity of telomerase is deceased with age
• Telomerase activity is highest in germ cells and

present at lower levels in stem cells, very low in
somatic tissues

with every cell division
there is progressive shortening of telomere present at the tips of chromosomes
Shortened telomere is repaired by the presence of RNA enzyme, telomerase
After repetitive mitosis for a maximum of 60 to 70 times,
Telomerase activity is terminated
Lost telomere is not repaired
DNA cannot be protected
Telomere shortening (below a critical level) causes activation of p53
No mitosis
cellular senescence (Aging) Dr. PRIYANKA SACHDEV

2. Genetic control in invertebrates
• Clock (clk) genes responsible for controlling the rate

and time of ageing identified in lower invertebrates
• e.g. clk-1 gene mutation in the metazoa, results in

prolonging the lifespan

3. Diseases of accelerated ageing
• A heritable condition associated with signs of

accelerated ageing process known as progeria
• Werner’s syndrome, a rare autosomal recessive

disease, characterised by premature ageing
• children is characterised by baldness, cataracts,and
coronary artery disease.
4. Oxidative stress hypothesis (free
radical-mediated
injury)
With ageing, there is generation of toxic oxygen free
radicals
Fail to get eliminated
Their accumulation
cell damage Dr. PRIYANKA SACHDEV

5. Hormonal decline
• With age, there is loss of secretion of some hormones resulting in their
functional decline.
6. Defective host defenses

• Ageing causes impaired immune function
• reduced ability to respond to microbes
7. Failure to renew
• Ageing causes accumulation of senescent cells without corresponding
renewal of lost cells.

PATHOGENESIS OF AGING
• 1. TELOMERE THEORY
• 2. Genetic control in invertebrates
• 3. Diseases of accelerated ageing
• 4. Oxidative stress hypothesis (free radical-
mediated
injury)
• 5. Hormonal decline
• 6. Defective host defenses
• 7. Failure to renew
ORGAN CHANGES IN
AGEING
1.Cardiovascular system: Atherosclerosis, arteriosclerosis
with calcification, Mönckeberg’s medial calcification,
brown atrophy of the heart
2. Nervous system: Atrophy of gyri and sulci, Alzheimer’s

disease, Parkinson’s disease.
3. Musculoskeletal system: Degenerative bone

diseases,frequent fractures, muscular degeneration
4. Eyes: Deterioration of vision due to cataract and vascular changes in
retina.
5. Hearing: Disability in hearing due to senility is related to otosclerosis.
6. Immune system: Reduced IgG response to antigens
7. Skin: Laxity of skin due to loss of elastic tissue.
8. Cancers: 80% of cancers occur in the age range of 50-80 years.

POLLS ????
B

A


NEXT CLASS
• Every MWF (Monday , Wednesday ,

Friday)→PATHOLOGY
• Every TTS (Tuesday , Thursday , Saturday) →

PHARMACOLOGY

TOMORROW
• 17th Nov → Tuesday → PHARMACOLOGY
PHARMACOKINETICS (Part 2)


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CELL ADAPTATIONS

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Dr. PRIYANKA SACHDEV

a) Hematopoietic cells in bone marrow

Dr. PRIYANKA SACHDEV

a) Parenchyma – liver, pancreas, renal tubules

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

• Cells are the structural and functional units of

• Normal cells have a fairly narrow range of function or steady

Dr. PRIYANKA SACHDEV

Physiological and pathological stress

Cellular adaptation (reversible on withdrawal of stimulus)

If the irritant stimulus persists for long time

Reversible cell injury

Irreversible cell injury (Cell death)

• i.e., when the limits of adaptive response to a stimulus

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

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Dr. PRIYANKA SACHDEV

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• The cell is phagoctosed

• The cell is phagoctosed

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

• It is an energy dependent process.

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

• A) Physiological → Programmed cell death

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

• 1. Cell death in tumours exposed to chemotherapeutic

Dr. PRIYANKA SACHDEV

Dr. PRIYANKA SACHDEV

1. Extrinsic pathway – it is initiated by extracellular stimulus

2. Intrinsic pathway – it is result of increased mitochondrial

Extrinsic pathway Intrinsic pathway

Initiation Execution Initiation Execution

1. Initiation phase : starts with stimulus ( either extrinsic or

2. Execution phase: executioner caspases act to cause cell death.

Dr. PRIYANKA SACHDEV

Extrinsic pathway Intrinsic pathway

Initiation Execution Initiation Execution

1. Fas protein (CD95)

Dr. PRIYANKA SACHDEV

Fas receptor (Death receptor)

Multiple Fas proteins come together

Cytoplasmic death domains combine to form a death domain

Activate pro- caspsase 8 to active caspase 8

1. Fas protein (CD95)

Dr. PRIYANKA SACHDEV

Multiple Fas proteins come together

Cytoplasmic death domains combine to form a death domain