Apoptosis

A Greek word meaning Dropping off tree leaves

DR: Warda musbah

 Apoptosis
-
A Greek word meaning dropping off tree leaves,
cell suicide or programmed cell death.

-Normally, growth factors bind to their receptors in the

cells and prevent the release of cytochrome C and SMAC.
So, withdrawal or absence of growth factors can result in
release of these mediators and initiate the intrinsic
pathway.

-It is initiated by activated caspases enzymatic

degradation of proteins and DNA recognition and
removal of dead cells by phagocytosis.
A B
Physiologic examples of apoptosis:
1. Embryogenesis
o Development of lumen within
hollow organs (e.g bowel and heart).
2. Hormone-dependent involution
in adults.
o Post-lactational atrophy of breast.
3. Involution of Thymus in the
adult.
4. Cells that are programmed to die
o The cells of the outer layer of
epidermis
o Cells in the gut epithelium.
Pathologic examples of apoptosis:
1. Councilman bodies = dead
hepatocytes in viral hepatitis.
2. Psammoma bodies: apoptosis of
neoplastic cell with subsequent
calcification.
3. Tumor cell death by cytotoxic T cells.
4. Neurons that are lost in Alzheimer's
disease.
5. HIV-positive T-lymphocytes die by
apoptosis.
 MORPHOLOGIC FEATURES
. The characteristic morphologic changes in apoptosis seen in histologic and
electron microscopic examination are

Electron Microscope:
1. Involvement of single cells or small clusters of cells in the background of
viable cells.

2. The apoptotic cells are round to oval shrunken masses of intensely eosinophilic
cytoplasm (mummified cell) containing shrunken or almost-normal organelles

3. The nuclear chromatin is condensed or fragmented (pyknosis or karyorrehexis).

4. The cell membrane may show convolutions or projections on the surface.

5. There may be formation of membrane- bound near spherical bodies on or
around the cell called apoptotic bodies containing compacted organelles.

6. Characteristically, unlike necrosis, there is no acute inflammatory

reaction around apoptosis.

7. Phagocytosis of apoptotic bodies by macrophages takes place at varying

speed.
 Light Microscopy :
1. The apoptotic cells appear as round or oval mass having
intensely eosinophilic cytoplasm.

2. The nuclei appear as fragments of dense nuclear chromatin

and shows pyknosis. Apoptosis does not elicit an inflammatory
reaction in the host.
 Mechanisms of Apoptosis :
Divided into A) initiation phase and B) execution phase.

A- Initiation phase.
Initiation of apoptosis occurs principally by signals from two distinct
pathways: -

A- The intrinsic (mitochondrial) pathway

It is initiated by the release of cytochrome C and SMAC (second
mitochondrial activator of caspases) from the mitochondrial
activation of caspase-9

B- The extrinsic (death receptor) pathway:

It is activated by binding of Fas ligand to CD95 or binding of TRAIL
to death receptors DR4 and DR5 activation of caspase 8
 2- Execution phase, during which other caspases (3,6,7)
trigger the degradation of critical cellular components.
Regulation Of Apoptosis:

 Regulation is primarily by pro- and antiapoptotic members of

Bcl proteins.

 Bcl2 family of anti-apoptotic proteins are Bcl-2, Bcl-xL and Mcl-1.

 pro-apoptotic sensors proteins are Bim, Bid and Bad (also called
BH3-only proteins).

 Pro-apoptotic effectors of Bcl2 family Bax, Bak

Normal cells have bcl-2 and bcl-xL (anti-apoptotic proteins ) present
in the mitochondrial membrane. They inhibit apoptosis because their protein
products prevent the leakage of mitochondrial cyt ‘c’ into the
cytoplasm.
When there is absence of growth
factors or hormones

activate Pro-apoptotic sensors

(BH3 only protein)

activates Bcl-2 family effectors

Bax and Bak

which damage mitochondrial

membrane

leakage of cytochrome c protein

into cytoplasm.

Activates caspase cascade.

 Comparison of cell death by apoptosis and necrosis
Feature Apoptosis Necrosis

Induction May be induced by physiological or Invariably due to pathological injury

pathological stimuli
Extent Single cells Cell groups

Biochemical events Energy-dependent fragmentation of DNA Impairment or cessation of ion

by endogenous endonucleases, lysosmes homeostasis, lysosmes leak lytic
intact. enzymes
Cell membrane integrity Maintained Lost
Cell shrinkage and fragmentation to Cell swelling and lysis
Morphology
form apoptotic bodies with dense
chromatin

Inflammatory response None Usual

Ingested (phagocytosed) by Ingested (phagocytosed) by

Fate of dead cells
neighboring cells neutrophils, macrophages.
 PATHOLOGIC CALCIFICATION

It refer to abnormal deposition of calcium salts, together with smaller •

amounts of iron ,magnesium & other mineral salts in areas other
than bone or teeth.
Types of pathologic calcification: •
1)Dystrophic calcification
2) Metastatic calcification

Gross appearance
Calcium salts appear as white granules or grey, chalky masses.
Calcium deposits have firm consistency and gritty feelings on cutting like stones.
Microscopic appearance:
Calcium salts appear as blue granules or masses with H& E.
Special stain Von Kossa gives a black color to Ca salts which may be intracellular
or extracellular.
morphology

a)Gross Morphology
a

Ca++ salts appear as fine ,white Coronary Atherom

granule or clumps , felt as gritty
deposits.

b)Microscopic Morphology
Intracellular or extracellular Calcified mital valve
basophilic deposits.

calcified aortic stenosis

 1)Dystrophic calcification:
It refers to deposition of calcium salts in dead or dying tissue, despite normal
serum levels of calcium and in the absence of derangements in calcium

metabolism.

• Common sites:
 Areas of coagulation.
 Caseous & liquifactive necrosis.
 Foci of enzymatic fat necrosis.
 Damaged heart valves.
 Atheromas of advanced atherosclerosis
 Dead parasitic lesions like trichinosis, Onchocercosis.
 Thrombosis.
 Tumours (Psammoma bodies in some tumors (meningiomas , papillary
carcinoma of thyroid and ovary).
• 2-Metastatic calcification:
It refers to deposition of calcium salts in normal tissues due to some degenerat
in calcium metabolism, leading to hypercalcaemia.

Excessive mobilization of calcium from the bone.

Excessive absorption of calcium from the gut.

Common sites

(Organs which secrete or excretes acids like stomach, kidneys and lungs)

Interstitial tissues of blood vessels .

Kidneys.

lungs.

gastric mucosa.
Excessive mobilisation of calcium from the bone These
causes are more common and include the following:
1. Hyperparathyroidism

2. Bony destructive lesions such as multiple myeloma, metastatic

carcinoma.

3. Hypercalcaemia as a part of paraneoplastic syndrome e.g. in breast

cancer.

4. Prolonged immobilisation of a patient results in disuse atrophy of the

Excessive absorption of calcium from the gut. These causes
are
as under:
1. Hypervitaminosis D from excessive intake or in sarcoidosis.

2. Milk-alkali syndrome caused by excessive oral intake of

calcium in the form of milk and administration of calcium
carbonate in the treatment of peptic ulcer.

3. Idiopathic hypercalcaemia of infancy (Williams syndrome).

Calcification at wall of artery
Calciphylaxis:
A newly described life-threatening type of metastatic
calcification in small blood vessels of the skin in patients
suffering from chronic renal failure.

Painful multiple skin necrosis with burn like ulcerations ,

secondary infections and septicemia is common.

Parathyroidectomy may be life saving.

Multiple skin necrosis with burn like
ulcerations , secondary infections