2. Objectives
Define necrosis and apoptosis
List the different types of necrosis, examples
of each and its features
List the different conditions associated with
apoptosis, its morphology and its mechanism
Know the difference between apoptosis and
necrosis
3. Cell Death
Death of cells occurs in two ways:
1. Necrosis--(irreversible injury) changes produced by
enzymatic digestion of dead cellular elements
2. Apoptosis--vital process that helps eliminate unwanted
cells--an internally programmed series of events
effected by dedicated gene products
4. Morphology of necrosis :
1. Cellular swelling or rupture
2. Denaturation and coagulation of
cytoplasmic proteins
3. Breakdown of cell organelles
4. Breakdown of nuclear DNA
5.
6. Patterns of Necrosis In Tissues or Organs
As a result of cell death the tissues or organs display
one of these six macroscopic changes:
1. Coagulative necrosis
2. Liquifactive necrosis
3. Caseous necrosis
4. Fat necrosis
5. Gangrenous necrosis
6. Fibrinoid necrosis
7. Patterns of Necrosis In Tissues or Organs
1. Coagulative necrosis:
The outline of the dead cells are maintained
and the tissue is somewhat firm.
Microscopically cell outline is preserved but
there is loss of nuclei.
Example: myocardial infarction
1. Liquefactive necrosis:
The dead cells undergo disintegration and
affected tissue is liquefied.
Example: cerebral infarction.
8. Patterns of Necrosis In Tissues or Organs
3. Caseous necrosis:
a form of coagulative necrosis (cheese-like).
Example: tuberculosis lesions.
4. Fat necrosis:
enzymatic digestion of fat.
Example: necrosis of fat by pancreatic enzymes.
5. Gangrenous necrosis:
Necrosis (secondary to ischemia) usually with superimposed
infection.
Example: necrosis of distal limbs, usually foot and toes in diabetes.
6. Fibrinoid necrosis: typically seen in vasculitis
and glomerular autoimmune diseases
9. Coagulative necrosis generally occurs due to an
infarct (lack of blood flow from an obstruction
causing ischaemia) and can occur in all the cells of
the body except the brain.
The heart, kidney, adrenal glands or spleen are
good examples of coagulative necrosis.
Cells that undergo coagulative necrosis can
become dry, hard, and white.
What is interesting is that gel-like appearance
occurs in dead tissues, but the architecture of the
cells is maintained for at least some days.
Coagulation occurs as the proteins are degraded
and denatured, and an opaque film starts to form.
.
10. Gross appearance: a pale segment may be
seen in contrast to surrounding healthy
tissues. The segment may be hard to the
touch.
Microscopic appearance: in an H&E staining
tissue, eosinophilia like-cell (cells presenting
pink on a histology slide) will be noticeable.
Anucleated cells (cells without a nucleus)
should be observable with preserved cell
outlines
12. Coagulative necrosis
Figure : Demonstrate the
histology slide of the
kidney in figure 2.The
green star shows healthy
cells that are less pink and
have nuclei present.The
blue star is a Bowman's
capsule.The yellow star
indicates the necrotic
portion. Notice that the
architectural structure of
the cell is still present, but
no nuclei can be seen.You
could almost draw a line
between damaged and
non-damaged cells.
16. … a mess - so many
cells have died - the
tissue is not
recognizable. Nuclei
have become pyknotic
(shrunken and dark),
undergone karorrhexis
(fragmentation) and
karyolysis(dissolution)
Necrotic myocardium
17. Infarcts (vascular distribution) are wedge-shaped
with a base on the organ capsule.
Coagulative necrosis: is due to loss of blood supply
Spleen
18. Depending on circumstances:
1. necrotic tissue may be walled off by scar tissue,
2. totally converted to scar tissue,
3. get destroyed (producing a cavity or cyst),
4. get infected (producing an abscess or "wet gangrene"),
5. or calcify.
If the supporting tissue framework does not die, and the dead
cells are of a type capable of regeneration, you may have
complete healing.
Remember: True coagulation necrosis involves groups of cells, and
is almost always accompanied, by acute inflammation (infiltrate)
19. Liquefactive necrosis
e
can be associated from bacterial, viruses, parasites
or fungal infections. Unlike coagulative necrosis,
liquefactive necrosis forms a viscous liquid mass as
the dead cells are being digested.
The micro-organisms can release enzymes to
degrade cells and initiate an immune and
inflammatory response.
Cellular dissolution and digestion of dying cells may
also release further enzymes, which speeds up the
liquefying process.
bacterial hydrolytic enzymes or lysosomal hydrolytic
enzymes. These are proteases (collagenases,
elastases), DNases and lysosomal enzymes.
.
20. A creamy yellow liquid should be present as lots of
leukocytes are found to be dead, this is generally
called pus.
an infarct that involves the nervous system (such as
the brain) should present as coagulative necrosis but
does not occur, instead liquefactive necrosis is
present.
21. Gross appearance: liquid-like layer can be
seen; pus should be present.Yellowing,
softening or swelling of the tissue should be
seen. Malacia (softening, or loss of
consistency) should be present. A cystic space
should be present for tissue resolution.
Microscopic appearance: macrophages and
neutrophils, both dead and alive, should be
present. Debris and lysed cells should be seen
with inflammation. Partial space should be
filled with lipids and debris.There is a loss of
neurons and glial cells, with the formation of
clear space
22. LIQUEFACTIVE NECROSIS
Characterized by digestion of dead cells
resulting in transformation of the tissue into a
liquid viscous mass
Is characteristic of focal bacterial , or
occasional fungal infections because microbes
stimulate the accumulation of inflammatory
cells
E.g. hypoxic death in central nervous system
If the process is initiated by acute
inflammation, the material is creamy yellow
because of the presence of dead white
cells called pus
23. Liquefactive Necrosis
Rate of dissolution of the necrotic cells is faster than the rate of
repair. Usually results in an abscess secondary to bacterial infection.
Liquefactive necrosis : hydrolysis of dead tissues or cells (rapidly
destroyed by lysosomal enzymes from neutrophilic leukocytes (i.e.,
bacterial infections), or clostridia or snake poison.
Liquefactive necrosis that is caused by neurophilic
leukocytes is called pus.
30. Fat Necrosis
Specific to adipose tissue with triglycerides.
With enzymatic destruction(lipases) of cells, fatty acids are
precipitated as calcium soaps.
Grossly- chalky white deposits in the tissue.
Microscopically –.
basophilic (bluish) calcium deposits are present. Anucleated
adipocytes with a cytoplasm that is more pink and contains
amorphous mass of necrotic material. Inflammation would
be present
32. Microscopically, fat
necrosis adjacent to the
pancreas is seen here.
There are some
remaining steatocytes at
the left which are not
necrotic, as seen as a
green star.The necrotic
fat cells at the right have
vague cellular outlines,
have lost their peripheral
nuclei, and their
cytoplasm has become a
pink amorphous mass of
necrotic material, as
seen as a yellow star.
33. Caseous necrosis:
A form of coagulative necrosis but
appear cheese-like
Example:
tuberculosis lesions
fungal infections
Coccidioidomycosis
blastomycosis
histoplasmosis
34. CASEOUS NECROSIS
Distinctive form of coagulative necrosis
most often encountered in tuberculous
infection
The term caseous is derived from cheesy
white gross appearance of area of necrosis
which is friable and white
Microscopic appearance
Necrotic focus – collection of fragmented or
lysed cells and amorphous granular debris
enclosed with in distinctive inflammatory
border – granulomatous reaction
37. Caseous necrosis: confluent cheesy tan granulomas in the lung in a
patient with tuberculosis.
This is characteristic of a poorly -
understood subtype of immune injury,
seen in certain granulomatous
diseases (tuberculosis and certain
fungal infections (coccidioidomycosis,
blastomycosis and histoplasmosis)
The macrophage-derived protein
tumor-necrosis factor alpha
("cachectin") is the principal toxin
that causes cells to undergo
caseous necrosis
38. Pulmonary tuberculosis:tubercle contains amorphous finely
granular, caseous ('cheesy') material typical of caseous necrosis.
Removal
of the
dead
tissue
leaves
behind
a scar
39. Caseous necrosis is characterized by acellular pink areas of
necrosis, surrounded by a granulomatous inflammatory process.
N
40. Gangrenous necrosis
Necrosis (secondary to ischemia) usually
with superimposed infection.
Example: necrosis of distal limbs, usually
foot and toes in diabetes
41. Types of the gangrenes
Dry gangrene – dead necrotised tissue remains
uninfected.
Wet gangrene-necrotic tissue becomes infected
Gas gangrene – Wet gangrene infected by one
of the gas forming Clostridia
42. Dry gangrene
Gangrene begins in distal part of limb due
to ischemia
Causes-
Atherosclerosis of anteries supplying limb
Thromboangitis obliterans
Raynauds disease
Trauma
Ergot poisoning
43. Due to ischemia tissues undergoes infarction and line
of separation is formed between the necrotic tissue
and healthy tissue. At the margins of necrotic tissue,
granulation tissue develops
Morphology
Grossly the affected part is dry shrunken and dark in
colour resembling the mummified foot
Black colour is due to release of haemoglobin from
the haemolysed RBC’s which are acted upon by the
hydrogen disulfide produced by bacteria which
results in the formation of black iron sulphide
Gradually the gangrenous tissue falls from the
healthy tissue at the line of separation
Because of the risk of infection it should be
surgically separated
44. “Wet" gangrene “ of the lower extremity in
patient with diabetes mellitus:
1. liquefactive component from
superimposed infection or
2. coagulative necrosis from loss of blood
supply.
45. Gas gangrene
It is wet gangrene infected by one of the
gas forming Clostridia (Gram positive
anaerobic bacteria)
Gas forming Clostridia enters the tissue
through a contaminated wound or as a
complication of operation on colon which
normally contains Clostridia
Clostridia rapidly spreads through tissues
especially in muscles and cause extensive
necrosis and massive edema
46. Morphology
Gross – the affected part is edematous, swollen
and has crepitations on palpation due to
accumulation of gas in tissues
Microscopically
Muscle fibres undergo coagulative necrosis with
liquefaction
At the periphery, a zone of leukocytic infiltration,
oedema and congestion are found
47. FIBRINOID NECROSIS
Special form of necrosis seen in immune
reactions involving blood vessels
Occurs when complexes of antigens and
antibodies are deposited in the walls of
arteries
Along with these complexes fibrin which has
leaked out of vessels give bright pink
amorphous appearance called fibrinoid
(Fibrin like
48. Demonstrates gangrene of
the lower extremity. In this
case, the term "wet"
gangrene is more applicable
because of the liquefactive
component from
superimposed infection in
addition to the coagulative
necrosis from loss of blood
supply.
Demonstrates gangrene, or
necrosis of many tissues in a
body part. In this case, the toes
were involved in a frostbite
injury.This is an example of
"dry" gangrene in which there
is mainly coagulative necrosis
49. Fibrinoid necrosis: afferent arteriole and part of the glomerulus
are infiltrated with fibrin, (bright red amorphous material)
51. Objectives
Define necrosis and apoptosis
List the different types of necrosis, examples
of each and its features
List the different conditions associated with
apoptosis, its morphology and its mechanism
Know the difference between apoptosis and
necrosis
52. Cell Death
Apoptosis
• vital process that helps eliminate unwanted cells
• an internally programmed series of events effected
by dedicated gene products
53. Apoptosis
Physiologic process to die
This process helps to eliminate unwanted cells by an internally
programmed series of events effected by dedicated gene products. It
serves several vital functions and is seen under various settings.
Remember: apoptosis require energy to die
54. Apoptosis
SEEN IN THE FOLLOWING CONDITIONS:
A. Physiologic
1. During development for removal of excess cells during
embryogenesis
2. To maintain cell population in tissues with high
turnover of cells, such as skin, bowels.
3. To eliminate immune cells after cytokine depletion,
and autoreactive T-cells in developing thymus.
4. Hormone-dependent involution - Endometrium, ovary,
breasts etc.
55. Apoptosis
SEEN IN THE FOLLOWING CONDITIONS:
B. Pathologic
1. To remove damaged cells by virus
2. To eliminate cells after DNA damage by radiation,
cytotoxic agents etc.
3. Cell death in tumors.
56. Morphology of Apoptosis
1. Shrinkage of cells
2. Condensation of nuclear chormatin peripherally under nuclear membrane
3. Formation of apoptotic bodies by fragmentation of the cells and nuclei.
The fragments remain membrane-bound and contain cell organelles with
or without nuclear fragments.
4. Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes.
5. Unlike necrosis, apoptosis is not accompanied by inflammatory reaction
60. MECHANISMS OF APOPTOSIS
1. Cause of chromatin condensation is internucleosomal
DNA fragmentation mediated by calcium-sensitive
endonuclease.
2. Alteration in cell volume due to action of
transglutaminase.
3. Phagocytosis of apoptotic bodies is mediated by
receptors on the macrophages.
4. Apoptosis is dependent on gene activation and new
protein synthesis, e.g. bcl-2, c-myc oncogene and
p53.
61. apoptosis
. Occurs more frequently, involves one cell
at a time, localised.
Controlled program of cell death.
Contains intrinsic and extrinsic pathways.
Caspase dependent pathway.
Inflammation absent.
Cell shrinks in size and the condensation of
chromatin occur.
No leakage and no release of enzymes as
small blebs are being released. Hence no
damage to surrounding tissues.
Intact plasma membrane structure.
Eosinophilia cell-like not present (cells
presenting pink on a histology slide).
Nuclear changes: fragments into
nucleosome-size fragments or the nucleus
usually dissolves into apoptotic bodies.
Karyorrhexis and pyknosis.
62. necrosis
Occurs less frequently, involves many cells,
may not be localised and is pathological.
Abnormal and uncontrolled cell death that is
associated with a pathological condition.
Caused by external and internal injuries.
Caspase independent pathway.
Inflammation present.
Cell swells and burst, releasing its content at
once.
Swelling of the mitochondria and endoplasmic
reticulum occurs.
Leakage and enzymatic digestion of
neighbouring cellular contents.
Disrupted plasma membrane structure.
Eosinophilia cell-like present (cells presenting
pink on a histology slide).
Nuclear changes: pyknosis, karyorrhexis and
karyolysis.
63. Genes that regulate apoptosis:
Oncogene Bcl-2
Bcl-2 overexpression prevents apoptosis
Antagonized by cell death (ced) genes & others (bax,bad)
Localized to mitochondria, nuclear envelope and ER
Tumor suppresor gene p-53
Will cause cells with DNA damage (eg amplified myc) to go
apoptosis
Induce bax expression
Reversed by overexpression of bcl-2