This document discusses cell death and necrosis. It begins by introducing cell injury and defining it as stresses that cells encounter internally and externally. There are two main types of cell death - necrosis and apoptosis. Necrosis is the irreversible cell injury and death that occurs when damage becomes too severe for the cell to recover. Apoptosis is programmed cell death that is important for normal physiology. The document further explores the mechanisms, morphology, and types of necrosis including coagulative, liquefactive, caseous, fat, and fibrinoid necrosis. It also discusses the mechanisms, initiators, regulators and roles of apoptosis. Gangrene is defined as a condition caused by critically insufficient blood supply that results in cell death.

2. CELL DEATH AND
NECROSIS
Presented by-
Dr Ekta Dwivedi

3. INTRODUCTION
Most forms of disease state begin with cell injury
and consequently loss of cellular function.
Cell injury is defined as- a variety of stresses a cell
encounters as a result of changes in its internal and
external environment.
The cellular response to injury varies and
depends upon
 Type of cell and tissue invovled
 Extent of injury
 Type of injury

4. CELLULAR RESPONSES TO STRESS AND NOXIOUS
STIMULI
Cells are active participants in their environment, constantly
adjusting their structure and function to accommodate changing
demands and extracellular stresses.
Cells tends to maintain their intracellular milieu within a fairy
narrow range of physiologic parameters; that is, they maintain
normal homeostasis.
As cells encounter physiologic stresses or pathologic stimuli,
they can undergo adaptation.
The principle adaptative responses are:-
-Hypertrophy,
- Hyperplasia,
-Atrophy,
-Metaplasia

5. If the adaptive capability is exceeded or if the external stress is
inherently harmful, cell injury develops.

6. OVERVIEW OF CELL INJURY OR CELL DEATH
REVERSIBLE CELL INJURY-
In early stages or mild forms of injury the functional or morphologic changes
are reversible if the damaging stimulus is removed.
IRRIVERSIBLE CELL INJURY (CELL DEATH)-
With continuing damage, the injury becomes irreversible, at which time the
cell cannot recover and it dies. There are two types of cell death-
Necrosis
Apoptosis

7. Genetic cause
Acquired causes

8. Based on underlying agent:
Hypoxia and ischaemia
Physical agents
Chemical agents and drugs
Microbial agents
Immunologic agents
Nutritional Imbalences
Psychological factors

9. Deficiency of oxygen or hypoxia results in
failure to carry out cellular activities.
Most common, causes of hypoxia are:
Reduced supply of blood to cells- ischaemia
Oxygen deprivation can result from other causes like-
anaemia, carbon monoxide poisoning,
cardiorespiration insufficiency and increase in
demand of tissues

10. Mechanical trauma
Thermal trauma
Electricity
Radiation rapid changes in atmospheric pressure

11. Chemical poisons: cyanide, arsenic,mercury.
Strong acid and alkalis
Insecticides and pesticides
High oxygen concentration
Hypertonic glucose and salt
Alcohol and narcotic drugs
Theraputic drugs

12. Infection caused by
Bacteria
Rickettsiae
Viruses
Fungi
Protozoa
Metazoa
Parasites

13. Immunity is a double edged word :
Hypersensitivity reactions
Anaphylatic reactions
Autoimmune diseases

14. Nutritional deficiency diseases :
deficiency of nutrients ( eg. Starvation), of protein
calorie ( eg. Marasmus, kwashiorkor)
Of minerals ( eg. Anaemia)
Nutritional excess
Obesity
Atterosclerosis
Heart disease
Hypertension

15. Mental stress
Strain
Anxiety
Overwork
Frustration

16. Reversible cell injury
Irreversible cell injury

17. HYPOXIA/ISCHAEMIA
↓ ATP
↓ Intercellular pH
(cytosol)
Damaged sodium
pump
(membrane)
↓ Protein
synthesis (RER)
Ultrastructural/Functional Changes
REVERSIBLE CELLINJURY

18. 2 essential features:
Inability of the cell to reverse mitochondrial
dysfunction
Disturbance in cell membrane function
In addition: depletion of proteins, leakage of
lysosomal enzymes into cytoplasm, reduced
intracellular pH and further reduction inATP.

19. Continued hypoxia leads to influx of large amount of
Calcium ions.
Normal Ca ions – in ECF 10-3 M (millimoles)
Cytosole 10-7 M
Leads to mitochondrial dysfunction
Morphological mitochondrial changes:
 Vacuoles in mitochondria
 Deposition of amorphous Ca in mitochondrial matrix.

21. Mechanism:
Accelerated degradation of membrane phospholipids.
Cytoskeletal damage
Toxic oxygen radicals
Hydrolytic enzymes
Serum estimation of liberated intracellular enzymes

23. MEMBRANE DAMAGE
Nuclear changes
(Pyknosis, Karyolysis,
Karyorrhexis)
Cell Death
(myelin figures)
Serum enzyme
estimation ( SGOT,
LDH)
Libration of intacellular enzymes

26. See Ch. 1, p. 9,
Fig. 1-9

27. MECHANISMS OF CELL INJURY
ATP DEPLETION : failure of energy dependent functions-
reversible injury-necrosis
MITOCHONRIAL DAMAGE: ATP depletion-failure of energy
dependent functions- ultimately, necrosis; under some conditions,
leakage of proteins that cause apoptosis
INFLUX OF CALCIUM: activation of enzymes that damage
cellular components and may also trigger apoptosis
ACCUMULATIN OF REACTIVE OXYGEN SPECIES: covalent
modification of cellular proteins, lipids, nucleic acids
INCREASED PERMEABILITY OF CELLULAR
MEMBRANES: may affect plasma membrane, lysosomal
membranes, mitochondrial membranes; typically culminates in
necrosis
ACCUMULATION OF DAMAGED DNA AND MISFOLDED
PROTEINS: triggers apoptosis

29. MORPHOLOGY OF CELL INJURY
REVERSIBLE CELL INJURY-
The two main morphologic correlates of reversible cell injury are cellular
swelling and fatty change.
-Cellular swelling is the result of energy-dependent ion pumps in the plasma
membrane, leading to an inability to maintain ionic and fluid homeostasis.
-Fatty change occur in hypoxic injury and various forms of toxic or metabolic
injury.
It is manifested by the appearance of small or large lipid vacuoles in the
cytoplasm.
OTHER MORPHOLOGIC FEATURES:-
-Membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of
ER, and eosinophilia ( due to decreased cytoplasmic RNA)

30. Cell death is a state of irreversible
injury
In living body it may occur as:
Local or focal change (autolysis, necrosis and
apoptosis)
Changes that follow( gangrene and pathologic
calcification)
End of life ( somatic death)

31. -Necrotic cells are unable to maintain membrane integrity, and
their contents often leak out.
-The enzymes responsible for digestion of the cell are derived
either from the lysosomes of the dying cells themselves or from
the lysosomes of leukocytes that are recruited as part of the
inflammatory reaction to the dead cells.

33. Disintegration of the cell by its own
hydrolytic enzymes liberated from lysosomes
It is rapid in some tissues rich in hydrolytic
enzymes such as pancreas and gastric mucosa.
Morphologically , autolysis is identified by :
 Homogeneous and eosinophilic cytoplasm
 Loss of cellular details
 Remains of cell as debris

34. Defined as- focal death along
with degradation of tissue by
hydrolytic enzymes librated by
cells, accompanied by
inflammation.
2 essential features:
Cell digestion by lytic
enzymes
Denaturation of proteins

35. Morphologic changes in
necrosis:
Cytoplasmic
 Homogenous and intensely eosinophilic
 Occasionally: vacuolation or dystrophic calcification
Nuclear
 Pyknosis- condensation of nuclear chromatin
 Karyolysis – undergo dissolution
 Karyorrhexis- fragmentation into many clumps

36. 5 types :
Coagulative necrosis
Liquefaction (colliquative) necrosis
Caseous necrosis
Fat necrosis
Fibrinoid necrosis

37. Most common type
Caused by irreversible focal injury, mostly from sudden
cessation of blood flow (ischaemia)and less often from
bacterial and chemical agents
Organs affected are: heart, kidney and spleen.

38. Foci of coagulative necrosis:
In early stages: pale, firm,
and slightly swollen.
With progression: become more
yellowish, softer, and shrunken.

39. Hallmark of coagulative
necrosis: conversion of normal
cells into their ‘tombstones’ i.e.
outlines of the cells are retained
so that the cell type can still be
recognised but their cytoplasm
and nuclear details are lost.
Necrosed cells are swollen and
appear more eosinophillic than
normal

40. InfarctKidney
Theaffected area on right shows cells with intensely eosinophilic cytoplasmof
tubular cells but the outlines of tubules are still maintained.
Thenuclei show granular debris.
Theinterface between viable and non-viable area shows nonspecific chronic
inflammation and proliferating vessels
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41. Microscopic changes are the result of:
 Denaturation of proteins
 Enzymatic digestion of the cell.
Eventually, the necrosed focus is infiltrated by
inflammatory cells and
The dead cells are phagocytosed leaving
granular debris and fragments of cells.

42. It occurs commonly due to ischaemic injury and
bacterial or fungal infections.
It occurs due to degradation of tissue by the
action of powerful hydrolytic enzymes.
Common eg. Infarct brain and abscess cavity.

43. Morphology
• Gross
– Theaffected area is soft with liquefiedcentre
containing necrotic debris.
– Later, acyst wall isformed.
• Microscopically,
– the cystic spacecontains necrotic cell debrisand
macrophages filled with phagocytosedmaterial.
– Thecyst wall is formed by proliferating capillaries,
inflammatory cells, and gliosis (proliferating glialcells)
in the caseof brain
– proliferating fibroblasts in the caseofabscesscavity
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44. LIQUEFACTIONNECROSIS
Liquefactivenecrosisbrain
Thenecrosed area on right side of the field showsa
cystic spacecontaining cell debris, while thesurrounding
zoneshowsgranulation tissue andgliosis.
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45. Found in the centre of foci of tuberculous
infection.
It is a combined feature of coagulative and
liquefactive necrosis.

46. Foci of caseous necrosis, as the
name implies, resemble dry
cheese and are soft, granular and
yellowish.
This appearence is partly
attributed to the histotoxic
effects of lipopolysaccharides
present in the capsule of the
tubercle bacilli, Mycobacterium
tuberculosis.

47. The necrosed foci are
structureless, eosinophilic and
contain granular debris.
The surrounding tissue shows
characteristic granulomatous
iflammatory reaction
consisting of epitheloid cells
with interspersed giant cells of
langhan’s or foreign body type
and peripherally lymphocytes.

48. CASEOUSNECROSIS
Caseous necrosis lymphnode
There is eosinophilic, amorphous, granular material, while the peripheryshows
granulomatous inflammation.
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49. It is a special form of cell death occurring at two
anatomically different locations but
morphologically similar lesions.
These are:
Following pancreatic necrosis
Traumatic fat necrosis commonly in breast

50. Fat necrosis in either of the 2 instances results in
hydrolylsis of neutral fat present in adipose
cells into glycerol and free fatty acids.
The damaged adipose cells assume cloudy
appearance when only free fatty remain
behind , after glycerol leaks out.
The leaked out free fatty acids, complex with Ca
to form Ca soaps (sponification)

51. FATNECROSIS
Fatnecrosis in acutepancreatitis.
Theareas of white chalky deposits represent foci of fat necrosis with
calcium soapformation (saponification) at sites oflipid breakdown in the
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52. Morphology
• Grossly
– fat necrosis appears as
yellowish-white andfirm
deposits.
– Formation of calcium
soapsimparts the
necrosed foci firmer and
chalky white appearance.
• Microscopically
– the necrosed fat cells
havecloudy appearance
– surrounded by an
inflammatory reaction.
Formation of calciumsoaps
is identified in the tissue
sections asamorphous,
granular andbasophilic
terialwww.facebook.com/notesde
mnta
al

53. It is characterized by the deposition of fibrin-
like material which has the staining properties of
fibrin.
It is encountered in various examples of
immunologic tissue injury (eg. Autoimmune
diseases, arthus reaction), artioles in
hypertension, peptic ulcer etc.

54. FIBRINOIDNECROSIS
Fibrinoidnecrosisin an artery in a patientwith polyarteritisnodosa.
Thewall of the artery shows acircumferential bright pink area of necrosis withprotein
deposition and inwfwlawm.facmebaootkio.conm(/dnoaterskdennutacllei of neutrophils).

55. Identified by brightly
eosinophilic, hyaline-like
deposition in the vessel
wall or on the luminal
surface of a peptic ulcer
Local haemorrhages may
occur due to rupture of
these blood vessels.

56. Apoptosis is a form of ‘coordinated and
internally programmed cell death’ which is of
significance in variety of physiologic pathologic
conditions.
Apoptosis in Greek meaning ‘falling off’ or
‘dropping off’.

57. Shrinking of cell : with dense cytoplasm and almost
normal organelles.
Convolution of cell membrane with formation of membrane-
bound near-spherical bodies called apoptotic bodies
containing compacted organelles.
Chromatin condensation around the periphery of nucleus
No acute inflammation.
Phagocytosis of apoptotic bodies by macrophages

58. Initiators of apoptosis
1. Absence of stimuli eg. Hormone, growth
factors, cytokines.
2. Activators of programmed cell death. Eg.
TNF receptors.
3. Intracellular stimuli eg. Heat, radiation,
hypoxia etc.
Regulators of apoptosis.eg. bcl-2, p53,
caspases, bax etc.

59. Progammed cell death.
1. Fas receptor activation- leads to activation of
caspase and subsequent proteolysis.
2. Ceramide generation- hydrolysis of plasma
membrane ceramide is generated which further
leads to mitochondrial injury.
3. DNAdamage-
 produced by various agents such as ionising radiation,
chemotherapeutic agents, activated oxygen species lead to
apoptosis
 DNA damage affects nuclear protein p53 which induces the
synthesis of cell death protein bax.

60. Phagocytosis
The dead apoptotic cells and their fragments
possess cell surfacereceptors which facilitate
their identification by adjucent phagocytes.

61. Initiators of apoptosis
(transmembrane, intracellar)
Regulators of apoptosis
(bcl-2, others)
Programmed cell death
Fas receptoractivation
(cytotoxic T cells)
DNA damage
(radiation,
chemotherapy,
free radicals
Caspases
ceramide
P53
Bax
Mitochondrial injury
DNAdamage
APOPTOSIS
PHAGOCYTOSIS
MECHANISM
OF
APOPTOSIS

63. 1. Development of embryo
2. Physiologic involution of cells in hormone-
dependent tissues eg. Endometrial shedding.
3. Normal cell destruction followed by
replacement proliferation eg. Intestinal
epithelium

64. 1. Cell death in tumor
2. Cell death by cytotoxic T cells.
3. Cell death in viral infections
4. Pathologic atrophy of organ and tissues on
withdrawal of stimuli eg. Atrophy of kidney or
salivary glandon obstruction of ureter or ducts
respectively.
5. Cell death in response to injurious agents involved
in causation of necrosis eg. radiation., hypoxia and
mild thermal injury
6. Pgrogressive depletion of CD4+ T cells inAIDS

67. Gangrene is a potentially life-threatening condition
caused by a critically insufficient blood supply
(necrosis).
This may occur after an injury or infection, or in
people suffering from any chronic health problem
affecting blood circulation.
The primary cause of gangrene is reduced blood
supply to the affected tissues, which results
in cell death.
Diabetes and long-term smoking increase the risk of
suffering from gangrene.

68. Dry
Wet
Gas
In either type of gangrene, coagulation necrosis
undergo liquefaction by the action of putrefactive
bacteria.

69. Dry gangrene is a form of coagulative
necrosis that develops in ischemic tissue, where the blood
supply is inadequate to keep tissue viable.
Dry gangrene is often due to peripheral artery disease, but can
be due to acute limb ischemia.
The limited oxygen in the ischemic limb
limits putrefaction and bacteria fail to survive.
The affected part is dry, shrunken and dark reddish-black.
The line of separation usually brings about complete
separation, with eventual falling off of the gangrenous tissue if
it is not removed surgically, a process called autoamputation.

70. Wet, or infected, gangrene is characterized by thriving
bacteria and has a poor prognosis (compared to dry gangrene)
due to septicemia resulting from the free communication
between infected fluid and circulatory fluid.
The tissue is infected by saprogenic microorganisms
eg.Clostridium perfringens or Bacillus fusiformis , which
cause tissue to swell and emit a fetid smell.
Wet gangrene usually develops rapidly due to blockage of
venous (mainly) and/or arterial blood flow.

71. The affected part is saturated
with stagnant blood, which
promotes the rapid growth of
bacteria.
The toxic products formed by
bacteria are absorbed, causing
systemic manifestation
of septicemia and finally death.
The affected part is edematous,
soft, putrid, rotten and dark

72. Gas gangrene is a bacterial
infection that produces gas within tissues.
It can be caused by Clostridium, most
commonly alpha toxin producing Clostridium
perfringens, or various non-clostridial species.
Infection spreads rapidly as the gases produced by
bacteria expand and infiltrate healthy tissue in the
vicinity.
Because of its ability to quickly spread to
surrounding tissues, gas gangrene should be treated
as a medical emergency.

73. Gas gangrene is caused by bacterial exotoxin-
producing clostridial species, which are mostly
found in soil.
These environmental bacteria may enter the muscle
through a wound and subsequently proliferate in
necrotic tissue and secrete powerful toxins.
These toxins destroy nearby tissue, generating gas at
the same time.
A gas composition of 5.9% hydrogen, 3.4% carbon
dioxide, 74.5% nitrogen, and 16.1% oxygen was
reported in one clinical case.
Progression to toxemia and shock is often very rapid.

74. Metastatic calcification is
deposition of calcium salts in
otherwise normal tissue,
because of elevated serum
levels of calcium.
Occur because of deranged
metabolism as well as increased
absorption or decreased
excretion of calcium and related
minerals, as seen in
hyperparathyroidism.

75. Dystrophic calcification is caused
by abnormalities or degeneration
of tissues resulting in mineral
deposition, though blood levels of
calcium remain normal.
Metastatic calcification is often
found in many tissues throughout
a person or animal, whereas
dystrophic calcification is
localized.

76. References:-
• Robbinson's basic pathology 8 ed
• HarshMohan - Textbook of
Pathology 6thEd.
• Color atlas of pathology