Cell injury

1. CELLULAR INJURY
DATE OF PRESENTATION:
By
Dr. D. VAMSHIKRISHNA, MD (H).

2. CELL INJURY
• Cell injury is defined as the effect of a variety
of stresses due to etiologic agents a cell
encounters resulting in changes in its internal
and external environment.

3. STRESS
STRESS
STRESS
STRESS= ETIOLOGICAL AGENTS LIKE BACTERIA
CHANGES IN
INTERNAL AND
EXTERNAL
ENVIRONMENT
OF CELL
Effects
Affected
cell

4. STRESS
ALTERED FUNCTIONAL
DEMAND
MILD TO MODERATE STRESS
SEVERE STRESS AND
PERSISTANT STRESS
ADAPTATIONS
-ATROPHY
-HYPERTROPHY
-HYPERPLASIA
-DYSPLASIA
IRREVERSIBLE CELL
INJURY
-CELL DEATH
REVERSIBLE CELL INJURY
-DEGENERATIONS
-SUBCELLULAR
ALTERATIONS
-INTRACELLULAR
ACCUMULATIONS
CELLULAR RESPONSES TO CELL INJURY.

5. ETIOLOGY OF CELL INJURY
• The cells may be broadly injured by two major
ways:
• A. Genetic causes
• B. Acquired causes

6. ETIOLOGY OF
CELL INJURY
GENETIC CAUSES
ACQUIRED
CAUSES
1. Hypoxia and ischemia
2. Physical agents
3. Chemical agents and drugs
4. Microbial agents
5. Immunologic agents
6. Nutritional derangements
7. Ageing
8. Psychogenic diseases
9. Iatrogenic factors
10. Idiopathic diseases.

7. HYPOXIA AND ISCHEMIA
• Hypoxia is the most common cause of cell
injury
TWO REASONS
Reduced blood supply
to cells due to
interruption in blood
flow leading to
ischemia
Due to defects in oxygen
carrying RBC’S or due to
or HEART DISEASES,
LUNG DISEASES, due to
increased demand from
tissues.

8. INTERRUPTED BLOOD FLOW
ABNORMAL RBC’S
HEART DISEASES
LUNG DISEASES

9. PHYSICAL AGENTS
Physical agents in causation of disease are:
• Mechanical Trauma (e.g. Road Accidents)
• Thermal Trauma (e.g. By Heat And Cold)
• Electricity
• Radiation (e.g. Ultraviolet And Ionizing)
• Rapid Changes in atmospheric pressure

10. COLD TRAUMA
ELECTRICITY TRAUMA
HEAT TRAUMA
RADIATION TRAUMA

11. CHEMICALS AND DRUGS
- Chemical poisons such as cyanide, arsenic,
mercury.
- Strong acids and alkalis
- Environmental pollutants
- Insecticides and pesticides
- Oxygen at high concentrations
- Hypertonic glucose and salt
- Social agents such as alcohol and narcotic drugs
- Therapeutic administration of drugs.

12. MICROBIAL AGENTS
Injuries by microbes include
• Infections caused by bacteria, rickettsiae,
viruses, fungi, protozoa, metazoa, and other
parasites.

13. PSYCHOGENIC DISEASES
• There are no specific biochemical or
morphologic changes in common acquired
mental diseases due to mental stress, strain,
anxiety, overwork and frustration
• e.g. depression, schizophrenia.
• However, problems of drug addiction,
alcoholism, and smoking result in various organic
diseases such as liver damage, chronic bronchitis,
lung cancer, peptic ulcer, hypertension, ischemic
heart disease etc.

15. IMMUNOLOGIC AGENTS
Immunity is a ‘double-edged sword’:
• it protects the host against various injurious
agents but it may also turn lethal and cause
cell injury
e.g.
• Hypersensitivity reactions;
• Anaphylactic reactions; and
• Autoimmune diseases.

16. AGEING
• Cellular ageing or senescence leads to
impaired ability of the cells to undergo
replication and repair, and ultimately lead to
cell death culminating in death of the
individual.

17. PATHOGENESIS OF CELL INJURY

18. Objective of today's topic
• Types of Cell- injuries.
• Pathogenesis of Cell-injury
• Pathogenesis in Reversible and Irreversible
Hypoxic Cell-injury in particular
• Outcomes/Events in Reversible and
Irreversible Hypoxic Cell injury.

19. • Injury to the normal cell by one or more of the
above listed etiologic agents may result in a
state of
REVERSIBLE
CELL INJURY
IRREVERSIBLE
CELL INJURY
CELL REPAIR AND HEAL
CELL DEATH

20. OUTCOME OF THE CELL-INJURY DEPENDS ON:
OF TARGET CELL
TYPE,
DURATION,
SEVERITY
OF INJURIOUS AGENT
TYPE,
STATUS ,
ADAPTABILITY

21. Small Dose of Chemical/Physical Agent
REVERSIBLE CELL INJURY
Large Dose of Chemical/Physical Agent
IRREVERSIBLE CELL INJURY
BASED ON TYPE, DURATION, SEVERITY:

22. Short Duration of Ischemia
REVERSIBLE CELL INJURY
Long Duration of Ischemia
IRREVERSIBLE CELL INJURY

23. BASED ON TYPE, STATUS, ADAPTABILITY OF TARGET CELL:
IF A CELL IS HIGHLY SUSCEPTABLE TO HYPOXIA
EARLY CELL INJURY
EXAMPLE:
Skeletal muscle can withstand hypoxic injury for
long-time,
While cardiac muscle suffers Irreversible cell injury
if exposed to Hypoxia for > 20 mins

24. Skeletal Muscle Cardiac Muscle

25. PATHOGENESIS OF ISCHAEMIC AND
HYPOXIC INJURY

26. • Ischemia and hypoxia are the most common
forms of cell injury.
• It leads to
- REVERSIBLE CELL INJURY
- IRREVERSIBLE CELL INJURY

27. REVERSIBLE CELL INJURY IN HYPOXIA

28. • If hypoxia is of short duration -> the effects
may be reversible on rapid restoration of
circulation.
Example:
• In coronary artery occlusion, the myocardial
contractility, metabolism and ultra structure
are reversed if the circulation is quickly
restored

29. CORONARY ARTERY OCCLUSION

30. EVENTS IN REVERSIBLE CELL INJURY ARE:
1. DECREASED GENERATION OF CELLULAR ATP:
2. INTRACELLULAR LACTIC ACIDOSIS:
3. DAMAGE TO PLASMA MEMBRANE PUMPS:
4. REDUCED PROTEIN SYNTHESIS:

31. 1. DECREASED GENERATION OF CELLULAR ATP:
• All living cells require continuous supply of
oxygen to produce ATP which is essentially
required for a variety of cellular functions.
ATP is generated from:
- AEROBIC PATHWAY
- ANEROBIC PATHWAY

32. ATP in human cell is derived from 2 sources
Requires Oxygen
Takes place in the
mitochondria.
AEROBIC
RESPIRATION
Anaerobic
Glycolytic
oxidation
ATP is generated
from
Glucose/Glycogen
in the absence of
Oxygen
ANEROBIC
PATHWAY

33. COMPLETE ATP DEPLETION
BOTH OXYGEN AND GLUCOSE
SUPPLY IS COMPROMISED
SEVERE CELL INJURY
WITH INTERRUPTED BLOOD
SUPPLY
WITH DEFECTS IN OXYGEN
CARRYING RBC’S OR HEART OR
LUNG DISEASES
ONLY OXYGEN COMPROMISED
ATP IS GENERATED BY
ANEROBIC PATHWAY
CELL INJURY IS LESS

34. Cells which depend only
on Aerobic Respiration
for ATP generation
MYOCARDIUM CELLS
PROXIMAL TUBULAR
CELLS KIDNEYS
NEURONS OF CNS
Hence these
tissues suffer
more severely and
rapidly due to
hypoxia

35. Low oxygen supply to the cell
Mitochondria fails (No Oxygen No ATP generation)
Switches to Anaerobic Glycolytic Pathway for the requirement of ATP.
Accumulation of Lactic Acid
Decreased Intracellular pH.
Clumping of Nuclear Chromatin.
2. INTRACELLULAR LACTIC ACIDOSIS:

36. CHROMATIN CLUMPING

37. 3. DAMAGE TO PLASMA MEMBRANE PUMPS

38. DECREASED A.T.P
Decreased Production of PHOSPHOLIPIDS(ATP)-Dependent Sodium pump
FAILURE
Repair of Cell membrane is stopped
Increased accumulation of
Na in cell
Swelling of Cell
(HYGROPIC SWELLING)
Membrane damage
Calcium influx into cell
(Particularly mitochondria)
Swelling of Mitochondria
(Amorphous densities)

39. Swelling of
Mitochondria
HYGROPIC SWELLING

40. Endoplasmic
Reticulum
Golgi apparatus
4. REDUCED PROTEIN SYNTHESIS:

41. Membranes of endoplasmic
Reticulum and Golgi apparatus
swell up.
Ribosomes are
detached from granular (rough)
endoplasmic reticulum
Reduced protein synthesis

42. Other changes:
•Loss of Microvilli and Intramembranous particles
•Focal projections of the cytoplasm (blebs).
•Myelin figures may be seen lying in the cytoplasm

43. Note:
Up to this point,
withdrawal of acute stress
that resulted in reversible cell injury
can restore the cell to normal state.

44. IRREVERSIBLE CELL INJURY
IN HYPOXIA/ISCHEMIA

45. Persistence of ischemia (i.e., reduced
blood flow to a tissue/organ) or hypoxia
Irreversible damage to the structure and function of the cell
Even after reperfusion with oxygen
i.e., CELL DEATH
Continuous ↓ in ATP,
↓ in Proteins,
↓ intracellular pH, and
leakage of lysosomal enzymes into the plasma.

46. CHANGES IN IRREVERSIBLE CELL INJURY ARE:
1. CALCIUM INFLUX
2. ACTIVATED PHOSPHOLIPASES
3. INTRACELLULAR PROTEASES
4. ACTIVATED ENDONUCLEASES
5. LYSOSOMAL HYDROLYTIC ENZYMES

47. 1. CALCIUM INFLUX
Due to continued hypoxia - Large cytosolic influx of calcium ions occurs
(Esp. after reperfusion of irreversibly injured cell)
Vacuoles Formation in the Mitochondria
Deposition of amorphous calcium salts in the mitochondrial matrix
VACUOLES

48. 2. ACTIVATED PHOSPHOLIPASES:
Increased cytosolic influx of calcium into the cell
Activation of endogenous phospholipases
Damage to phospholipids layer of Cell membrane
Damage to membrane function

49. phospholipids bilayerPhospholipid

50. 3. INTRACELLULAR PROTEASES
Activated Intracellular Proteases
(released by Lysosomes)
Digestion of cytoskeleton of cell
Cytoskeleton Damage

52. 4. ACTIVATED ENDONUCLEASES
Activated lysosomal enzymes such as Proteases and Endonucleases.
Damage to DNA/Nuclear proteins
1- PYKNOSIS:
Condensation and
clumping of nucleus
2- KARYORRHEXIS:
Nuclear Fragmentation
Into small bits
3- KARYOLYSIS:
Dissolution of Nucleus
Three types of nuclear damage can happen:

53. 5. LYSOSOMAL HYDROLYTIC ENZYMES
Lysosomal Membrane Damage
Escape of lysosomal hydrolytic enzymes into cell medium
Activation of hydrolytic enzymes by low pH and Low oxygen
Enzymatic digestion of cellular components
CELL DEATH
DEAD CELLS PHAGOCYTOSED BY MACROPHAGES

54. Lysosomes
Hydrolytic enzymes
Digestion of cell organelles

55. Lysosome enzymes:
• Hydrolase,
• RNAase,
• DNAase,
• Protease,
• Glycosidase,
• Phosphatase,
• Lipase,
• Amylase.

56. COMMON ENZYME MARKERS IN SERUM FOR DIFFERENT
FORMS OF CELL DEATH:
ENZYME DISEASE
Aspartate aminotransferase
(AST, SGOT)
Viral Hepatitis, Alcoholic Liver Disease
Acute Myocardial Infarction
Alanine aminotransferase
(ALT, SGPT)
More specific for diffuse liver cell damage
than AST e.g. Viral Hepatitis
Creatine Kinase-MB
(CK-MB)
Acute Myocardial Infarction, Myocarditis
Lipase More specific for acute pancreatitis
Amylase Acute Pancreatitis
Sialadenitis
Lactic dehydrogenase
(LDH)
Acute Myocardial Infarction
Myocarditis
Skeletal muscle injury
Cardiac troponin (CTn) Specific for Acute Myocardial Infarction

57. Objectives of today topic
- Learn the Morphological forms seen in
Reversible Cell Injury and Irreversible cell
Injury

58. MORPHOLOGY OF REVERSIBLE CELL INJURY

59. Morphologic Forms Of Reversible Cell Injury:
• 1. Hydropic change
• 2. Hyaline change
• 3. Mucoid change
• 4. Fatty change

60. 1. HYDROPIC CHANGE/DEGENERATION
• Accumulation of water within the cytoplasm
of the cell.
• Synonym= CLOUDY SWELLING , VACUOLAR
DEGENERATION (Due to cytoplasmic
vacuolation).
• It is entirely reversible.
• Commonest form in cell injury
• Earliest form in cell injury

61. Etiology:
- Hypoxia
- Microbes
- Chemicals agents
- Physical agents
- Etc…

62. • PATHOGENESIS
• Cloudy swelling results from impaired
regulation of sodium and potassium at the
level of cell membrane.

63. MORPHOLOGIC FEATURES:
• Grossly, the affected organ such as kidney, liver, pancreas,
or heart muscle is enlarged due to swelling.
• The cut surface bulges outwards and is slightly opaque.
MICROSCOPICALLY:
• The features of Hydropic swelling of kidney are as under
i) The tubular epithelial cells are swollen
ii) cytoplasm contains small clear vacuoles
iii) Small cytoplasmic blebs may be seen.

67. 2. HYALINE CHANGE/DEGENERATION
• The word ‘hyaline’ or ‘hyalin’ means glassy.
• Hyalinisation is a common descriptive
histologic term.
• It means glassy, homogeneous, eosinophilic
appearance of proteinaceous material in
haematoxylin and eosin-stained sections.
• It does not refer to any specific substance.

68. • Hyaline change is seen in heterogeneous
pathologic conditions and may be intracellular
or extracellular.

69. INTRACELLULAR HYALINE
• Intracellular hyaline is mainly seen in
epithelial cells.
A few examples are as follows:
1. Hyaline droplets in the proximal tubular
epithelial cells due to excessive reabsorption
of plasma proteins in proteinuria.

70. Hyaline droplets in proximal tubular epithelial cells

71. 2. Hyaline degeneration of rectus abdominalis
muscle called Zenker’s degeneration,
occurring in typhoid fever.
Zenker’s degeneration

72. 3. Mallory’s hyaline/Mallory bodies- seen in the
hepatocytes in alcoholic liver cell injury.

73. 4. Russell’s bodies representing excessive
immunoglobulin in the rough endoplasmic
reticulum of the plasma cells
RUSSELL’S BODIES

74. EXTRACELLULAR HYALINE
• Extracellular hyaline commonly seen in
connective tissues.
• A few examples of extracellular hyaline change
are as under:

75. 1. Hyaline degeneration in leiomyomas of the
uterus

76. 2. Hyalinised old scar of fibrocollagenous
tissues.
3. Hyaline arteriolosclerosis in renal vessels in
hypertension and diabetes mellitus.

77. 3. MUCOID CHANGE/ DEGENERATION
• Mucoid means mucus-like
• Mucin (constituent of mucus) is a glycoprotein
normally produced by epithelial cells of
MUCUS MEMBRANES and MUCUS GLANDS
and by some CONNECTIVE TISSUE (CT) cells.
• The mucin produced by CT cells is called
MYXOID.

78. MUCUS GLANDS
MUCUS

79. What is Mucoid Degeneration?
• Excessive mucus production by the
- Epithelial cells of mucous membranes and
mucous glands (EPITHELIAL MUCIN)
- Connective tissues (CONNECTIVE TISSUE MUCIN)

80. EPITHELIAL MUCIN
Examples of functional excess of epithelial
Mucin:
1. Catarrhal inflammation of mucous
membrane (e.g. of respiratory tract,
alimentary tract).
2. Cystic fibrosis of the pancreas/Lungs.
3. Mucin-secreting tumors (e.g. of ovary,
stomach, large bowel etc)

81. RESPIRATORY TRACT CATARRAL INFLAMMATION
- EXCESS MUCUS PRODUCTION

82. CYSTIC FIBROSIS OF THE LUNGS.

83. CONNECTIVE TISSUE MUCIN
• Connective tissue mucin or myxoid change are
as under:
1. Mucoid or myxoid change in some tumours
like fibroadenoma.
2. Myxomatous change in the dermis in
Myxoedema.

84. MYXOEDEMA

85. 4. FATTY DEGENERATION (STEATOSIS)
• Intracellular accumulation of neutral fat
within parenchymal cells.
• Fatty change is particularly common in the
liver but may occur in other non-fatty tissues
as well e.g. in the heart, skeletal muscle,
kidneys (lipoid nephrosis) and other organs.

86. FATTY LIVER

87. MORPHOLOGY OF IRREVERSIBLE CELL INJURY
(CELL DEATH)

88. • Cell death is a state of irreversible injury.
LOCALLY
1- AUTOLYSIS
2- NECROSIS
3- APOPTOSIS
CHANGES FOLLOWING
LOCAL CHANGE
1- GANGRENE
2- CALCIFICATION
PROCESSES INVOLVED IN
CELL DEATH

89. AUTOLYSIS (self-digestion)
• Disintegration of the cell by its own hydrolytic
enzymes liberated from Lysosomes
RAPID
in tissues rich in
hydrolytic
enzymes-
PANCREAS,
GASTRIC
MUCOSA
INTERMEDIATE
in tissues like the
HEART, LIVER AND
KIDNEY
SLOW
in fibrous tissue.
PACE OF AUTOLYSIS

90. NECROSIS
• Necrosis is defined as a localized area of death
of tissue followed later by
degradation/breakdown of tissue by
hydrolytic enzymes liberated from dead cells;
it is invariably accompanied by inflammatory
reaction.

91. NECROSIS
DEAD
TISSUE
INFLAMMATION
DEGRADATION
/BREAKDOWN
OF TISSUE by
HYDROLYTIC
ENZYME

92. ETIOLOGICAL AGENTS:
- Hypoxia,
- Chemical
- Physical agents
- Microbial agents
- Immunological etc…

93. 5 TYPES OF NECROSIS:
• Coagulative
• Liquefaction (Colliquative)
• Caseous
• Fat
• Fibrinoid Necrosis
Based on
Etiology and
Morphologic
appearance

94. 1. COAGULATIVE NECROSIS
• Most common type of necrosis caused by
irreversible focal injury.
• Cause:
- From sudden cessation of blood flow
(ischemic necrosis)
- Less often from bacterial and chemical agents.
The organs commonly affected are the heart,
kidney, and spleen.

95. APPEARANCE
GROSSLY/MACROSCOPICALLY
- Pale
- Firm
- Slightly swollen
EARLY STAGE LATE STAGE
- Yellowish
- Softer
- Shrunken.
INFARCT

96. MICROSCOPICALLY
Hallmark of coagulative necrosis = ‘TOMB STONES’
i.e. outlines of the cells are retained and the cell type can still be
recognized but their cytoplasmic and nuclear details are lost.

97. OTHER FINDINGS MICROSCOPICALLY:
• Nuclear changes of pyknosis, karyorrhexis and
karyolysis
• Cell digestion and liquefaction fail to occur.
• Eventually, the necrosed focus is infiltrated by
inflammatory cells and the dead cells are
phagocytosed leaving granular debris and
fragments of cells

98. 2. LIQUEFACTION (COLLIQUATIVE) NECROSIS
• Due to ischemic injury and bacterial or fungal
infections
• Liquefaction is due to Hydrolytic enzymes.
• The common examples are infarct brain and
abscess cavity.

99. • Grossly, the affected area is soft with
liquefied centre containing necrotic debris.
Later, a cyst wall is formed.

100. • Microscopically, the cystic space contains
necrotic cell debris and macrophages filled
with phagocytosed material.
• The cyst wall is formed by
- Proliferating capillaries,
- Inflammatory cells, and
- Gliosis (proliferating glial cells) in the case of
brain and
• Abscess cavity
- Proliferating fibroblasts

102. 3. CASEOUS NECROSIS
• Caseous (caseous= cheese-like) necrosis is
found in the centre of foci of tuberculous
infections.
• It combines features of both coagulative and
liquefactive necrosis.

104. 4. FAT NECROSIS
• Fat necrosis is a special form of cell death
occurring at mainly fat-rich anatomic locations
in the body.
• Examples are:
1. Traumatic fat necrosis of the breast,
2. Mesenteric fat necrosis due to acute
pancreatitis.

105. TRAUMATIC FAT NECROSIS OF BREAST

106. MESENTERIC FAT NECROSIS

107. • In fat necrosis:
HYDROLYSIS AND RUPTURE OF ADIPOCYTES
CHANGES INTO GLYCEROL & FREE FATTY
ACIDS.
Free fatty acids complex with
Calcium to form CALCIUM SOAPS
(SAPONIFICATION)
Release of neutral fat

108. SAPONIFICATION
Fat necrosis appears as yellowish-white and
firm Deposits.
Formation of calcium soaps imparts the
necrosed foci FIRMER AND CHALKY WHITE
APPEARANCE.

109. 5. FIBRINOID NECROSIS
• Fibrinoid necrosis is characterized by deposition
of fibrin-like material which has the staining
properties of fibrin such as phosphotungistic acid
haematoxylin (PTAH) stain.
• It is encountered in various examples of
immunologic tissue injury.
• E.g.
- Immune Complex Vasculitis
- Autoimmune Diseases
- Arthus Reaction Etc

110. APOPTOSIS

111. • Apoptosis is a form of ‘coordinated and
internally programmed cell death’ .
• When the cell is not needed, pathway of cell
death is activated (‘cell suicide’).
• Unlike necrosis, apoptosis is not accompanied
by any inflammation and collateral tissue
damage.

112. APOPTOSIS IN BIOLOGIC PROCESSES
1. Physiological apoptosis
2. Pathological apoptosis

113. Physiologic Processes:
1. Physiologic involution of cells in hormone-
dependent tissues e.g. endometrial shedding,
regression of lactating breast after
withdrawal of breast-feeding.
2. Normal cell destruction followed by
replacement proliferation such as in intestinal
epithelium.
3. Involution of the thymus in early age.

115. Pathologic Processes:
1. Cell death in tumors exposed to
chemotherapeutic agents.
2. Progressive depletion of CD4+T cells in the
pathogenesis of AIDS.
3. Pathologic atrophy of organs and tissues on
withdrawal of stimuli e.g. prostatic atrophy
after orchiectomy.

116. 5. Cell death in response to low dose of injurious
agent involved in causation of necrosis e.g.
radiation, hypoxia and mild thermal injury.
6. In degenerative diseases of CNS e.g. in
Alzheimer’s disease, Parkinson’s disease, and
chronic infective dementias.
7. Heart diseases e.g. in acute myocardial
infarction (20% necrosis and 80% apoptosis).

117. MOLECULAR MECHANISMS OF APOPTOSIS
Several physiologic and pathologic
processes activate apoptosis in a variety
of ways.
Molecular events involved in apoptosis:
1- INITIATORS OF APOPTOSIS
2- INTIAL STEPS IN APOPTOSIS
3- FINAL PHASE OF APOPTOSIS
4- PHAGOCYTOSIS

118. 1. Initiators of apoptosis:
• All cells have inbuilt effector mechanisms for
cell survival and signals of cell death.
• It is the loss of this balance that determines
survival or death of a cell.

119. A cell may be initiated to programmed cell
death by:
Withdrawal of normal cell
survival signals:
e.g. absence of certain
hormones, growth
factors, cytokines.
Agents of cell injury
e.g. Heat, Radiation, Hypoxia,
Toxins, Free Radicals.
OR

120. 2. Initial steps in apoptosis
After the cell has been initiated into self-destruct mode,
Cell death signaling mechanisms gets activated from
I. Intrinsic (mitochondrial) pathway
II. Extrinsic (cell death receptor initiated) pathway.
• However, finally mediators of cell death are activated
caspases.
• Caspases are a series of proteolytic or protein-splitting
enzymes which act on nuclear proteins and organelles
containing protein components.

121. Intrinsic (mitochondrial) pathway
Increased mitochondrial permeability activates this
pathway
Cytochrome- c (protein) released from mitochondria
into the cytoplasm of the cell
Cytochrome- c triggers the cell into apoptosis.
activates Caspases-9 APOPTOSIS

122. • The major mechanism of regulation of this
mitochondrial protein (Cytochrome- c) is by
pro-apoptotic and anti-apoptotic members
of Bcl proteins.

124. • BCL-2 is localized to the outer membrane of
mitochondria, where it plays an important
role in promoting cellular survival and
inhibiting the actions of pro-apoptotic
proteins.
BCL-2 proteins (Anti-apoptotic proteins)
Bad
Bim
BH3-only proteins (Pro- apoptotic proteins)

125. Extrinsic (cell death receptor initiated) pathway
It works by Activation of death receptors on the cell
membrane.
Cell Death Receptors are:
- Type 1 Tumour Necrosis Factor Receptor (TNF-
R1) and
- a related transmembrane protein called Fas
(CD95) and its ligand (FasL). (Fas belongs to TNF
Receptor family)

126. TNFR1
Receptor
TNF-α
(Death
Ligand)
Extracellular
Intracellular
Cell membrane
ADAPTER
Tumor Necrosis
Factor Receptor Type
1-associated Death
Domain (TRADD)
Activation of
Caspases 8 and 10
ADAPTER
Fas-associated
protein
Death domain
(FADD)
Fas
Receptor
FasL
(Ligand)
APOPTOSIS

127. 3. Final phase of apoptosis
• The activated caspases have proteolytic action
Proteolytic actions lead to
1. Nucleus damage
2. Chromatin clumping
3. Cytoskeleton damage
4. Disruption of endoplasmic reticulum
5. Mitochondrial damage
6. Disturbed cell membrane.
CELL DEATH

128. 4. Phagocytosis
Thrombospondin
molecules
Dead
Apoptotic
Cell
Phosphatidylserine
molecule
phagocyte
Phagocytosed dead cell

129. CHANGES AFTER CELL DEATH

130. • Two types of pathologic changes may
superimpose following cell injury:
1. Gangrene (after necrosis)
2. Pathologic calcification (after degenerations
as well as necrosis).

131. GANGRENE
• Gangrene is
- Necrosis of tissue
- associated with superadded Putrefaction
Combination of
- Coagulative necrosis, due to ischemia (dry
gangrene); and
- Liquefactive necrosis (wet gangrene) if a
bacterial infection is superimposed.

132. • There are 2 main types of gangrene:
1. Dry Gangrene
2. Wet Gangrene, and
- Gas gangrene- a variant of wet gangrene

133. Dry Gangrene
• This form of gangrene begins in the distal part of a
limb due to ischemia.
Seen in:
1. Severe atherosclerosis: causes dry gangrene in the
toes and feet of an old patient.

134. 2. Buerger’s disease (thrombosis of artery due
to smoking)
3. Ergot Poisoning.
4. Raynauds Disease.

135. • It is usually initiated in one of the toes which
is farthest from the blood supply,
• Dry gangrene is not accompanied by infection
(containing so little blood that even the
invading bacteria find it hard to grow in the
necrosed tissue)
• The gangrene spreads slowly upwards until it
reaches a point where the blood supply is
adequate to keep the tissue viable.

136. A line of separation is formed at this point between
the gangrenous part and the viable part

137. • MORPHOLOGIC FEATURES
DRY, SHRUNKEN AND DARK BLACK, resembling the foot of a mummy.
Hemoglobin + Hydrogen disulfide (H2S)
BLACK IRON SULFIDE.
(produced by bacteria)

138. The line of separation usually brings about complete
separation with eventual falling off of the gangrenous
tissue if it is not removed surgically (i.e. spontaneous
amputation)

139. Wet Gangrene
• Wet gangrene usually develops due to blockage
of both venous as well as arterial blood flow.
• More rapid.
• The affected part is saturated with stagnant
blood, which promotes the rapid growth of
bacteria.
• It is Dangerous: The toxic products formed by
bacteria are absorbed, causing systemic
manifestation of sepsis and finally death.

140. • Wet gangrene occurs in naturally moist
tissues and organs such as the bowel, lung,
mouth, cervix, vulva etc.
• The spreading wet gangrene generally lacks
clear-cut line of demarcation.

141. • Examples:
Diabetic foot which is due to high glucose
content in the necrosed tissue which
favors growth of bacteria.
Bed sores occurring in a bed-ridden
patient due to pressure on sites like the
sacrum, buttocks and heel.

142. • MORPHOLOGIC FEATURES
• Grossly: Soft, Swollen, Putrid, Rotten And Dark
• Dark black due to the same mechanism as in dry
gangrene.

144. GAS GANGRENE
• Gas gangrene is a bacterial infection that
produces gas in gangrene tissue.
• Caused by gas-forming clostridia: (anaerobic
bacteria)
• This deadly form of gangrene usually is caused
by Clostridium perfringens bacteria.

145. • Gross oedematous, painful and crepitant due to
accumulation of gas bubbles of carbon dioxide within
the tissues formed by fermentation of sugars by
bacterial toxins.
• Dark black and is foul smelling.

146. PATHOLOGIC CALCIFICATION
• Deposition of calcium salts in tissues other
than osteoid or enamel is called pathologic or
heterotopic calcification.
• Two distinct types of pathologic calcification:
1- Dystrophic calcification
2- Metastatic calcification

147. • Dystrophic calcification is characterized by
- deposition of calcium salts in dead or
degenerated tissues
- with normal calcium metabolism and normal
serum calcium level.
• Metastatic calcification, on the other hand,
occurs
- in apparently normal tissues and
- associated with deranged calcium metabolism
and hypercalcaemia.

148. DYSTROPHIC CALCIFICATION
• ETIOLOGY:
Dystrophic calcification may occur due to 2
types of causes:
1- Calcification in Dead tissue
2- Calcification in Degenerated tissue.

149. 1. Calcification in Dead tissue
• Caseous necrosis in tuberculosis is the most
common site for dystrophic calcification.
Living bacilli may be present even in calcified
tuberculous lesions

150. • Liquefaction necrosis in chronic abscesses
may get calcified.

151. • Fat necrosis following acute pancreatitis or
traumatic fat necrosis in the breast results in
deposition of calcium soaps.

152. • Gamna-Gandy bodies in chronic venous
congestion (CVC) of the spleen is characterized
by calcific deposits admixed with
haemosiderin on fibrous tissue.

153. • Infarcts may sometimes undergo dystrophic
calcification.

154. • Haematomas in the vicinity of bones may
undergo dystrophic calcification

155. • Dead parasites like in hydatid cyst,
Schistosoma eggs, and cysticercosis are some
of the examples showing dystrophic
calcification.

156. cysticercosis

157. • Microcalcification in breast cancer detected by
mammography.

158. 2. Calcification in Degenerated tissues
• Atheromas in the aorta and coronaries
frequently undergo calcification.

159. • Mönckeberg’s sclerosis shows calcification in
the degenerated tunica media of muscular
arteries in elderly people

160. • Calcinosis cutis is a condition of unknown
cause in which there are irregular nodular
deposits of calcium salts in the skin and
subcutaneous tissue

161. • Senile degenerative changes may be
accompanied by dystrophic calcification
• Eg: pineal gland calcification

162. Pathogenesis of Dystrophic calcification
In cell injury (Degeneration or Necrosis)
Phosphatases breaks phospholipids of cell
membrane and
this causes release of phosphatases
Damaged mitochondria increase
Uptake of calcium into it.
CALCIUM PHOSPHATES
Precipitates as CALCIUM PHOSPHATES

163. METASTATIC CALCIFICATION
• Since metastatic calcification occurs in normal
tissues due to hypercalcaemia include either
of the following two groups of causes:
1. Excessive mobilization of calcium from the
bone.
2. Excessive absorption of calcium from the
gut.

164. 1. Excessive mobilization of calcium from the
bone.
• Hyperparathyroidism:

165. • Prolonged immobilization of a patient results
in disuse atrophy of the bones and
hypercalcaemia.
• Bony destructive lesions such as multiple
myeloma.

166. 2. Excessive absorption of calcium from the gut.
• Less often, excess calcium may be absorbed
from the gut causing hypercalcaemia and
metastatic calcification.
• Causes:
- Hypervitaminosis D from excessive intake or
- Sarcoidosis
- 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.

167. • Sites of metastatic calcification:
• Metastatic calcification may occur in any
normal tissue of the body but preferentially
affects the following organs and tissues:
• Kidneys: especially at the basement
membrane of tubular epithelium and in the
tubular lumina causing nephrocalcinosis

168. • Lungs: especially in the alveolar walls
(Alveolar calcinosis)

169. Cornea Synovium

170. Pathogenesis of Metastatic Calcification
Rapid changes in pH levels at tissues
(of Lungs, Stomach, Kidney)
Elevated Calcium ions Inorganic phosphate Ions (in serum)
Excessive binding
Formation of CALCIUM PHOSPHATE
CALCIFICATION

171. • Metastatic calcification is reversible upon
correction of underlying metabolic disorder,
but Dystrophic calcification is not
reversible/Irreversible.