This document discusses various types of cell injury and cell death. It describes how cells transition from a normal state to a reversibly injured state to irreversibly injured and eventually dead through apoptosis or necrosis. The main causes of cell injury are oxygen deprivation, physical or chemical agents, infections, immune reactions, genetics, and nutritional imbalances. The key mechanisms of injury are ATP depletion, mitochondrial damage, calcium dysregulation, oxidative stress, membrane damage, and DNA/protein damage. Different patterns of necrosis like coagulative, liquefactive, and caseous are described. Apoptosis and other forms of programmed cell death like necroptosis are also outlined. Intracellular accumulations in various diseases are briefly discussed.

1. Adapted
Cell
+ Stress
Injury
Normal
cell
Reversibly
injured cell
Irreversibly
Injured cell
Dead cell
Apoptosis
Necrosis
- Stress
Overview

4. Cell injury
If the limits of adaptive responses are exceeded or
if cells are exposed to injurious agents or
stress, deprived of essential nutrients or
become compromised by mutations
that affect essential cellular constituents
a sequence of events follows that is termed cell
injury

5. Causes of Cell Injury......
Oxygen Deprivation
Physical Agents
Chemical Agents and Drugs
Infectious Agents
Immunologic Reactions
Genetic Derangements
Nutritional Imbalances

6. Oxygen Deprivation
Hypoxia – deficiency of oxygen
Ischemia – loss of blood supply (arterial
flow or reduced venous drainage)
Causes of Cell Injury

7. Physical Agents
Mechanical trauma
Extremes of temperature – burns, deep
cold
Radiation
Electric shock
Causes of Cell Injury

8. Chemical Agents and Drugs
 Hypertonic concentration of salt –
deranging electrolyte homeostasis
 Poisons – arsenic, cyanide, or mercuric salts
 Insecticides and Herbicides
 Air pollutant – carbon monoxide
 Occupational hazard – asbestos
 Alcohol and Narcotic drugs
Causes of Cell Injury

9. Infectious Agents
Parasites
Fungi
Bacteria
Rickettsiae
Viruses
Causes of Cell Injury

10. Immunologic Reactions
Anaphylactic reaction to foreign
protein or drug
Reactions to endogenous self-antigens
– autoimmune diseases
Causes of Cell Injury

11. Genetics Derangements
Congenital malformation – Down
syndrome
Decreased life of red blood cell –
Thalassemia, Sickle cell anemia
Inborn errors of metabolism
Causes of Cell Injury

12. Nutritional Imbalances
Protein-calorie deficiencies
Vitamin deficiencies
Anorexia nervosa
Excesses of lipids – Obesity,
Atherosclerosis
Metabolic diseases – Diabetes
Causes of Cell Injury

13. Mechanisms of Cell Injury
 Depletion of ATP
 Mitochondrial Damage
 Influx of Intracellular Calcium and Loss of
Calcium Homeostasis
 Accumulation of Oxygen-Derived free
radical (Oxidative stress)
 Defects in Membrane Permeability
 Damage to DNA and Proteins

14. Mechanisms of Cell Injury
Depletion of ATP
Na+K+ATPase (Na-pump)
Ca2+Mg2+ATPases (Ca-pump)
Causes
 Hypoxia, Ischemia
 Chemical Injury
Membrane
transport
Protein synthesis,
Lipogenesis etc
ATP

15. Na
+ K+
Ca2+
Mechanisms of Cell Injury
Depletion of ATP

16. Mitochondrial Damage
Mechanisms of Cell Injury
Causes
 Hypoxia, Toxins
 Cytosolic Ca2+
 Oxidative stress (ROS)

17. Mitochondrial Damage
Mechanisms of Cell Injury
• Mitochondrial permeability transition pore
(formation of high-conductance channel)
• Leakage of Cytochrome c into cytosol
•Abnormal oxidative phosphorylation and ROS
formation.
ATP production
Mitochondrial Oxidative Phosphorylation

18. Mechanisms of Cell Injury
Mitochondrial
Damage

19. Influx of Intracellular Calcium
and Loss of Calcium Homeostasis
Mechanisms of Cell Injury
 Opening of mitochondrial permeability transition
pore and failure of ATP generation.
 Activation of many enzymes with potentially
deleterious effects on cells.
 Induction of apoptosis by direct activation of caspases
and by increasing mitochondrial permeability.

20. Mechanisms of Cell Injury

21. Accumulation of Oxygen-Derived
Free Radicals (Oxidative Stress)
 The Oxidation-Reduction reaction (normal
metabolic processes)
-superoxide anion (O2 , ONE ELECTRON)
-hydrogen peroxide (H2O2, TWO ELECTRON)
-hydroxyl ion (OH ,Three electrons)
Mechanisms of Cell Injury

22. Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
 Absorption of radiant energy (ultraviolet light, X-ray)
Mechanisms of Cell Injury
H20
Ionizing radiation
OH H

23. Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
 Transition Metals – iron, copper
Mechanisms of Cell Injury
H202 OH-
OH
Fe3+
Fe2+
“Fenton reaction”

24. Continue……
 Rapid brust of ROS production in activated
leukocytes during inflammation.
 Enzymatic metabolism of exogenous chemicals or
drugs generate free radicals. (ccl4 generate .ccl3 )
 Nitric oxide can act as free radical which generated
by macrophages, endothelial cells, neurons.

25. Effects of the free radicals on cell injury
 Lipid peroxidation of Membranes
- Plasma membrane
- Organellar membrane
Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Double bonds in unsaturated fatty acids
membrane damage

26. Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Effects of the free radicals
 Oxidative modification of proteins
-Oxidation of amino acid side chains
Protein-protein cross-linkages
-Oxidation of the protein backbone
Protein fragmentation
 Damage active sites of enzymes
 Disrupts structural conformation of proteins
 Enhances protein degradation

27. Accumulation of Oxygen-Derived Free
Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Effects of the free radicals
 Lesions in DNA
 DNA single and double-strand break
Cross linking of DNA strand
DNA fragmentation

28. Superoxide dismutase
(SOD)

31. Defects in Membrane Permeability
 Decreased phospholipid synthesis Mitochondrial
dysfunction or hypoxia
 Increased phospholipid breakdown by phospholipases
 Cytoskeletal abnormalities by proteases activation
 Reactive oxygen species Lipid peroxidaton
Mechanisms of Cell Injury
Mechanism of Membrane damage

32. Cellular and biochemical sites of damage in
cell injury

33. Cell Injury
Cell Injury – Reversible
– Irreversible
Cell Death – Necrosis
– Apoptosis

34. Morphology of Cell Injury
 Plasma membrane alteration
 Mitochondrial Changes
 Dilation of Endoplasmic reticulum
 Nuclear Alteration
Reversible Injury
 Cellular swelling
 Fatty change

36. Cellular swelling
Normal Liver cells
Swollen Liver cells

37. Necrosis
Necrosis refers to a spectrum of morphologic changes
that follow cell death in living tissue largely resulting
from the denaturation of intracellular proteins and
enzymatic digestion of lethally injured cell.

38. Morphology of Necrotic Cells
 Increased Eosinophilia
- loss of RNA (basophilia)
- denatured cytoplasmic protein
 Nuclear Changes
- Pyknosis
- Karyorrhexis
- Karyolysis
 Myelin figure : From damaged cell membrane
– large, whorled phospholipid mass

39. Nuclear change
 Karyolysis: Basophilia of chromatin fade due to loss
of DNA.
 Pyknosis : Nuclear shrinkage and increased
basophilia.
 Karyorrhexis: Fragmentation of pyknotic nucleus.

40. Morphologic pattern of Necrotic Cell
 Coagulative necrosis
 Liquefactive necrosis
 Gangrenous necrosis
 Caseous necrosis
 Fat necrosis
 Fibrinoid necrosis

41. Morphologic pattern of Necrotic Cell
 Coagulative Necrosis: Architecture of dead
tissue preserved.
– protein denatures
– proteolysis inhibited
Esonophilic , anucleated cells persists.
Example: Ischaemia leads to coagulative
necrosis in all organs except brain.

42. This is an example of coagulative necrosis. This is the typical pattern
with ischemia and infarction (loss of blood supply and resultant tissue
anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis
(infarction) in the renal cortex of the kidney.

43. Ischemic necrosis of the myocardium
A, Normal myocardium.
B, Myocardium with coagulation necrosis

44. Morphologic pattern of Necrotic Cell
 Liquefactive Necrosis : Digestion of dead cells and
transformation of tissue into liquid viscous mass.
 Focal bacterial (or fungal) infections
Accumulation of inflammatory cells and enzymes
liberation necrotic materials is creamy yellow
called PUS.
 Hypoxic death of cells within CNS

45. The liver shows a small abscess here filled with many neutrophils.
This abscess is an example of localized liquefactive necrosis

46. Coagulative and Liquefactive necrosis
A, Kidney infarct exhibiting coagulative necrosis
B, A focus of liquefactive necrosis in the kidney

47. Morphologic Pattern of Necrotic Cell
 Caseous necrosis:
 Example: Tuberculous infection
 Gross appearance: cheese like ( friable white like)
 Microscopic – Structureless collection of lysed cells
and amorphous granular debris enclosed within a
inflammatory border GRANULOMA

48. A tuberculous lung with a large area of caseous
necrosis

49. Tuberculous granuloma showing an area of central
necrosis, epithelioid cells, multiple Langhans’-type
giant cells, and lymphocytes.

50. Fat Necrosis
Acute pancreatitis :
Resulting from release of activated pancreatic lipases
Lipase split TG into FA
Fat saponification
( FA combines with calcium to produce chalky white
areas)

51. Foci of fat necrosis with saponification in the
mesentery

52. Gangrenous Necrosis
 Typically coagulative necrosis
 Generally occurs in lower limb due to
ischaemia.
 Bacterial infection cause liquefactive
necrosis called wet gangrene.

53. Fibrinoid Necrosis
Special form of necrosis
Occur in immune reactions involving
blood vessels
Immune complexs together with fibrin
leaked out of vessels
Bright pink amorphous appearance.

55. Ischemic injury

56. Mechanisms of Cell Injury
Ischemic injury

57. Figure: Sequence of
events leading to fatty
change and cell necrosis
in carbon tetrachloride
(CCl4) toxicity. RER,
rough endoplasmic
reticulum; SER,
smoothendoplasmic
reticulum.
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Chemical
injury

58. Ischemic- Reperfusion injury
How it occurs?
 Oxidative stress: Generation of ROS
Intracellular calcium overload
Inflammation : Cytokines release
Complement activation

59. Apoptosis
 Pathway of Cell death that is induced by a tightly
regulated suicide program in which cells destined to
die activate intrinsic enzymes that degrade cells own
nuclear DNA and nuclear and cytoplasmic proteins.
“Programmed Cell Death”
 Causes of Apoptosis
- Physiologic situations
- Pathologic conditions

60. Morphology of
Apoptosis
Cell shrinkage
Chromosome
condensation
Formation of
cytoplasmic blebs
and apoptotic
bodies
Phagocytosis of
apoptotic cells or
cell bodies

61. Apoptosis in Physiologic Situations
 Programmed destruction of cell during
embryogenesis
 Hormone-dependent involution
- endometrial cells (menstrual cycle)
 Cell deletion in proliferating cell population
 Death of host cells - neutrophils
 Elimination of self reactive lymphocyte

62. Apoptosis in Pathologic Conditions
 Cell death produced by injurious stimuli – radiation,
cytotoxic drug
 Accumulation of misfolded proteins ER stress
 Cell injury in certain viral diseases – viral hepatitis
 Pathologic atrophy
 Cell death in tumors, transplants rejection

64. Mitochondrial pathway

65. Dysregulated apoptosis
Defective apoptosis and increased cell survival:
 Malignancy
 Autoimmune disorder
Increased apoptosis and excessive cell death:
 Neurodegenerative diseases
Ischemic injury
Death of virus infected cells

66. Necroptosis
Hybrid form of cell death that shares aspects of both
necrosis and apoptosis.
 Morphologically resembles necrosis but
mechanistically it is genetically programmed cell
death.
 Programmed necrosis
Caspase independent programmed cell death but
dependent on RIP1 and RIP3 complex signaling.

67. Examples of necroptosis
 Formation of mammalian bone growth plate.
 Cell death in steatohepatitis, acute pancreatitis,
reperfusion injury, neurodegenerative dieases.
 Host defense against certain virus: cytomegalovirus.
Pyroptosis
 Another programmed cell death occurs in cells infected by
microbes.
 Accompanied by release of fever inducing cytokine IL-1
and it bears some similarities with apoptosis.
 Activation of caspase-1 and generates IL-1 and cause cell
death.

69. Intracellular Accumulations
Manifestation of “metabolic derangements” characterized
by intracellular accumulation of abnormal amounts of
various substances that may be harmless or varying degrees
of injury.
Types:
Normal cellular component: water, lipid, proteins,CHO.
Abnormal substance:
 Exogenous: Minerals or infected agents products
 Endogenous: Abnormal metaboloic products.

70. Mechanisms of
intracellular
accumulations
(1)abnormal
metabolism
(2)alterations in protein
folding and transport
(3)deficiency of critical
enzymes
(4)inability to degrade
phagocytosed
particles

71. Lipids
 Accumulation of Lipids
- Triglycerides
- Cholesterol/ Cholesterol ester
- Phospholipid
A. Steatosis (fatty change)
Abnormal accumulation of triglycerides within liver
parenchymal cells
– fatty liver in chronic alcoholism

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Lipid accumulation

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Fatty liver

74. Lipids
B. Cholesterol and Cholesterol Esters:
Atherosclerosis : Accumulation of cholesterol-laden
macrophage (foam cell) and smooth muscle cells in
the intima of aorta and arteries .
Cholesterolosis : Accumulation of foam cells in the
lamina propria of gallbladder.
Xanthomas: Foam cells in subepithelial connective
tissue of skin and tendons.
Niemann-Pick diseases type –C: Choleserol
accumulation in multiple organs.

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76. Proteins
Accumulation of protein droplets in proximal renal
tubule : Renal disease
 Defective intracellular transport and secretion of
protein : Alpha 1 antitrypsin deficiency.
 Accumulation of cytoskeletal proteins: Keratin,
vimentin
 Abnormal proteins aggregation : Amyloidosis

77. Protein reabsorption droplets in the renal tubular
epithelium.
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© 2005 Elsevier

78. Glycogen
“Patients with abnormal metabolism of glucose or
glycogen”
 Diabetes mellitus: disorder of glucose metabolism
- glycogen accumulate in epithelial cells of
renal tubules,
liver cells,
beta-cells of the islets of Langerhans
heart muscle cells

79.  Glycogen storage disease (Glycogenosis)
- genetic diseases
- defect of enzymes in the synthesis or breakdown
of glycogen accumulation cell injury death
Glycogen

80. Pigments
 Exogenous pigments
Carbon ( anthracosis)
Coal dust ( pneumoconiosis)
Tattooing: Localized exogenous pigmentation.

81. Pigments
 Endogenous pigment
Lipofuscin – Insoluble pigment ,found in liver and
heart of aging patients or severe malnutrition.
Melanin – Brown black colour
Hemosiderin – Golden yellow colour

82. Pathologic Calcification
Abnormal tissue deposition of Calcium
Salts
Two forms
1. Dystrophic calcification
2. Metastatic calcification

83. Pathologic Calcification
 Dystrophic Calcification
- Area of tissue necrosis
- Aging or damage heart valve
- Atherosclerosis

84.  Metastatic Calcification
Occur in normal tissue in “hypercalcemia”
Site : Gastric mucosa, kidneys, lungs,
systemic arteries, pulmonary veins.
Pathologic Calcification
Hypercalcemia
• Hyperparathyroidism
• Resorption of bone tissue
• Renal failure
•Vitamin D related disorder

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