CELL INJURY, APOPTOSIS
AND NECROSIS
CONCEPTS IN CELL INJURY
• Cell injury results from a disruption of one
or more of the cellular components that
maintain ce...
CONCEPTS IN CELL INJURY
• Cell injury may be reversible, result in cell
adaptation, or lead to cell death.
• Injury at one...
CAUSES OF CELL INJURY -
THE PATIENT’S VIEW
• Hypoxia
• Infectious agents
• Physical injury
• Chemicals/drugs
• Immune resp...
• Ischemia ("ischemic hypoxia"; "stagnant
hypoxia"): Loss of arterial blood flow (* literally,
"holding back the blood")
•...
Hypoxemia: Too little available oxygen in the blood
Oxygen problems ("hypoxic hypoxia")
Too little oxygen in the air
Failu...
Direct Physical Action
Major problems are
hemorrhage &
ischemia
INFECTIOUS DISEASE
Primary HerpesCandidiasis
Tuberculosis Actinomycosis
PHYSICAL INJURY
Thermal Burn Traumatic ulcer
CHEMICAL/DRUG INJURY
Gingival
Hyperplasia
Asprin Burn
GENETIC DERANGEMENTS
Down's Syndrome
Ehlers-Danlos
Cancer
NUTRITIONAL IMBALANCE
Diabetes
Scurvy
Reversible Injury
• Mitochondrial oxidative phosphorylation is
disrupted first  Decreased ATP 
– Decreased Na/K ATPase ...
HYPOXIA - ISCHEMIA MODEL
Impaired function of the
plasma membrane
ATP-dependent
Na+ pump
⇑Na+ influx
⇑Ca++ influx
⇑K+ effl...
Irreversible Injury
• Mitochondrial swelling with formation of
large amorphous densities in matrix
• Lysosomal membrane da...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Cell Injury
• Membrane damage and loss of calcium
homeostasis are most crucial
• Some models of cell death suggest that
a ...
Clinical Correlation
• Injured membranes are leaky
• Enzymes and other proteins that escape
through the leaky membranes ma...
Reactive oxygen and nitrogen species ROS/RNS
Free radical – each molecule or its fragment, which can exists independently
...
Free Radicals
• Free radicals have an unpaired electron in
their outer orbit
• Free radicals cause chain reactions
• Gener...
Examples of Free Radical Injury
• Chemical (e.g., CCl4, acetaminophen)
• Inflammation / Microbial killing
• Irradiation (e...
Mechanism of Free Radical Injury
• Lipid peroxidation  damage to cellular
and organellar membranes
• Protein cross-linkin...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
IRREVERSIBLE CELL INJURY
Definition:
Necrosis is local death of cells while the individual is a life
followed by morpholog...
Changes in the cytoplasm:
i. Swelling and granularity of the
cytoplasm
ii. Loss of cellular membrane
iii. Fusion of cells
Nuclear changes:
Occur due to hydrolysis of
nucleoproteins:
i. Pyknosis i.e. the nucleus becomes shrunken
condensed and de...
TYPES OF NECROSIS
The variable types of necrosis differ as regards
causes, gross and microscopic pictures.
(1) Coagulative necrosis:
It is m...
(2) Liquifactive necrosis
The necrosed tissue undergoes rapid softening
e.g. infarction of the nervous tissue which has
ab...
The two lung abscesses
seen here are examples
of liquefactive necrosis in
which there is a liquid
center in an area of
tis...
Lung Abscess: Microscopic appearance
(Liquefactive Necrosis)
(3) Caseous necrosis:
• It is characteristic of tuberculosis. The necrotic
tissue undergoes slow partial liquefaction form...
Caseous necrosis with
granulomatous inflammation
T.B LUNG :
(Large Area Of Caseous Necrosis)
AREA ,YELLOW-WHITE
AND CHESSY
(4) Fat necrosis
it is necrosis of adipose tissue including
two types:
a) Traumatic: caused by trauma to
adipose tissue e....
(5) Fibrinoid necrosis
This is characterized by swelling,
fragmentation, increased eosinophilia of
collagen fibers and acc...
(6) Zenker’s necrosis:
Of the rectus abdominus muscle and
diaphragm as a complication of :
bacterial infection particula...
Gangrene
• Gangrene is defined
as the gradual
destruction of living
tissue, due to an
obstruction in the
supply of blood a...
(7) Gangrenous necrosis:
The tissue in this case have undergone
ischaemic cell death and coagulative
necrosis followed by ...
“Dry Gangrene”
"wet gangrene in patient
with Diabetes millitus”
CLOSTRIDIAL GANGRENE
• (including "gas gangrene"), a dread
complication of dirty, blood-deprived
wounds. The clostridia di...
FOURNIER'S GANGRENE
• Fournier's gangrene, bacterial gangrene
of the scrotum (the dreaded "black sack
disease")
Apoptosis
Definition:
• It is programmed death of cells in living tissues. It is
an active process differing from necrosis...
•ROBBIN’S BASIC PATHOLOGY, 7TH
EDD, MAJOR
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
Cell injury, apotosis and necrosis(1)
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Cell injury, apotosis and necrosis(1)

  1. 1. CELL INJURY, APOPTOSIS AND NECROSIS
  2. 2. CONCEPTS IN CELL INJURY • Cell injury results from a disruption of one or more of the cellular components that maintain cell viability. • Cell injury is common to all pathologic processes.
  3. 3. CONCEPTS IN CELL INJURY • Cell injury may be reversible, result in cell adaptation, or lead to cell death. • Injury at one point induces a cascade of effects.
  4. 4. CAUSES OF CELL INJURY - THE PATIENT’S VIEW • Hypoxia • Infectious agents • Physical injury • Chemicals/drugs • Immune response • Genetic derangement • Nutritional imbalance
  5. 5. • Ischemia ("ischemic hypoxia"; "stagnant hypoxia"): Loss of arterial blood flow (* literally, "holding back the blood") • Local causes – Occlusion of the arteries that bring in fresh blood – Occlusion of the veins which allow blood to leave, so that fresh blood can flow in – Shunting of arterial blood elsewhere ("steal syndromes"; "Robin Hood" syndromes) • Systemic causes – Failure of the heart to pump enough blood
  6. 6. Hypoxemia: Too little available oxygen in the blood Oxygen problems ("hypoxic hypoxia") Too little oxygen in the air Failure to properly ventilate the lungs Failure of the lungs to properly oxygenate the blood Failure of the heart to pump enough blood through the lungs Tremendously increased dead space (i.e., pulmonary thromboembolus) Hemoglobin problems ("anemic hypoxia") Inadequate circulating red cell mass ("anemia") Inability of hemoglobin to carry the oxygen (carbon monoxide poisoning, methemoglobinemia) "High affinity" hemoglobins that will not give up their oxygen to the tissues
  7. 7. Direct Physical Action Major problems are hemorrhage & ischemia
  8. 8. INFECTIOUS DISEASE Primary HerpesCandidiasis Tuberculosis Actinomycosis
  9. 9. PHYSICAL INJURY Thermal Burn Traumatic ulcer
  10. 10. CHEMICAL/DRUG INJURY Gingival Hyperplasia Asprin Burn
  11. 11. GENETIC DERANGEMENTS Down's Syndrome Ehlers-Danlos Cancer
  12. 12. NUTRITIONAL IMBALANCE Diabetes Scurvy
  13. 13. Reversible Injury • Mitochondrial oxidative phosphorylation is disrupted first  Decreased ATP  – Decreased Na/K ATPase  gain of intracellular Na  cell swelling – Decreased ATP-dependent Ca pumps  increased cytoplasmic Ca concentration – Altered metabolism  depletion of glycogen – Lactic acid accumulation  decreased pH – Detachment of ribosomes from RER  decreased protein synthesis • End result is cytoskeletal disruption with loss of microvilli, bleb formation, etc
  14. 14. HYPOXIA - ISCHEMIA MODEL Impaired function of the plasma membrane ATP-dependent Na+ pump ⇑Na+ influx ⇑Ca++ influx ⇑K+ efflux ⇑ H2O influx Cellular swelling Membrane blebs and loss of villi ER swelling
  15. 15. Irreversible Injury • Mitochondrial swelling with formation of large amorphous densities in matrix • Lysosomal membrane damage  leakage of proteolytic enzymes into cytoplasm • Mechanisms include: – Irreversible mitochondrial dysfunction  markedly decreased ATP – Severe impairment of cellular and organellar membranes
  16. 16. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  17. 17. Cell Injury • Membrane damage and loss of calcium homeostasis are most crucial • Some models of cell death suggest that a massive influx of calcium “causes” cell death • Too much cytoplasmic calcium: – Denatures proteins – Poisons mitochondria – Inhibits cellular enzymes
  18. 18. Clinical Correlation • Injured membranes are leaky • Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum
  19. 19. Reactive oxygen and nitrogen species ROS/RNS Free radical – each molecule or its fragment, which can exists independently And contains one or two unpaired electrons Reactive oxygen species - species, which contain one or more oxygen atoms and are much more reactive than molecular oxygen ROS/RNS Free radicals superoxide radical hydroperoxyl radical hydroxyl radical nitric oxide hydrogen peroxide
  20. 20. Free Radicals • Free radicals have an unpaired electron in their outer orbit • Free radicals cause chain reactions • Generated by: – Absorption of radiant energy – Oxidation of endogenous constituents – Oxidation of exogenous compounds
  21. 21. Examples of Free Radical Injury • Chemical (e.g., CCl4, acetaminophen) • Inflammation / Microbial killing • Irradiation (e.g., UV rays  skin cancer) • Oxygen (e.g., exposure to very high oxygen tension on ventilator) • Age-related changes
  22. 22. Mechanism of Free Radical Injury • Lipid peroxidation  damage to cellular and organellar membranes • Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins • DNA damage due to reactions of free radicals with thymine
  23. 23. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  24. 24. IRREVERSIBLE CELL INJURY Definition: Necrosis is local death of cells while the individual is a life followed by morphological changes in the surrounding living tissue, (cell placed immediately in fixative are dead but not necrotic). Causes of cell necrosis: most common causes of cell death are viruses, ischaemia, bacterial toxins, hypersensitivity, and ionizing radiation. Morphologic change in necrosis: The changes don’t appear in the affected cells by light microscopy before 2-6 hours according to the type of the affected tissue. NECROSIS
  25. 25. Changes in the cytoplasm: i. Swelling and granularity of the cytoplasm ii. Loss of cellular membrane iii. Fusion of cells
  26. 26. Nuclear changes: Occur due to hydrolysis of nucleoproteins: i. Pyknosis i.e. the nucleus becomes shrunken condensed and deeply stained. ii. Karyorrhexis: rupture of nuclear membrane with fragmentation of the nucleus. iii. Karyolysis: the nucleus dissolves and disappears. Finally the affected tissue changes to homogeneous eosinophilic mass with nuclear debris.
  27. 27. TYPES OF NECROSIS
  28. 28. The variable types of necrosis differ as regards causes, gross and microscopic pictures. (1) Coagulative necrosis: It is mainly caused by sudden ischaemia e.g. infarction of heart, kidney and spleen. The protein of the affected tissue becomes denaturated. Grossly, it appears dry pale opaque. It is triangular ? subcapsular with the base towards the capsule of the affected organ. This is due to the fan like distribution of the supplying blood vessels. The infarct area is surrounded by narrow zone of inflammation and congestion. Microscopically, the structural outline of the affected tissue is preserved but the cellular details are lost. TYPES OF NECROSIS
  29. 29. (2) Liquifactive necrosis The necrosed tissue undergoes rapid softening e.g. infarction of the nervous tissue which has abundant lysosomal enzymes. Also, this type of necrosis occurs in case of suppurative inflammation (Abscess) where liquefaction occurs under the effect of proteolytic enzymes of PNLs liquefaction of the amoebic abscess occurs due to the effect of strong proteolytic enzymes and hyaluronidase secreted by E. Histolytica. Grossly: the affected tissue appears as homogenous amorphous substance. Microscopically: it appears as homogenous eosinophilic structure.
  30. 30. The two lung abscesses seen here are examples of liquefactive necrosis in which there is a liquid center in an area of tissue injury. One abscess appears in the upper lobe and one in the lower lobe. Liquefactive necrosis is typical of organs in which the tissues have a lot of lipid (such as brain) or when there is an abscess with lots of acute inflammatory cells whose release of proteolytic enzymes destroys the surrounding tissues.
  31. 31. Lung Abscess: Microscopic appearance (Liquefactive Necrosis)
  32. 32. (3) Caseous necrosis: • It is characteristic of tuberculosis. The necrotic tissue undergoes slow partial liquefaction forming yellow cheesy material. • Microscopically, it shows amorphous granular eosinophilic material lacking the cell outlines. • Unlike coagulative necrosis, the necrotic cells do not retain their cellular outlines, and do not disappear by lysis, as in liquifactive necrosi • Grossly, the caseous material resembles clumpy cheese, hence the name caseous necrosis. • The cause of necrosis in TB is hypersensitivity reaction caused by the tuberculoprotein content of the cell wall of Mycobacterium..
  33. 33. Caseous necrosis with granulomatous inflammation T.B LUNG : (Large Area Of Caseous Necrosis) AREA ,YELLOW-WHITE AND CHESSY
  34. 34. (4) Fat necrosis it is necrosis of adipose tissue including two types: a) Traumatic: caused by trauma to adipose tissue e.g. breast and subcutaneous tissue. b) Enzymatic: which occurs in case of acute haemorrhagic pancreatitis. Obstruction of the pancreatic duct leads to release of lipase which splits the fat cells of the omentum into fatty acid (combine with Ca giving chalky white calcification) and to glycerol which is absorbed in the circulation.
  35. 35. (5) Fibrinoid necrosis This is characterized by swelling, fragmentation, increased eosinophilia of collagen fibers and accumulation of mucopolysaccharides and fibrin due to vascular exudation of fibrinogen at the site of lesion, e.g.: a) Collagen diseases (Rheumatic fever, Rheumatoid, Sclerodermia, Lupus erythematosus and Polyarteritis nodosa). b) In the wall of blood vessels in malignant hypertension
  36. 36. (6) Zenker’s necrosis: Of the rectus abdominus muscle and diaphragm as a complication of : bacterial infection particularly typhoid fever. The striated muscles lose its striation, swell and fuse together in homogeneous structureless mass.
  37. 37. Gangrene • Gangrene is defined as the gradual destruction of living tissue, due to an obstruction in the supply of blood and oxygen to an area of the body (Pipkin and Janelli, 2000) Obstruction of the blood supply to the bowel is almost followed by gangrene.
  38. 38. (7) Gangrenous necrosis: The tissue in this case have undergone ischaemic cell death and coagulative necrosis followed by liquifactive action of putrefactive organisms. When coagulative pattern is dominant the process is termed dry gangrene. When the liquifactive action of the bacteria is more pronounced it is called wet gangrene.
  39. 39. “Dry Gangrene” "wet gangrene in patient with Diabetes millitus”
  40. 40. CLOSTRIDIAL GANGRENE • (including "gas gangrene"), a dread complication of dirty, blood-deprived wounds. The clostridia digest tissue enzymatically and rapidly, often transforming it into a bubbly soup.
  41. 41. FOURNIER'S GANGRENE • Fournier's gangrene, bacterial gangrene of the scrotum (the dreaded "black sack disease")
  42. 42. Apoptosis Definition: • It is programmed death of cells in living tissues. It is an active process differing from necrosis by the following points: • Occurs in both physiological and pathological conditions. • Starts by nuclear changes in the form of chromatin condensation and fragmentation followed by cytoplasmic budding and then phagocytosis of the extruded apoptotic bodies. • Plasma membrane are thought to remain intact during apoptosis until the last stage so does not initiate inflammatory reaction around it.
  43. 43. •ROBBIN’S BASIC PATHOLOGY, 7TH EDD, MAJOR

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