1. CELL INJURY, APOPTOSIS
AND NECROSIS

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. 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. CAUSES OF CELL INJURY -
THE PATIENT’S VIEW
• Hypoxia
• Infectious agents
• Physical injury
• Chemicals/drugs
• Immune response
• Genetic derangement
• Nutritional imbalance

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. 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. Direct Physical Action
Major problems are
hemorrhage &
ischemia

8. INFECTIOUS DISEASE
Primary HerpesCandidiasis
Tuberculosis Actinomycosis

9. PHYSICAL INJURY
Thermal Burn Traumatic ulcer

10. CHEMICAL/DRUG INJURY
Gingival
Hyperplasia
Asprin Burn

11. GENETIC DERANGEMENTS
Down's Syndrome
Ehlers-Danlos
Cancer

12. NUTRITIONAL IMBALANCE
Diabetes
Scurvy

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. 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. 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

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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

19. 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

20. 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

21. 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

22. 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

23. 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

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25. 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

26. Changes in the cytoplasm:
i. Swelling and granularity of the
cytoplasm
ii. Loss of cellular membrane
iii. Fusion of cells

27. 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.

28. TYPES OF NECROSIS

29. 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

31. (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.

32. 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.

33. Lung Abscess: Microscopic appearance
(Liquefactive Necrosis)

34. (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..

35. Caseous necrosis with
granulomatous inflammation
T.B LUNG :
(Large Area Of Caseous Necrosis)
AREA ,YELLOW-WHITE
AND CHESSY

36. (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.

38. (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

40. (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.

41. 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.

42. (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.

43. “Dry Gangrene”
"wet gangrene in patient
with Diabetes millitus”

44. 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.

45. FOURNIER'S GANGRENE
• Fournier's gangrene, bacterial gangrene
of the scrotum (the dreaded "black sack
disease")

47. 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.

50. •ROBBIN’S BASIC PATHOLOGY, 7TH
EDD, MAJOR