2. When the cell is exposed to an injurious
agent or stress, a sequence of events follows
that is loosely termed as cell injury.
Cell injury is reversible up to a certain
point, but if the stimulus persists or is
severe enough from the beginning, the
cell reaches to a point of no return and
suffers irreversible cell injury and ultimately
cell death.
Cell death, is the ultimate result of cell injury
3. There are two principal patterns of cell death, necrosis and
apoptosis.
Necrosis is the type of cell death that occurs after ischemia
and chemical injury, and it is always pathological.
Apoptosis occurs when a cell dies through activation of an
internally controlled suicide program.
4.
5. Earliest changes associated with cell injury are reversible. They
are:
1. Swelling & vacuolization of cytoplasm called hydropic/
vacuolar degeneration.
2. Mild mitochondrial swelling, the rough endoplasmic reticulum
and plasma membrane damage.
3. Defect in protein synthesis.
4. Mild eosinophilia of cytoplasm (due to decrease in cytoplasmic
RNA)
Within limits, the cell can compensate for these derangements and,
if the injurious stimulus is removed the damage can be reversed.
6. Persistent or excessive injury, however, causes cells to pass the
threshold into irreversible injury. Irreversible injury is marked by
1. severe mitochondrial damage with the appearance of large,
amorphous densities in mitochondria.
2. Severe plasma/cell membrane damage
3. Increased eosinophilia
4. Numerous myelin figures
5. Rupture of lysosomes leakage and enzymatic digestion of cellular
contents
6. Nuclear damage:
i. pyknosis (shrinkage),
ii. karyolysis (dissolution)
iii. karyorrhexis (break down)
7.
8.
9.
10. • Epithelial cells stain evenly
pink (eosinophilic) in
cytoplasm, with purple,
basophilic, nucleic acids
confined to the nuclei
• Apical surfaces are
ciliated
• Interstitia is not
infiltrated with
immune cells nor
congested with
proteins
11. • Increased eosinophilic staining
• Decreased basophilic staining in
nucleus
• Plasma membrane rounding,
blebbing, loss of cilia, due to
loss of connections with
cytoskeleton
• Integrity of tubules is degrading,
but basement membranes are
intact
• Nuclei largely intact, slightly
narrowed, pyknotic
12. • Cellular
fragmentation
• Loss and fading of
nuclei—karyolysis ( due
to loss of DNA)
• Burst membranes
• Loss of tissue
architecture
13. Cellular swelling (synonyms: hydropic change, vacuolar degeneration, cellular edema) is an acute reversible
change resulting as a response to nonlethal injuries. It is an intracytoplasmic accumulation of water due to
incapacity of the cells to maintain the ionic and fluid homeostasis. It is easy to be observed in parenchymal
organs : liver (hepatitis, hypoxia), kidney (shock), myocardium (hypoxia, phosphate intoxication). It may be
local or diffuse, affecting the whole organ.
14.
15. Causes of both reversible and irreversible injury are the same. They are:
1) Oxygen Deprivation (Hypoxic cell injury). It common cause of cell injury and cell
death. Hypoxia can be due to
a) Ischemia (obstruction of arterial blood flow), E.g. in myocardial infarction and
atherosclerosis.
b) Inadequate oxygenation of the blood e.g. lung disease and carbon monoxide
poisoning
c) Decreased oxygen-carrying capacity of the blood e.g. anemia
d) Inadequate tissue perfusion due to cardiorespiratory failure, hypotension, shock
etc
Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or
die. Also some cell types are more vulnerable to hypoxic injury then others e.g.
neurons are most susceptible followed by cardiac muscle, hepatocytes and then
skeletal muscles.
16. 2)Physical Agents e.g. mechanical trauma, burns and
deep cold, sudden changes in atmospheric pressure,
radiation, and electric shock
3)Chemical Agents and Drugs e.g. oxygen in high
concentrations, poisons, pollutants, insecticides,
industrial and occupational hazards, alcohol and
narcotic drugs and therapeutic drugs.
4)Infectious Agents
5) Immunologic agents e.g. thyroid damage caused
by autoantibodies.
6) Genetic Derangements eg sickle cell anemia.
7) Nutritional Imbalances
17. 1. Depletion of ATP
2. Cell membrane damage/defects in membrane permeability:
3. Mitochondrial damage:
It is seen specially in hypoxic injury and cyanide poisoning.
4. Ribosomal damage:
It is seen in alcohol damage of liver cells and with antibiotic use.
5. Nuclear and DNA damage:
6. Influx of intracellular calcium leading to loss of normal calcium balance:
ischemia causes an increase in intracellular calcium concentration. Increased
Ca2+ in turn activates a number of enzymes which cause damage.
7. Free radical injury
18.
19.
20. Increased cytosolic calcium and
ROS causes mitochondrial
injury
Mitochondrial damage and ER
swelling releases cytochrome
c, to cytosol.
Hydrolytic enzymes are
activated causing apoptosis
or necrosis.
21.
22. Free radical injury: Accumulation of oxygen-derived free radicals (oxidative stress):
Free radicals are highly reactive and harmful atoms that have single unpaired
electron in an outer orbit. They are referred to as reactive oxygen species/free
radicals. The free radicals are produced in our cells through several ways, called as
the free radical generating systems. They are produced via:
i. Normal metabolism/ respiration: Small amounts of harmful reactive oxygen is
produced as a bi-product of mitochondrial respiration during normal respiration
(reduction-oxidation reactions that occur in normal metabolism).
ii. Ionizing radiation injury e.g. UV light, x-rays result in production of free radicals.
iii. Chemical toxicity: enzymatic metabolism of exogenous chemicals or drugs.
iv. Oxygen therapy and reperfusion injury
v. Immune response or inflammation (neutrophil oxidative burst)
vi. Transition metals such as iron and copper can trigger production.
The common free radicals are
superoxide anion radical (O2-),
hydrogen peroxide (H2O2),
and hydroxyl ions (OH).
Nitric oxide (NO) is an important chemical mediator generated by various cells and it
can also act as a free radical.
23. Free radicals cause damage to lipids, proteins, and nucleic acids. The main
damaging effects of these reactive species are:
1. Lipid peroxidation of membranes damage of membranes & organelles
etc.
2. Oxidative modification of proteins protein fragmentation.
3. DNA damage lead to cell aging and malignant transformation of cells.
Certain substances in the cells remove/ inactivate the free radicals in order to
minimize injury caused by them. They are called as the free radical scavenging
system. They are:
Antioxidants: vitamins E, A and C (ascorbic acid).
Enzymes: which break down hydrogen peroxide and superoxide anion e.g.
Catalase, Superoxide dismutases, Glutathione peroxidase and
mannitol.
24.
25.
26.
27. The morphologic appearance of necrosis is the result of
denaturation of intracellular proteins and enzymatic digestion.
Necrotic cells are unable to maintain membrane integrity and
their contents often leak out, a process that may elicit
inflammation in the surrounding tissue.
The enzymes that digest the necrotic cell are derived from the
lysosomes of the dying cells themselves and from the
lysosomes of leukocytes that are called in, as part of the
inflammatory reaction.
Digestion of cellular contents and the host response may take
hours to develop. The earliest histologic evidence of necrosis
may not become apparent until 4 to 12 hours.
28. Pyknosis- characterized by nuclear shrinkage and increased
basophilia.
Karyorrhexis- the pyknotic nucleus undergoes fragmentation. With the
passage of time (a day or two), the nucleus
in the necrotic cell totally disappears.
Karyolysis- the basophilia of the chromatin
fades which appears to reflect loss of
DNA because of enzymatic
degradation by due to endonucleases.
29. Increased eosinophilia in hematoxylin and eosin (H & E) stains,
attributable in part to the loss of cytoplasmic RNA (which binds the blue
dye, hematoxylin) and in part to denatured cytoplasmic proteins (which
bind the red dye, eosin).
When enzymes have digested the cytoplasmic organelles, the cytoplasm
becomes vacuolated and appears moth-eaten.
Dead cells may be replaced by large, whorled phospholipid masses
called myelin figures that are derived from damaged cell membranes.
These phospholipid precipitates are then either phagocytosed by other
cells or further degraded into fatty acids; calcification of such fatty acid
residues results in the generation of calcium soaps. Thus, the dead cells
may ultimately become calcified.
31. Architecture of dead tissues is
preserved for a span of at least some
days.
Tissues exhibit a firm texture
Injury denatures proteins and enzymes
blocking proteolysis of the dead cells;
Eosinophilic, anucleate cells may
persist for days or weeks.
Ultimately the necrotic cells are
removed by phagocytosis of the
cellular debris by infiltrating
leukocytes.
32.
33. Digestion of the dead cells
Transformation of the tissue into a
liquid viscous mass.
The necrotic material is frequently
creamy yellow because of the
presence of dead leukocytes and is
called pus.
34.
35. Not a specific pattern.Term is
commonly used in clinical
practice.
Usually applied to a limb, generally the
lower leg, that has lost its blood supply
and has undergone, typically,
coagulative necrosis
Sepsis induced DIC has led to extensive
arterial thrombosis, resulting in profound tissue death.
36. “Caseous” (cheeselike) is derived from
the friable white appearance of the
area of necrosis
Necrotic area appears as a collection
of fragmented or lysed cells and
amorphous granular debris enclosed
within a distinctive inflammatory
border; this appearance is
characteristic of a focus of
inflammation known as a granuloma.
37. Focal areas of fat destruction, typically
resulting from release of activated
pancreatic lipases into the substance
of the pancreas and the peritoneal
cavity.
Lipases split the triglyceride esters
contained within fat cells. Free fatty
acids can combine with calcium to
produce grossly visible chalky-white
areas (fat saponification).
38.
39. Deposits of “immune complexes,”
(antigens and antibodies) together
with fibrin that has leaked out of
vessels, results in a bright pink and
amorphous apperance in H&E stains
(called as fibrinoid).
40. Programmed cell death
It occurs
– Especially during fetal development
– In response to hormonal cycles (e.g. endometrium)
– Normal turnover in proliferating tissues (e.g. intestinal
epithelium)
Cells shrink, not swell
Nuclei condense and DNA fragments
Cells fragment into membrane-bound bits
Bits are phagocytosed by macrophages
41. In this fetal thymus there is involution of
thymic lymphocytes by the mechanism
of apoptosis. In this case, it is an
orderly process and part of normal
immune system maturation. Individual
cells fragment and are consumed by
phagocytes to give the appearance of
clear spaces filled with cellular debris.
Apoptosis is controlled by many
mechanisms. Genes such as BCL-2
are turned off and Bax genes turned
on. Intracellular proteolytic enzymes
called caspases produce much cellular
breakdown.
42.
43.
44.
45.
46. Normally, growth factors and other survival signals
stimulate the production of anti-apoptotic proteins
such as BCL2, BCL-XL and MCL,thus rotecting from
apoptosis.
When cells are deprived of survival signals, suffer
DNA damage, or develop ER stress due to
accumulation of misfolded proteins, BH-3 only
proteins (apoptosis initiator) are upregulated
through increased transcription and post –
transcriptional modifications.
Apoptosis initiators are BAD, BIM, BID, Puma and
Noxa.
47. Regulated apoptosis initiators,
activate pro-apoptotic family
members, BAX and BAK, which
form oligomers that insert into
mitochondrial membrane and
allow proteins from the inner
mitochondrial membrane to leak
out into the cytoplasm and they
block the function of BCL2 and
BCL-XL.
The mitochondrial proteins,
further cause release of
cytochrome C into the cytosol.
Cytochrome C binds to protein
called APAF-1 (apoptosis-
activating factor-1) which further
activates the Caspase-9 and lead
to Apoptosis.
48. This pathway is initiated by engagement of
– plasma membrane death receptors. These
are members of tumor Necrosis Factor
(TNF) receptor family. (which contain
cytoplasmic domain involved in protein-
protein interections.
Type 1 TNF –are the best known death
receptors and a related proteinis called Fas
(CD95).
The ligand for Fas is called Fas ligand(FasL),
which is expressed on Tcells.
When FasL binds to Fas, three or more
molecules of Fas are brought together and
their cytoplasmic death domains form a
binding site for an adaptor protein called
FADD (Fas-associated death domain).
FADD actives pro caspase-8 and caspase
10 , which initiate the executioner caspases
sequence, leading to apoptosis.
The extrinsic pathway can be inhibited by
protein called FLIP.
