01-CELL INJURY 1.ppt for pathology it is easy

Pathology

1. CELL INJURY,

2. Cell Injury, Definitions
When the cell is exposed to an injurious agent or
stress, a sequence of events follows that is loosely
termed cell injury.
Cell injury is reversible up to a certain point
 If the stimulus persists or is severe enough from the
beginning, the cell reaches a point of no return and
suffers irreversible cell injury and ultimately cell
death.
Cell death, is the ultimate result of cell injury

3. Atrophy
There are some muscle fibres
here that show atrophy.
The number of cells is the
same as before the atrophy
occurred, but the size of some
fibres is reduced.
This is a response to injury by
"downsizing" to conserve the
cell.
In this case, innervation of the
small fibres in the centre was
lost.
This is a trichrome stain.

4. Hypertrophy
This is cardiac hypertrophy
involving the left ventricle.
The number of myocardial
fibres does not increase, but
their size can increase in
response to an increased
workload, leading to the
marked thickening of the left
ventricle in this patient with
systemic hypertension.

5. Hyperplasia
The prominent folds of
endometrium in this uterus
opened to reveal the
endometrial cavity are an
example of hyperplasia.
Cells forming both the
endometrial glands and the
stroma have increased in
number.
As a result, the size of the
endometrium has increased.
This increase is physiologic
with a normal menstrual cycle.

6. Metaplasia
Metaplasia of laryngeal
respiratory epithelium has
occurred here in a smoker.
The chronic irritation has led to
an exchanging of one type of
epithelium (the normal
respiratory epithelium at the
right) for another (the more
resilient squamous epithelium
at the left).
Metaplasia is not a normal
physiologic process and may
be the first step toward
neoplasia.

7. Dysplasia
This is dysplasia. The
normal cervical
squamous epithelium has
become transformed to a
more disorderly growth
pattern, or dysplastic
epithelium.
This is farther down the
road toward neoplasia,
but dysplasia is still a
potentially reversible
process.

8. Causes of Cell Injury
1) Oxygen Deprivation (Hypoxia). It is a common
cause of cell injury and cell death.
-Hypoxia can be due to :
A- inadequate oxygenation of the blood due to
Cardiorespiratory failure
B- loss of the oxygen-carrying capacity of the blood, as
in anemia or carbon monoxide poisoning.
Depending on the severity of the hypoxic state, cells
may adapt, undergo injury, or die.

9. Causes of Cell Injury cont.
2) Physical Agents :
- Mechanical trauma,
- Burns,
- Deep cold
- Sudden changes in atmospheric pressure,
- radiation, and electric shock

10. Causes of Cell Injury cont.
3) Chemical Agents and Drugs
-oxygen, in high concentrations
- poisons, such as arsenic, cyanide, or mercuric
salts
- environmental and air pollutants
- insecticides, herbicides, industrial and
occupational hazards
- alcohol and narcotic drugs and therapeutic
drugs

11. Causes of Cell Injury cont.
4) Infectious Agents e.g. bacteria, fungi,
viruses and parasites.
5) Immunologic Reactions.
6) Genetic Derangements.
7) Nutritional Imbalances

12. MECHANISM OF CELL INJURY
1.DEPLETION OF ATP:

. ATP depletion and decreased ATP synthesis
are associated with both hypoxic and
chemical (toxic) injury.
. ATP is required for many synthetic and
degradative processes within the cell.

13. MECHANISM OF CELL INJURY cont.
ATP is produced in two ways.
A- The major pathway is oxidative
phosphorylation of adenosine diphosphate.
B-The second is the glycolytic pathway, which
generate ATP in absence of oxygen using
glucose derived from body fluids or from
glycogen

14. MECHANISM OF CELL INJURY cont.
Effects of depleted ATP
a) The activity of the plasma membrane
energy-dependent sodium pump is reduced.
It causes sodium to accumulate
intracellularly and potassium to diffuse out of
the cell causing cell swelling, and dilation of
the endoplasmic reticulum.

15. MECHANISM OF CELL INJURY cont.
b) If oxygen supply to cells is reduced, as in
ischemia, oxidative phosphorylation ceases
and cells rely on glycolysis for energy
production (anaerobic metabolism) resulting in
depletion of glycogen stores. Glycolysis results
in the accumulation of lactic acid which
reduces the intracellular pH, resulting in
decreased activity of many cellular enzymes.

16. MECHANISM OF CELL INJURY cont.
c) Failure of the Ca2+ pump leads to influx of
Ca2+, with damaging effects on numerous
cellular components
d) Ribosomes detach from the RER and
polysomes breakdown into monosomes,
leading to reduction in protein synthesis.
Ultimately, irreversible damage to
mitochondrial and lysosomal membranes
occurs, and cell undergoes necrosis

17. MECHANISM OF CELL INJURY cont.

e) In cells deprived of oxygen or glucose,
proteins may become misfolded, and trigger
the unfolded protein response leading to cell
injury and even death.

18. MECHANISM OF CELL INJURY cont.
2- Mitochondrial Damage:
. Mitochondria are important targets for all
types of injury, including hypoxia and toxins.

19. MECHANISM OF CELL INJURY cont.
Mitochondria can be damaged by :
A- Increases of cytosolic Ca2+
B- Oxidative stress
C- Breakdown of phospholipids, and by
D- Lipid breakdown products.

20. MECHANISM OF CELL INJURY cont.
. Mitochondrial damage results in the formation of a
high-conductance channel, called mitochondrial
permeability transition, present in the inner
mitochondrial membrane. In the initial phase it is
reversible but once mitochondrial permeability
transition is irreversble it becomes a deathblow to
the cell.
Mitochondrial damage can also be associated with
leakage of cytochrome c into the cytosol.

21. MECHANISM OF CELL INJURY cont.
3.INFLUX OF INTRACELLULAR CALCIUM &
LOSS OF CALCIUM HOMEOSTASIS .
. Ischemia causes an increase in cytosolic calcium
concentration. Increased Ca2+ in turn activates a
number of enzymes, e.g.
- ATPases (thereby hastening ATP depletion),
-Phospholipases (which cause membrane damage),
- Proteases (which break down both membrane and
cytoskeletal proteins), and
-Endonucleases (which are responsible for DNA and
chromatin fragmentation).

22. MECHANISM OF CELL INJURY cont.
4. ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
- Small amounts of partially reduced reactive oxygen
forms are produced as a byproduct of mitochondrial
respiration.
- Some of these free radicals can damage lipids,
proteins, and nucleic acids.
- They are referred to as reactive oxygen species.

23. MECHANISM OF CELL INJURY cont.
- Cells have defense systems to prevent
injury caused by these products.
- An imbalance between free radical-
generating and radical-scavenging systems
results in oxidative stress causing cell injury.

24. MECHANISM OF CELL INJURY cont.
Free radical-mediated damage are seen in
-chemical and radiation injury
- ischemia-reperfusion injury
- cellular aging, and
- microbial killing by phagocytes.

25. MECHANISM OF CELL INJURY cont.
-Free radicals are chemical species that have single
unpaired electron in an outer orbit.
-They are initiated within cells in several ways:
a) Absorption of radiant energy (e.g., ultraviolet light, x-
rays).
b) Enzymatic metabolism of exogenous chemicals or
drugs .

26. MECHANISM OF CELL INJURY cont.
c) The reduction-oxidation reactions that occur during
normal metabolic processes. During normal
respiration, small amounts of toxic intermediates are
produced; these include superoxide anion radical
(O2-), hydrogen peroxide (H2O2), and hydroxyl ions
(OH).
d) Transition metals such as iron and copper
e) Nitric Oxide (NO), an important chemical mediator
generated by various cells, can act as a free radical.

27. MECHANISM OF CELL INJURY cont.
-The main effects of these reactive species are
Lipid peroxidation of membranes: result in extensive
membrane, organellar, and cellular damage.
Oxidative modification of proteins. resulting in protein
fragmentation.
Lesions in DNA. This DNA damage has been
implicated in cell aging and malignant transformation
of cells

28. MECHANISM OF CELL INJURY cont.
-Cells have developed multiple mechanisms
to remove free radicals and thereby
minimize injury.
1- Antioxidants. Examples vitamins E and A
and ascorbic acid.
2- Enzymes which break down hydrogen
peroxide and superoxide anion e.g.
Catalase, Superoxide dismutases,and
Glutathione peroxidase.

29. MECHANISM OF CELL INJURY cont.
5. Defects In Membrane
Permeability:
- In ischemic cells, membrane damage may be
the result of ATP depletion and calcium-
modulated activation of phospholipases.
- It can also be damaged directly by certain
bacterial toxins, viral proteins etc.

30. MECHANISM OF CELL INJURY cont.
The biochemical mechanisms which contribute
to membrane damage are:
Mitochondrial dysfunction
 Cytoskeletal abnormalities
 Reactive oxygen species
 Lipid breakdown products

31. Figure 1-10 Cellular and biochemical sites of damage in cell injury.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September 2005 02:13 PM)
© 2005 Elsevier

32. Figure 1-11 Functional and morphologic consequences of decreased intracellular ATP during cell injury.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September 2005 02:13 PM)
© 2005 Elsevier

33. Reversible & Irreversible Cell Injury
Earliest changes associated with cell injury are :
decreased generation of ATP,
 loss of cell membrane integrity,
defects in protein synthesis, cytoskeletal
damage, and
DNA damage.


34. Reversible and Irreversible Cell Injury
Within limits, the cell can compensate for
these derangements and,
If the injurious stimulus is removed the
damage can be reversed.
Persistent or excessive injury, however,
causes cells to pass the threshold into
irreversible injury.

35. Reversible and Irreversible Cell Injury
Irreversble injury is marked by :
- severe mitochondrial vacuolization,
- extensive damage to plasma membranes,
- swelling of lysosomes and
- the appearance large, amorphous densities in
mitochondria..

36. Reversible and Irreversible Cell Injury
Two phenomena consistently characterize
irreversibility.
1) The inability to reverse mitochondrial
dysfunction (lack of oxidative
phosphorylation and ATP generation) even
after removal of the original injury.
2) Profound loss in membrane function

37. n
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September 2005 10:51 AM)
© 2005 Elsevier

38. Ischaemic cell injury
As the oxygen tension within the cell
decreases, there is loss of oxidative
phosphorylation and decreased generation of
ATP followed by sodium pump failure, with
loss of potassium, influx of sodium and
water, and cell swelling.
There is progressive loss of glycogen,
decreased protein synthesis and reduced
intracellular Ph.

39. Ischaemic cell injury cont.
If hypoxia continues, worsening ATP
depletion causes further morphologic
deterioration e.g. loss of ultrastructural
features such as microvilli and the formation
of "blebs" at the cell surface. "Myelin figures,"
may be seen within the cytoplasm or
extracellularly.
If oxygen is restored, all of these
disturbances are reversible.

40. Ischaemic cell injury cont
If ischemia persists, irreversible injury and necrosis
ensue.
 Irreversible injury is associated morphologically with
severe swelling of mitochondria, extensive damage
to plasma membranes, and swelling of lysosomes.
 Large, flocculent, amorphous densities develop in
the mitochondrial matrix.
The dead cell are phagocytosed by other cells.

41. ISCHEMIA-REPERFUSION INJURY
Restoration of blood flow to ischemic tissues can
result in recovery of cells if they are reversibly
injured.
Ischemia-reperfusion injury is a clinically
important process in such conditions as
myocardial infarction and stroke.

42. ISCHEMIA-REPERFUSION INJURY
New damaging processes are set in motion during
reperfusion, causing the death of cells that might
have recovered otherwise New damage may be
initiated during reoxygenation by increased
generation of oxygen free radicals from parenchymal
and endothelial cells and from infiltrating leukocytes
 Reactive oxygen species can further promote the
mitochondrial permeability transition,

43. ISCHEMIA-REPERFUSION INJURY
Ischemic injury is associated with inflammation as a
result of the production of cytokines and increased
expression of adhesion molecules by hypoxic
parenchymal and endothelial cells.
These agents recruit circulating polymorphonuclear
leukocytes to reperfused tissue; the ensuing
inflammation causes additional injury.
Activation of the complement pathway may
contribute to ischemia-reperfusion injury.

44. APOPTOSIS
Apoptosis is programmed cell death.
It is a pathway of cell death that is induced by a
tightly regulated intracellular program in which cells
destined to die activate their own enzymes to
degrade their own nuclear DNA, nuclear proteins
and cytoplasmic proteins.
The cell's plasma membrane remains intact, but its
structure is altered in such a way that the apoptotic
cell sends signal to macrophages to phagocytose it.

45. APOPTOSIS cont.
The dead cell is rapidly phagocytosed and cleared,
before its contents have leaked out, and therefore
cell death by this pathway does not elicit an
inflammatory reaction in the host.
Thus, apoptosis is fundamentally different from
necrosis, which is characterized by loss of
membrane integrity, enzymatic digestion of cells, and
frequently a host reaction.
Apoptosis and necrosis sometimes coexist.

46. CAUSES OF APOPTOSIS
Apoptosis means "falling off."
It occurs normally in many situations, and serves to
eliminate unwanted or potentially harmful cells and
cells that have outlived their usefulness.
It is also a pathologic event when cells are damaged
beyond repair, especially when the damage affects
the cell's DNA; in these situations, the irreparably
damaged cell is eliminated.
Apoptosis can be physiologic, adaptive, and
pathologic.

47. Apoptosis in Physiologic Situations
The programmed destruction of cells during
embryogenesis.
Hormone-dependent involution in the adult,
such as endometrial cell breakdown during
the menstrual cycle, the regression of the
lactating breast after weaning, and prostatic
atrophy after castration.
Cell deletion in proliferating cell
populations,eg. intestinal epithelia.

48. Apoptosis in Physiologic Situations
Death of host cells that have served their useful
purpose, such as neutrophils in an acute
inflammatory response, and lymphocytes at the end
of an immune response.
Elimination of potentially harmful self-reactive
lymphocytes..
Cell death induced by cytotoxic T cells, a defense
mechanism against viruses and tumors that serves
to eliminate virus-infected and neoplastic cells

49. Apoptosis in Pathologic Conditions
Cell death produced by a variety of injurious
stimuli eg. radiation and cytotoxic anticancer
drugs damage DNA.
Cell injury in certain viral diseases, such as
viral hepatitis.
Pathologic atrophy in parenchymal organs
after duct obstruction, such as occurs in the
pancreas, parotid gland, and kidney.
Cell death in tumors.

50. Morphology of Apoptosis
Cell shrinkage.
Chromatin condensation. This is the most
characteristic feature of apoptosis. The
chromatin aggregates peripherally, under the
nuclear membrane.
The nucleus itself may break up into
fragments.

51. Morphology of Apoptosis
Formation of cytoplasmic blebs and
apoptotic bodies. The apoptotic cell first
shows extensive surface blebbing, then
undergoes fragmentation into membrane-
bound apoptotic bodies composed of
cytoplasm and tightly packed organelles, with
or without nuclear fragments.
Phagocytosis of apoptotic cells or cell
bodies, usually by macrophages.

52. Morphology of Apoptosis
On histologic examination, in tissues stained
with hematoxylin and eosin, apoptosis
involves single cells or small clusters of cells.
The apoptotic cell appears as a round or oval
mass of intensely eosinophilic cytoplasm with
dense nuclear chromatin fragments.
There is no inflammation.

53. Figure 1-9 The sequential ultrastructural changes seen in necrosis (left) and apoptosis (right). In apoptosis, the initial changes consist of nuclear chromatin condensation
and fragmentation, followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. Signs of cytoplasmic blebs, and digestion and leakage of cellular
components. (Adapted from Walker NI, et al: Patterns of cell death. Methods Archiv Exp Pathol 13:18-32, 1988. Reproduced with permission of S. Karger AG, Basel.)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September 2005 10:51 AM)
© 2005 Elsevier

54. Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis → karyorrhexis →
karyolysis
Fragmentation into nucleosome size fragments
Plasma
membrane
Disrupted Intact; altered structure, especially orientation of
lipids
Cellular
contents
Enzymatic digestion; may leak
out of cell
Intact; may be released in apoptotic bodies
Adjacent
inflammation
Frequent No
Physiologic or
pathologic role
Invariably pathologic
(culmination of irreversible cell
injury)
Often physiologic, means of eliminating
unwanted cells; may be pathologic after some
forms of cell injury, especially DNA damage