Cell Injury

1
Cell Injury

• Robert Low MD PhD

2
Cell and tissue injury produce human
disease Injury-acute vs chronic

• sites within cells that are easily injured
• reversibility of injury and complete recover
• adaptation to chronic injury
• cell death-necrosis vs apoptosis
• Hypoxic injury-starving cells/tissues for oxygen
  problems of too much oxygen and cell damage from
  oxygen radicals

3
1

• Human disease occurs because of injury to
  cells/tissue

4
Cell Injury Damage or alteration of one or
more cellular components

1. Many types of injury we incur are tissue specific
   because of anatomic relationships and the
   tissue tropism of chemical and infectious agents.
2. Cell injury perturbs cell physiology the cell
   does not function at full capacity.

5
(No Transcript)
6
Basic Types of Tissues

• Epithelium
• Muscle (skeletal, smooth, cardiac)
• Nerve (CNS, PNS)
• Connective (bone, cartilage, soft tissue,
  adventitia, ligaments, blood and lymph, etc)

7
2

• Most human disease results from injury to
  Epithelium

8
Epithelium arises from each of three germ layers

1. Cells cover external surfaces (skin) line
   internal closed cavities, secretory glands and
   tubes- -GI, respiratory, GU tracts- -that
   communicate with external surfaces
2. Also includes liver, exocrine pancreas, parotid
   glands, thyroid, parathyroid, epithelium of
   kidney
3. Also vascular endothelium, mesothelium

9
3

• Injury to one tissue usually affects the adjacent
  or underlying tissue as well

10
(No Transcript)
11
Cell Injury Produces

• Signs- abnormal physical findings
• Symptoms- complaints experienced
• by the patient

12
Cell Injury Produces (cont)

1. Morphologic change- A visual change in the cell
   shape or appearance, seen when cells are stained
   and viewed by light microscopy or examined by
   E.M. in the injured tissue or seen grossly
   with the naked eye.

13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
Outcomes from cell injury depend upon

1. Type of injury
2. Severity of the injury
3. Duration of the damage
4. Type of cell being injured- Some cell types
   sustain injury better than others some tissues
   (e.g. liver) have a capacity to regenerate.

19
Cell Injury Vulnerable Sites

1. Cell membranes
2. Mitochondria
3. Endoplasmic reticulum
4. Nucleus

20
Cell Membrane- why so easily injured

1. Membrane faces the external environment sustains
   trauma, extracellular oxidants, proteases, etc.
2. Requires a constant supply of ATP for normal
   function (ion pumps).
3. Lipid molecules in the membrane are easily
   oxidized and support and oxidative chain reaction
   called lipid peroxidation.

21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
(No Transcript)
26
Consequences of Injury

1. No long term effects- - the cell damage is
   repaired, the effects of the injury are
   reversible.
2. The cell adapts to the damaging stimulus.
3. The cell dies, undergoing necrosis. The damage is
   irreversible.

27
(No Transcript)
28
Reversible Cell Injury

• Examples
• Cell swelling usually accompanies all types of
  injury. Results from an increase in water
  permeability. Reverses once membrane function is
  restored.
• Increase in extracellular metabolite because of a
  biochemical derangement. Ex. Increase in
  extracellular glycogen in diabetes.

29
Reversible Cell Injury (cont)

• Examples
• Fatty change in liver. Vacuoles of fat accumulate
  within the liver cell following many types of
  injury alcohol intoxication, chronic illness,
  diabetes mellitus, etc.
• Due to An increase in entry of free fatty acids.
• An increase in synthesis of free fatty
  acids.
• A decrease in fatty acid oxidation.

30
(No Transcript)
31
Adaptation- the cell responds successfully to
the injurious stimulus

• Examples
• Hypertrophy- the cell increases in size. Ex.
  cardiac myocytes of the left ventricle increase
  in size from essential hypertension.
• Atrophy- the cell decreases in size because of a
  loss of cell substance.

32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
Causes of Cell Atrophy

1. Loss of blood supply or innervation
2. Loss of endocrine factors (ex. TSH)
3. Decrease in the workload
4. Aging, chronic illness

38
(No Transcript)
39
(No Transcript)
40
Cell Death

• Necrosis
• Apoptosis

41
(No Transcript)
42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
Morphology of Necrosis
46
Coagulative Necrosis

• Dead cell remains a ghost-like remnant of its
  former self-classically seen in an MI.

47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
(No Transcript)
51
Pyknosis

• Intensely dark staining and shrunken nucleus,
  seen in a necrotic (dead) cell.

52
(No Transcript)
53
Karyorrhexis

• Fragmentation of pyknotic nucleus.

54
Karyolysis

• Extensive hydrolysis of the pyknotic nucleus
  with loss of staining. Represents breakdown of
  the denatured chromatin.

55
(No Transcript)
56
Liquefactive Necrosis

• The dead cell undergoes extensive autolysis,
  caused by the release of lysosomal hydrolases
  (proteinases, DNases, RNases, lipases, etc.)
• Seen classically in the spleen and brain
  following infarction.

57
(No Transcript)
58
Caseous Necrosis

• Seen in Tuberculosis (mycobacterium
  tuberculosis).
• Type of necrosis seen within infected tissues
  characterized as soft, friable, whitish-grey
  (resembles the milk protein casein).

59
Fat Necrosis

• Leakage of lipases from dead cells attack
  triglycerides in surrounding fat tissue and
  generate free fatty acids and calcium soaps.
• These soaps have a chalky-white appearance.
• Seen in the pancreas following acute
  inflammation.

60
(No Transcript)
61
Causes of Cell and Tissue Injury

1. Physical agents
2. Chemicals and drugs
3. Infectious pathogens
4. Immunologic reactions
5. Genetic mutations
6. Nutritional imbalances

62
Causes of Cell and Tissue Injury (cont)

• Hypoxia and Ischemia-
• cell injury resulting from inadequate levels of
  oxygen.
• Many important causes
• A. Inadequate blood supply
• B. Lung disease
• C. Heart failure
• D. Shock

63
(No Transcript)
64
Why So Important?

• All cells in the body require a continuous
  supply of oxygen in order to produce ATP via
  oxidative phosphorylation in mitochondria.
• ATP is absolutely critical for life.

65
Susceptibility of specific cells to ischemic
injury- -

• Neurons 3 to 5 min.
• Cardiac myocytes, hepatocytes, renal epithelium
  30 min. to 2 hr.
• Cells of soft tissue, skin, skeletal muscle
  many hours

66
(No Transcript)
67
Hypoxic Injury- changes which are
reversible

1. Decrease in extracellular ATP levels
2. Decrease in the Na pump, with cell swelling
3. Increase in glycolysis, with a decrease in
   intracellular pH
4. Decrease in protein synthesis

68
Hypoxic Injury- changes which are
irreversible

1. Activation of lysosomal enzymes. (recall that
   lysosomal enzymes are active at low pH, ca. pH
   4-5)
2. Degradation of DNA and protein.
3. Influx of calcium. (recall that calcium activates
   many lipases and proteases)

69
(No Transcript)
70
Hypoxic cells are exposed to damage from oxygen
radicals-

1. Hypoxic patients are given high levels of oxygen.
   This oxygen is toxic to the cells lining the
   alveolar spaces in the lung because the high 02
   produces oxygen radicals.

71
Hypoxic cells are exposed to damage from oxygen
radicals- (cont)

1. Hypoxic tissues are often infiltrated with PMNs.
   PMNs have enzymes, myleoperoxidases, which
   produce activated oxygen

72
Hypoxic cells are exposed to damage from oxygen
radicals- (cont)

1. Hypoxic tissues are often reperfused once the
   blood supply is restored. Xanthine oxidase,
   produced from proteolysis during hypoxia,
   generates free radicals when the 02 is brought
   back to normal levels.

73
(No Transcript)
74
GOOD/BAD REACTION
75
BAD REACTIONS
H202 H. 0H. (very reactive) FE H202
FE 0H. 0H- H202 02- 0H. 0H-
02
1 2 3
FENTON REACTION
HABER-WEISS REACTION
76
GOOD REACTIONS
2 H202 02 2H20 2 0H. 2 GSH 2 H20
GSSG H202 2 GSH 2 H20 GSSG
1 2
GLUTATHIONE PEROXIDASE
77
(No Transcript)