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Pathology > 1 - Cell Injury And Death > Flashcards

1 - Cell Injury And Death Flashcards

1
Q

What consist the core of pathology?

A

Etiology
Pathogenesis
Morphologic changes
Clinical manifestations

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2
Q

What is adaptation?

A

Ability to adjust to a new steady state

Reversible functional and structural responses

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3
Q

True or False.

The human cell is able to adapt and handle physiologic demands.

A

True

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4
Q

What are the two hallmarks of reversible injury?

A 
Biochemical hallmark (Reduced Oxidative Phosphorylation)
Morphologic hallmark (Cellular swelling)
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5
Q

What happens during the biochemical hallmark?

A
  1. Depletion of ATP
  2. Mitochondrial Damage
  3. Influx of water and calcium thereby, loss of calcium homeostasis
  4. Accumulation of oxygen-derived free radicals (Oxidative stress)
  5. Defect in membrane permeability
  6. Damage to DNA and proteins
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6
Q

What happens during the morphologic hallmark?

A
  1. Cellular swelling

2. Fatty change

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7
Q

What are the two types of cell death?

A

Necrosis and apoptosis

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8
Q

What are the phenomena that characterize reversibility?

A
  1. Inability to reverse mitochondrial dysfuntion

2. Production of profound disturbances in membrane function

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9
Q

This type of cell death is more common, always pathogenic, accidental and unregulated?

A

Necrosis

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10
Q

This type of cell death occurs through activation of internal suicide program, is highly regulated and may be pathologic or physiologic?

A

Apoptosis

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11
Q

This type of cell death is characterized by cellular swelling, denaturation and coagulation of intracellular proteins and enzymatic digestion of lethally injured cell causing leakage of cellular contents, moreover, causing inflammation.

A

Necrosis

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12
Q

This type of cell death is characterized by nuclear dissolution, fragmentation of cell without loss of membrane permeability and rapid removal of cellular debris?

A

Apoptosis

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13
Q

In apoptosis, there is no inflammation and cellular contents are contained in _____________.

A

Apoptotic bodies

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14
Q

Apoptotic bodies are phagocytosed by _______________.

A

Macrophages

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15
Q

What are the different causes of cell injury?

A
  1. Oxygen deprivation (Hypoxia)
  2. Physical agents
  3. Chemical agents or drugs
  4. Infectious agents
  5. Immunologic reactions
  6. Genetic derangements
  7. Nutritional imbalances
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16
Q

Among the different causes of cell injury, which is the most clinically significant?

A

Oxygen deprivation (Hypoxia)

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17
Q

What the primary organelle is affected during hypoxia?

A

Mitochondria

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18
Q

What are the causes of hypoxia?

A
  1. Ischemia
  2. Cardiorespiratory failure
  3. Decreased O2-carryng capacity of the blood
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19
Q

What are some instances that cause decrease the O2-carrying capacity of the blood?

A

Anemia, CO poisoning, sever blood loss

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20
Q

What are some examples of physical agents that cause cell injury?

A 
Mechanical trauma
Extreme heat or cold
Sudden changes in atmospheric pressure
Radiation
Electric shock
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21
Q

What are some examples of chemical agents and drugs that cause cell injury?

A 
Therapeutic drugs
Poisons
Environmental pollutants
Social stimuli and recreational drugs
Oxygen at high concentrations
Herbicides and insecticides
Glucose or salt in hypertonic concentrations
Industrial and occupational hazars
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22
Q

What are some examples of poisons that cause cell injury?

A

Cyanide, Arsenic and Mercuric salts

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23
Q

What are some examples of social stimuli that cause cell injury?

A

Alcohol and narcotics

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24
Q

True or False.
Even a little derangement from the normal glucose or salt concentration in the body may cause electrolyte imbalance, hence causing cell injury.

A

True

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25
Q

What are some examples of infectious agents that cause cell injury?

A

Viruses, bacteria, fungi, parasites

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26
Q

True or False.

Cell injury can either be due to the pathogenicity of the agent or the reaction of the body to the infectious agent.

A

True

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27
Q

What are some examples of immunologic reactions that cause cell injury?

A

Autoimmune diseases and too much immune response

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28
Q

What is the usual pathway of cell death in genetic derangements?

A

Apoptosis

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29
Q

What triggers cell death in genetic derangements?

A
  1. Decrease in functional proteins

2. Increase in damaged DNA or misfolded proteins

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30
Q

What are some examples of nutritional imbalances that cause cell injury?

A
  1. Decreased protein-calorie
  2. Decreased specific vitamins
  3. Self-imposed nutritional problems (anorexia nervosa)
  4. Increase cholesterol (obesity predisposes an individual to diabetes and cancer)
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31
Q

What are the principles of cell injury?

A
  1. The cellular response to injurious stimuli depends on the nature, duration and severity of injury.
  2. The consequence of cell injury depends on the type, state and adaptability of the injured cell.
  3. Cell injury results from different biochemical mechanisms acting on several essential cellular components.
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32
Q

What are the morphologic features of necrosis?

A
  1. Inability to maintain membrane integrity and their contents often leak out (elicit inflammation)
  2. Increased eosinophilia (due to loss of cytoplasmic RNA and denatured cytoplasmic proteins)
  3. Glassy homogenous appearance
  4. “Moth-eaten” cytoplasm due to enzymes
  5. Dead cells become calcified
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33
Q

When ATP is depleted 5-10% of normal levels, it can cause:

A 
Decreased sodium pump
Increased anaerobic glycolysis
Detachment of ribosomes
Misfolded proteins
Irreversible damage to mitochondria and lysosomal membranes
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34
Q

What happens when there is decrease sodium pump?

A

Increased influx of calcium, water and sodium and efflux of potassium ➡️ ER swelling, cellular swelling, loss of microvilli and cytplasmic blebs

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35
Q

What happens when there is increased anaerobic glycolysis?

A

Decrease in glycogen, increase in lactic acid, decrease in pH

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36
Q

What is the effect of pH decrease in the nucleus of the cell?

A

Clumping of nuclear chromatin

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37
Q

What happens when there is detachment of ribosomes?

A

Decrease in protein synthesis

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38
Q

Misfolded proteins accumulate in the __________.

A

Endoplasmic reticulum

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39
Q

Protein C and caspases (degradative enzymes) are found in the _____________.

A

Mitochondria

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40
Q

What is the mechanism of necrosis when there is mitochondrial damage?

A

Decrease in O2 supply, toxins, radiation, increase cytosolic Ca2+ and ROS ➡️ mitochondrial damage ➡️ decreased ATP generation and increased ROS production ➡️ multiple cellular abnormalities ➡️ NECROSIS

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41
Q

What is the mechanism of apoptosis when there is mitochondrial damage?

A

Decrease in survival signals and DNA & protein damage ➡️ increased pro-apoptotic proteins and decreased anti-apoptotic proteins ➡️ leakage of mitochondrial proteins and degradative enzymes ➡️ apoptosis

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42
Q

What is the normal cytosolic and extracellular concentrations of Ca2+?

A

Cytosolic Ca2+: ~0.1 umol

Extracellular Ca2+: 1.3 umol

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43
Q

Where is Ca2+ found in greatest concentrations?

A

Mitochondria and ER

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44
Q

These are chemical species that have single unpair electrons in the outer orbit

A

Free radicals

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45
Q

True or False.

Free radicals are unstable and decay spontaneously.

A

True

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46
Q

True or False.

Free radicals trigger apoptosis.

A

True

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47
Q

A condition wherein there is an excess of free radicals because of increased production or decreased scavenging of ROS

A

Oxidative stress

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48
Q

This are naturally produced oxygen derived free radicals which are degraded and removed by cellular defense mechanisms.

A

Reactive oxygen species (ROS)

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49
Q

What are the pathologic effects of free radicals?

A
  1. Lipid peroxidation in membranes
  2. Oxidative modificatio of proteins
  3. DNA damage
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50
Q

What is the consequence of lipid peroxidation?

A

Membrane damage

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51
Q

What is the consequence of protein modification?

A

Breakdown and misfolding of proteins

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52
Q

What is the consequence of DNA damage?

A

Mutations

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53
Q

What enzyme scavenges the superoxide radical in the mitochondria resulting in the formation of water, oxygen and hydrogen peroxide?

A

Superoxide dismutase

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54
Q

What enzymes scavenge the hydrogen peroxide in the mitochondria resulting in the formation of water and oxygen?

A

Glutathione peroxidase and catalase

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55
Q

What causes the generation of ROS?

A
  1. Redox reactions
  2. Radiaton energy
  3. Rapid burst of ROS (inflammation)
  4. Enzymatic metabolism of exogenous chemicals or drugs (causes free radicals but not ROS)
  5. Transition metals
  6. NO as free radical when combines with superoxide (NO2 and NO3-, highly reactive peroxynitrite anion)
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56
Q

True or False.

Cell have mechanisms the repair DNA and protein damage. However, if it can no longer repair, it leads to apoptosis.

A

True

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57
Q

What are the morphologic alterations in cell injury?

A
  1. All stresses and noxious influences exert their effects first at the molecular and biochemical level.
  2. There is time lag between the stress and morphologic changes of cell injury and death
  3. The morphologic alteration in cell injury is a result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cells.
  4. Necrotic tissues will not persist for a lifetime (will be phagocytosed by macrophages and leukocytes and eventually form scars)
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58
Q

What is the first morphological manifestation of cellular swelling?

A

Cellular swelling

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59
Q

This morphologic manifestation is characterized by small clear vacuoles within the cytoplasm and organ swelling

A

Cellular swelling

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60
Q

This is also known as hydropic change or vacuolar degeneration

A

Cellular swelling

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61
Q

This is characterized by lipid vacuoles in the cytoplasm of hepatocytes and myocardial cells which may be hypoxic and toxic

A

Fatty change

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62
Q

This is also known as steatosis

A

Fatty change

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63
Q

What are the nuclear changes involved in necrosis?

A
  1. Karyolysis
  2. Pyknosis
  3. Karyorrhexis
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64
Q

This is the type of nuclear change that is characterized by fading of chromatin basophilia

A

Karyolysis

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65
Q

This is the type of nuclear change that is characterized by nuclear shrinkage and increased basophilia

A

Pyknosis

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66
Q

This is the type of nuclear change that is characterized by pyknotic nucleus that undergoes fragmentation

A

Karyorrhexis

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67
Q

What are the patterns of tissue necrosis?

A
  1. Coagulative necrosis
  2. Liquefactive necrosis
  3. Gangrenous necrosis
  4. Caseous necrosis
  5. Fat necrosis
    F. Fibrinoid necrosis
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68
Q

True or False.
Necrosis of tissues has several morphologically distinct patterns which are important to recognize because they may provide clues about its underlying cause.

A

True

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69
Q

This pattern of necrosis is characterized by eosinophilic, anucleated cells without loss of architecture for a some days

A

Cogaulative necrosis

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70
Q

What is the primary cause of coagulative necrosis?

A

Ishemia

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71
Q

This is caused by obstruction of a blood vessel which may lead to coagulative necrosis of the supplied tissue in all organs except the brain

A

Ischemia

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72
Q

This is a localized are of coagulative necrosis

A

Infarct

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73
Q

What are two types of infarct?

A

White infarct: only one blood vessel

Red infarct: more than one blood vessel

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74
Q

This pattern of necrosis is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass

A

Liquefactive necrosis

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75
Q

What is a tell tale sign of a previous infarct?

A

Fibrotic scar

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76
Q

This pattern of necrosis is seen in focal bacterial, or occasionally, fungal infections

A

Liquefactive necrosis

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77
Q

This pattern of necrosis occurs when microbes stimulate the accumulation of dead leukocytes and the liberation of enzymes

A

Liquefactive necrosis

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78
Q

This pattern of necrosis may be seen with necrotic material which appears creamy yellow (pus) because of the presence of dead leukocytes

A

Liquefactive necrosis

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79
Q

This is the pattern of necrosis in hypoxic death of cells in the central nervous system

A

Liquefactive necrosis

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80
Q

Analogy: Pattern of Necrosis.
Brain: ___________
Meninges: _____________

A

Brain: Liquefactive (due to ischemia)
Meninges: Caseous

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81
Q

This pattern of necrosis is usually applies to the limb, generally the lower leg, that has lost its blood supply and undergone necrosis (usually coagulative) in multiple planes

A

Gangrenous necrosis

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82
Q

Analogy: Pattern of Necrosis.
Dry gangrene: ________
Wet gangrene: ________

A

Dry gangrene: No infection, coagulative

Wet gangrene: With infection, liquefactive

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83
Q

This pattern of necrosis is most often in foci of tuberculouse infection

A

Caseous necrosis

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84
Q

This pattern of necrosis has cheese-like gross appreance

A

Caseous necrosis

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85
Q

This pattern of necrosis has the presence of granuloma

A

Caseous necrosis

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86
Q

This appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border (epitheloid cells)

A

Granuloma

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87
Q

This pattern of necrosis refers to focal areas of fat destruction

A

Fat necrosis

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88
Q

This pattern of necrosis results from the release of activated pancretic lipases into the substance of the panccreas and the peritoneal cavity

A

Fat necrosis

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89
Q

This pattern of necrosis occurs in acute pancreatitis

A

Fat necrosis

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90
Q

This is the leakage of lipase from the acinar cells that degrade fat cells

A

Acute pancreatitis

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91
Q

This pattern of necrosis grossly appears chalky-white due to fat saponification

A

Fat necrosis

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92
Q

Fatty acids plus calcium

A

Fat saponification

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93
Q

This pattern of necrosis histologically appears as a foci of shadowy outlines of necrotic fat cells with basophilic calcium deposits, surrounded by an inflammatory reaction

A

Fat necrosis

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94
Q

This pattern of necrosis is seen in immune reactions involving blood vessels

A

Fibrinoid necrosis

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95
Q

This pattern of necrosis occurs when complexes of antigens and antibodies and deposited in the walls of arteries

A

Fibrinoid necrosis

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96
Q

This pattern of necrosis histologically appear bright pink, amorphous appearance with H&E stains because of fibrin

A

Fibrinoid necrosis

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97
Q

Necrosis or Apoptosis.

Enlarged cell size

A

Necrosis

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98
Q

Necrosis or Apoptosis.

Reduced cell size

A

Apoptosis

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99
Q

Necrosis or Apoptosis.

Pyknotic ➡️ Karyorrhexic ➡️ Karyolysis

A

Necrosis

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100
Q

Necrosis or Apoptosis.

Fragmentation of nucleus into nucleosome-sized fragments

A

Apoptosis

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101
Q

Necrosis or Apoptosis.

Disrupted plasma membrane

A

Necrosis

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102
Q

Necrosis or Apoptosis.

Intact plasma membrane but may have altered structure, especially with the orientation of lipids

A

Apoptosis

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103
Q

Necrosis or Apoptosis.

Cellular contents undergo enzymatic digestion and may leak out of the cell

A

Necrosis

104
Q

Necrosis or Apoptosis.

Cellular components are intact and may be release in apoptotic bodies

A

Apoptosis

105
Q

Necrosis or Apoptosis.

Adjacent inflammation frequently occurs

A

Necrosis

106
Q

Necrosis or Apoptosis.

No inflammation

A

Apoptosis

107
Q

Necrosis or Apoptosis.

Pathologic

A

Necrosis

108
Q

Necrosis or Apoptosis.

Ofter physiologic but may be pathologic (DNA damage)

A

Apoptosis

109
Q

This is a type of programmed necrosis that is caspase-independent, important death pathway in both pathologic and physiologic conditions and survival mecahnism in host cell damage

A

Necroptosis

110
Q

This is a type of programmed necrosis that is releases the cytokine IL-2 which causes fever with similar properties with apoptosis

A

Pyroptosis

111
Q

This is the steady state of cells

A

Homeostasis

112
Q

What are two types of cell injury?

A

Reversible and irreversible

113
Q

What is reversible injury?

A

A type of cell injury that is caused by a mild, transient damaging stimulus and is able to return to its normal function

114
Q

What is irreversible injury?

A

A type of cell injury where there is severe and progressive stimulus that causes the cell to enter a point of no return

115
Q

True or False.
Cell injury results when cells are severely stressed that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities.

A

True

116
Q

What are some examples of genetic derangement?

A 
Genetic abnormalities (extra chromosomes, single pair substitution)
Genetic defects (enzyme defects in inborn errors of metabolism)
DNA sequence variants (polymorphisms)
117
Q

True or False.

Any injurious stimuli may simultaneously tigger multiple interconnected mechanisms that damage cells

A

True

118
Q

What is the fundamental cause of necrotic cell death?

A

Reduction in ATP

119
Q

What are the major causes of ATP depletion?

A
  1. Reduced supply of oxygen and nutrients
  2. Mitochondrial damage
  3. Actions of some toxins
120
Q

What are the effects of ATP depletion critical cellular systems?

A
  1. Reduced activity of plasma membrane energy-dependent sodium pump
  2. Cellular metabolism is altered to increase rate of anaerobic glycolysis
  3. Influx of calcium into the cytosol
  4. Structural disruption of the protein synthetic apparatus which leads to reduced protein synthesis
  5. Unfolded protein response
  6. Irreversible damage to mitochondrial and lysosomal membrane
121
Q

True or False.

Mitochondria are critical players in cell injury and death pathways.

A

True

122
Q

How are mitochondria damaged?

A

Increase in cytosolic calcium, reactive oxygen species and oxygen deprivation

123
Q

What are the major consequences of mitochondrial damage?

A
  1. Formation of high-conductance channel in the mitochondrial membrane (Mitochondrial Permeability Transition Pore)
  2. Opening of conductance channel which results to loss of membrane potential, eventually failure of oxidation
  3. Abnormal oxidative phosphorylation which leads to formation of reactive oxygen species
  4. Increased permeability of the outer mitochondrial membrane may result in leakage into the cytosol (cytochrome c and caspases) into the cytosol
124
Q

True or False.

Ischemia and certain toxins cause increase in cytosolic calcium concentration

A

True

125
Q

How do ischemia and toxins cause increase in cytosolic calcium concentration?

A
  1. Release of calcium from intracellular stores

2. Increase influx of calcium across the plasma membrane

126
Q

How does intracellular calcium cause cell injury?

A
  1. Accumulation of calcium in mitochondria results in opening of mitochondrial permeability transition pore
  2. Increased cytosolic calcium activated enzymes with potentially deleterious effects on cells
  3. Increased intracellular calcium result in induction of apoptosis
127
Q

Accumulation of oxygen-derived free radicals are important mechanisms of cell damage in:

A
  1. Chemical and radiation injury
  2. Ischemia-reperfusion injury
  3. Cellular aging
  4. Microbial killing by phagocytes
128
Q

True or False.

An overt membrane damage is a consistent feature of most forms of cell injury, except apoptosis.

A

True

129
Q

True or False.

In ischemic cells, membrane defect may be the result of ATP depletion and calcium-mediated activation of phospholipases

A

True

130
Q

What are the biochemical mechanisms that contribute to membrane damage?

A
  1. ROS (by lipid peroxidation)
  2. Decreased phospholipid synthesis
  3. Increase phospholipid breakdown (due to activation of calcium-dependent phospholipases)
  4. Cytoskeletal abnormalities (by activationof proteases)
131
Q

What are the consequences of membrane damage?

A
  1. Mitochondrial membrane damage
  2. Plasma membrane damage
  3. Lysosomal membran damage
132
Q

What are the causes of mitochondrial membrane damage?

A

Decreased ATP generation and release of proteins that trigger apoptotic death

133
Q

What are the causes of plasma membrane damage?

A

Loss of osmotic balance and influx of fluid and ions, as well as loss of cellular contents

134
Q

What are the causes of lysosomal membrane damage?

A

Leakage of enzymes into the cytoplasm and activation of acid hydrolases

135
Q

True or False.
The “point of no return” at which the damage becomes irreversible, is still largely undefined and there are no reliable morphologic or biochemical correlated of irreversibility.

A

True

136
Q

What are the two phenomena that are consistently characterize irreversibility?

A
  1. The inability to reverse mitochondrial dysfunction even after resolution of the original injury
  2. Profound disturbances in membrane function
137
Q

True or False.
Leakage of intracellular proteins through the damaged cell membranes and ultimately into the circulation provide means of detecting tissue-specific cellular injury and necrosis using blood serum sample.

A

True

138
Q

What are the morpholic characteristics seen in reversible injury?

A
  1. Generalized swelling of cells and its organelles
  2. Blebbing of plasma membrane
  3. Detachment of ribosomes from the ER
  4. Clumping of nuclear chromatin
139
Q

True or False.
Severe mitochondrial damage with depletion ofATP and rupture of lysosomal and plasma membranes are typically associated with necrosis

A

True

140
Q

A pathways of cell death that is induces by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cell’s own DNA and nuclear and cytoplasmic proteins

A

Apoptosis

141
Q

These are fragment of apoptotic cells with contain portion of cytoplasm and nucleus

A

Apoptotic bodies

142
Q

What are causes of apoptosis in physiological situations?

A
  1. Destruction of cells during embryogenesis
  2. Involution of hormone-dependent tissues upon withdrawal
  3. Cell loss in proliferating cell populations
  4. Elimination of potentially harmful self-reactive lymphocytes
  5. Death of host cells that have served their purpose
143
Q

What are causes of apoptosis in pathologic situations?

A
  1. DNA damage
  2. Accumulation of misfolded proteins
  3. Cell death in certain infections (usually, viral)
  4. Pathologic atrophy in parenchymal organs after duct obstruction
144
Q

What are morphologic features of cells in apoptosis?

A
  1. Cell shrinkage
  2. Chromatin condensation
  3. Formation of cytoplasmic blebs and apoptotic bodies
  4. Phagocytosis of apoptotic cell or cell bodies, usually by macrophages
145
Q

What is the most characteristic morphological feature of apoptosis?

A

Chromatin condensation

146
Q

True or False.

Apoptosis results from the activation of caspases that cleave proteins after the aspartic residues.

A

True

147
Q

What is the marker of cells undergoing apoptosis?

A

Presence of cleaved, active caspases

148
Q

What are the two phases of apoptosis?

A

Initiation and execution phase

149
Q

What happens during the initiation phase?

A

Some caspases become catalytically active

150
Q

What happens during execution phase?

A

Other caspases trigger the degradation of critical cellular components

151
Q

What are the two distinct initiating pathways of apoptosis?

A

Intrinsic (Mitochondrial) pathway

Extrinsic (Death-receptor initiated) pathway

152
Q

What happens during the intrinsic pathway?

A

There is increased permeability if the mitochondrial outer membrane with consequent release of death inducing molecules from the mitochondrial intermediate space into the cytoplasm

153
Q

What family of anti-apoptotic proteins control the release of mitochondrial pro-apoptotic proteins (Caspases and Cytochrome c) into the cytosol during intrinsic phase?

A

BCL2 (BCL-XL)

154
Q

What are the pre-apoptotic proteins that are activated by the sensors?

A

BAX and BAK

155
Q

What happens during the extrinsic pathway?

A

It is iniatiated by engangement of plasma membrane death receptors on a variety of cells

156
Q

True or False.

Death receptors are member of the TNF receptor family.

A

True

157
Q

What are the best known receptors in the extrinsic pathway?

A

Type 1 TNF receptor along with Fas (CD95)

158
Q

What is the major mechanism of apoptosis in all mammalian cells?

A

Intrinsic pathway

159
Q

True or False.
The sensors that are present to antagonize the anti-apoptotic proteins also activate pre-apoptotic proteins called BAX and BAK.

A

True

160
Q

These pre-apoptotic proteins form channels in the mitochondrial membrane and this is where cytochrome c leaks out which would then lead to apoptosis

A

BAX and BAK

161
Q

What activates the sensors?

A

Loss of survival signals
DNA Damage
Other insults

162
Q

True or False
Once there is absence of survival signals, there will be activation of BH3 (BCL3) to antagonize BCL2 and eventually lead to apoptosis

A

True

163
Q

True or False
When the Fas ligand (FasL) binds to FAS, other FAS molecules are brought together and they form a binding site for FADD (Fas-Associated Death Domain)

A

True

164
Q

What regulates/inhibit the extrinsic pathway?

A

FLIP protein

165
Q

True or False.

FADD brings together multiple pro-caspase 8 molecules that generate the active caspase 8.

A

True

166
Q

How does the FLIP protein regulate the intrinsic pathway?

A

FLIP binds to pro-caspase 8 thus preventing its activation

167
Q

True or False.

In a viable tissue, they are not located in proximity to one another.

A

True

168
Q

This is the final phase of apoptosis mediated by caspase activation of the mitochondrial and death receptor pathway.

A

Execution phase

169
Q

Analogy: Caspases.
Instrinsic pathway: activation of ____________
Extrinsic pathway: activation of ___________

A

Instrinsic pathway: activation of caspase 9

Extrinsic pathway: activation of caspases 8 and 10

170
Q

Activation of both pathways will eventually lead to the activation of what executioner caspases?

A

Caspase 3 and 6

171
Q

Caspase 3 and 6 activate what enzyme?

A

DNAse which leads to nuclear fragmentatoin which wuould result in apoptotic bodies

172
Q

These are “bite-sized” fragments that are edible for phagocytosis

A

Apoptotic bodies

173
Q

This is an adhesive glycoprotein recognised by phagocytes

A

Thrombosponsin

174
Q

True or False.
In apoptotic bodies, the phosphatidylserine “flips” out and is expressed on the outer layer of the member, where it is recognized by several macrophage receptors.

A

True

175
Q

True or False.

Macrophages may produce proteins that bind to apoptotic cells and thus target the dead cells for engulfment.

A

True

176
Q

True or False.
Apoptotic bodies may also become coated with natural antibodies and proteins of the complement system notably C1q which are recognized by phagocytes.

A

True

177
Q

How then, are the apoptotic bodies cleared from tissue?

A

Apoptotic cells send signals.

178
Q

What are the signals that are send out by the apoptotic cells?

A

“Find me” signal

“Eat me” signal

179
Q

What happens during “Find me” signal?

A

Sensing stage
Recognized by the corresponding receptors on the surface of the phagocytes
Stimulates phagocyte migration

180
Q

What happens during “Eat me” signal?

A

Changes in glycosylation of surface proteins, Thrombospondin, C1q, Phosphatidylserine (normally present in the inner leaflet of the membrane but flips out in apoptotic cell which will serve as “eat me” signals to the phagocytes)

181
Q

Why is there a need for cytoskeletal rearrangement?

A

Necessary for internalization/engulfment of apoptotic bodies

182
Q

This is a process in which a cell eats it own contents and cytoplasmic materials are delivered to lysosomes for degradation

A

Autophagy

183
Q

True or False.

Autophagy is implicated in many physiological states such as aging and exercise and pathologic processes

A

True

184
Q

These are “autophagy-related genes that are required for the creation of autophagosome

A

Atgs

185
Q

What are the functions of autophagy?

A

Survival mechanism under various stress conditions.
Maintaining the integrity of cells by recycling essential metabolites and clearing cellular debris.
Involved in clearance of intracellular aggregates that accumulate during aging, stress and various other disease states.

186
Q

What are the three types of autophagy?

A

Chaperone-mediated
Microautophagy
Macroautophagy

187
Q

What is chaperone-mediated autophagy?

A

Direct mediated translocation across the lysosomal membrane by chaperon proteins (hsc-70 containing chaperone complex)
Specialized for each type of protein
Needs a carrier to translocate
Protein that serves as a bridge (Lamp-2A)

188
Q

What is microautophagy?

A

Simplest type

Inward invagination of lysosomal membrane for delivery

189
Q

What is macroautphagy?

A

Major form of autophagy involving the sequestration and transportation of portions of cytosol in a double-membrane bound autophagic vacuole (autophagosome)
Most complicated process.

190
Q

What is the final step of apoptosis?

A

Cell digestion and secretion of anti-inflammatory cytokines

191
Q

What is the role of autophagy in human disease?

A

Cancer
Neurodegenerative disorder
Infectious disease
Inflammatory bowel disease

192
Q

Autophagy in cancer

A

Autophagy can both promote cancer growth (autophagy function is to conserve thus may allow escape of damaged or mutated DNA from apoptosis) and acts as a defense against cancers (damaged DNA leads to failure of autophagy which then leads to apoptosis)

193
Q

Autophagy in neurodegenerative disorders

A

Associated with dysregulation of autophagy (Huntington’s disease)

194
Q

Autophagy in infectious diseases

A

Deletion of Atg5 increases susceptibility to tuberculosis

195
Q

Autophagy in inflammatory bowel disease

A

Crohn’s disease and ulcerative colitis

196
Q

This is a sign of injury and a manifestation of metabolic derangements in a cell and the substances (cytoplasm, organelles and nucleus) within it.

A

Intracellular accumulations

197
Q

What are the different mechanisms of intracellular accumulations?

A
  1. Abnormal metabolism
  2. Defect in protein folding and transport
  3. Lack of enzyme
  4. Indigestion of ingestible materials
198
Q

What happens when there is abnormal metabolism in cells?

A

There is inadequate removal of a normal substance secondary to defects in the mechanisms of packaging and transport

199
Q

Give an example of abnormal metabolism.

A

Fatty liver in obese patients or alcoholics

200
Q

What happens when there is abnormal metabolism in cells?

A

There is accumulation of an abnormal endogenous substance. If the cell has a defective protein metabolism, proteins will accumulate in the ribosomes.

201
Q

Give an example of defect in protein folding and transport.

A

a-1 antitrypsin deficiency

202
Q

What happens when there is lack of enzyme?

A

There is failure to degrade a metabolite due to inherited enzyme deficiencies

203
Q

Give an example of lack of enzyme.

A

Inborn errors of metabolism (lysosomal storage diseases)

204
Q

What happens when there is ingestion of ingestible materials?

A

Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites

205
Q

Give examples of ingestion of indigestible materials.

A
  1. Accumulation of coal dust in macrophages then the macrophages ingest the carbon particles without the capacity to degrade it becoming an anthracotic cell
  2. Tattooing
206
Q

Analogy: Mechanisms of intracellular accumulations.
Abnormal metabolism: ___________
Defect in protein folding and transport: ______________
Lack of enzyme: __________________
Ingestion of indigestible materials: ______________

A

Abnormal metabolism: Normal substance; abnormal mechanism of removal
Defect in protein folding and transport: Abnormal endogenous substance
Lack of enzyme: Lack of the machinery to degrade the metabolite
Ingestion of indigestible materials: Abnormal exogenous material and lack of machinery

207
Q

What are the different type or intracellular accumulations?

A
  1. Lipids (Steatosis and cholesterol & cholesterol esters)
  2. Proteins
  3. Hyaline Cartilage
  4. Glycogen
  5. Pigments (Exogenous and endogenous)
208
Q

This is the abnormal accumulation of triglycerides within the parenchymal cells

A

Steatosis (Fatty change)

209
Q

In what organs is steatosis normally found?

A

Mainly in the liver because it is the major organ involved in fat metabolism, but it also occurs in heart, muscle, and kidney

210
Q

What are the different types of cholesterol and cholesterol ester accumulations?

A

Atherosclerosis
Xanthomas
Cholesterolosis
Niemann-Pick disease, Type C

211
Q

What is atherosclerosis?

A

Progressive accumulation of cholesterol in the tunica intima

Cholesterol esters appears on the cleft spaces of the tunica intima are extracelular and appera needle-shaped

212
Q

What is xanthomas?

A

Tumorous masses composed of clusters of foamy cells found in the subepithelial connective tissue of the skin and in the tendons

213
Q

What is cholesterolosis?

A

Focal accumulation of cholesterol-laden macrophages that appear as foamy cells in the lamina propria of the gall bladder

214
Q

What is Niemann-Pick disease, Type C?

A

Lysosomal storage disease caused by the mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs

215
Q

How do protein accumulation appear histologically?

A

Intracellular accumulation of proteins usually appears as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
Proteins always appear pink under H&E stains

216
Q

What are the causes of protein accumulation?

A
  1. Reabsorption droplets in proximal renal tubules
  2. Accumulation of normal protein that are produced in excessive amounts
  3. Defective intracellular transport and secretion of critical proteins
  4. Accumulation of cytoskeletal proteins
  5. Aggregation of abnormal proteins
217
Q

What is mallory hyaline?

A

Keratin intermediate filaments. If the cell has defective enzyme to digest intermediate filament, it will accumulate appearing as mallory hyaline

218
Q

What happens during the reabsorption of droplet in proximal renal tubules?

A

Caused by proteinuria
Heavy protein leakage across the glomerular filter increases reabsorption of the protein into vesicles, the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell

219
Q

Where accumulation of normal proteins due to excessive production be found?

A

Seen in plasma cells which synthesize immunoglobulin

220
Q

What happens where there is aggregation of abnormal proteins?

A

Misfolded proteins that may deposit in the tissues intracellularly and extracellularly to interfere with normal functions (Amyloidosis)

221
Q

What is hyaline change?

A

Refers to an alteration within the cells or in the extracellular space that gives a homogenous, glassy, pink appearance in routine histologic sections stained with H&E; not an accumulated protein or substance

222
Q

What causes glycogen accumulation?

A

Excessive intracellular deposits of glycogen are seen in patients with abnormality in either glucose or glycogen metabolism

223
Q

How does glycogen accumulation appear histologically?

A

Glycogen masses appear as clear vacuoles within the cytoplasm

224
Q

What is the mechanism behind glycogen storage diseases or glycogenosis?

A

Enzymatic defects in the synthesis or breakdown of glycogen resulting in massive accumulation resulting into cell injury and death

225
Q

True or False.

Glycogen accumulation appears similar to cellular swelling.

A

True

226
Q

True or False.

Glycogen can impede the function of multiple organelles in the cell

A

True

227
Q

What are pigments?

A

Colored substances

228
Q

What are the different types of exogenous pigment accumulation in the body?

A

Carbon (coal dust)
Anthracosis
Tattooing

229
Q

This the most common ubiquitous air pollutant and exogenous pigment that accumulates in the body

A

Carbon (Coal Dust)

230
Q

This a state where there is blackening of the tissues of the lungs

A

Anthracosis

231
Q

Exogenous pigments are ingested by dermal macrophages

A

Tattoo

232
Q

What are the different endogenous pigments that may accumulate in the body?

A

Lipofuschin
Melanin
Hemosiderin

233
Q

What is a lipofuschin?

A

An insoluble pigment, aka lipochrome or wear-and-tear pigment
Derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes
Telltale signs of free radical injury and lipid peroxidation
Increased in old tissue due to excessive accumulation of ROS.

234
Q

What is melanin?

A

The only endogenous brown-black pigment

235
Q

What is hemosiderin?

A

A hemoglobin-derived golden yellow-to- brown, granular or crystalline pigment, one of the major storage form of iron
Hemosiderin-filled macrophages are found in areas with profuse bleeding or previously injured tissues
Increase in hemosiderin can be focal or can depend on many things
Repeated blood transfusion and increase absorption of dietary iron may increase hemosiderin pigments in the body

236
Q

What are pathologic calcifications?

A

Abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium and other mineral salts

237
Q

What are the two forms of pathologic calcifications?

A
  1. Dystrophic calcification

2. Metastatic calcification

238
Q

Dystrophic or Metastatic.

Occurs in dying tissues, in areas of necrosis (usually in the heart)

A

Dytrophic

239
Q

Dystrophic or Metastatic.

Normal serum level of calcium and absence of derangments on calcium metabolism

A

Dytrophic

240
Q

Dystrophic or Metastatic.

Areas of necrosis, advanced atherosclerosis, aging and damaged heart valves

A

Dystrophic

241
Q

Dystrophic or Metastatic.

Occurs in normal tissues (intestinal tissues of the gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins)

A

Metastic

242
Q

Dystrophic or Metastatic.

Hypercalcemia

A

Metastatic

243
Q

Four principal causes of hypercalcemia

A
  1. Hyperparthyroidism
  2. Resorption of bone tissue
  3. Vitamin-D related disorders
  4. Renal failure
244
Q

This occurs because of the retention of phosphate leading to secondary hyperparthyroidism

A

Renal failure

245
Q

What causes cellular aging?

A

Caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences

246
Q

This is a result of progressive decline in cellular function and vaibility

A

Cellular aging

247
Q

Mechanisms believed to play a role in cell aging

A
  1. DNA damage
  2. Cellular senescence
  3. Defective protein homeostasis
  4. Deregulated nutrient sensing
248
Q

What is an example of cellular aging caused by DNA damage?

A

Werner Syndrome (premature aging)

249
Q

Aging is associated with progressive replicative arrest of cell cycle

A

Cellular senescence

250
Q

What are the two mechanisms of cellular senescence?

A
  1. Telomere attrition

2. Activation of tumor suppressor genes

251
Q

What is telomere attrition?

A

Progressive shortening of the telomere which ultimately results in cell arrest

252
Q

What the tumor suppressor gens that are involved in controlling replicative senescence?

A

CDKN2A locus

253
Q

True or False.

Caloric restriction increases longevity by reducing insulin growth factor 1 (IGF-1) pathway and by increasing Sirtuins.

A

True

254
Q

What is the signalling pathway of insulin and insulin-like growth factor 1 (IGF-1)?

A
  1. Mimics the intracellular signaling of insulin
  2. Informs the cell of glucose availability thereby promoting
    an anabolic state as cell growth and replication
  3. Attenuation of IGF-1 signaling leads to lower rates of cell
    growth and metabolism
255
Q

What are sirtuins?

A
  1. Family of NAD-dependent protein deacetylases
  2. Promote the expression of several genes whose
    products increase longevity
  3. Increase insulin sensitivity and glucose metabolism
256
Q

What are the functions of increased sirtuin-6?

A
  1. Contribute to metabolic adaptations of caloric restriction
  2. Promote genomic integrity by activating DNA repair enzymes through deacylation.

Pathology (5 decks)

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