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BMS 100 > Pathology Concepts 1 – Types of Cell Injury > Flashcards

Pathology Concepts 1 – Types of Cell Injury Flashcards

1
Q

A cell/tissue has been stressed, but overcomes this stress and resumes normal physiologic function

A

Reversible cell injury
No notable long-term morphologic or physiologic changes

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2
Q

A cell/tissue has become damaged and will eventually die due to the severity of the damage

A

Irreversible cell injury

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3
Q

there is a change in cellular/tissue structure or function that is almost always due to long term stresses

A

Adaptation
These changes are usually somewhat reversible

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4
Q

examples of Adaptation

A

Examples: hypertrophy, hyperplasia, atrophy, metaplasia

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5
Q

what are the types of cell injury?

A
  • reversible cell injury
  • irreversible cell injury
  • adaptation
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6
Q

types of insults to tissues or cells

A

types of cellular response that happen:
* Hypoxia and ischemia
* Infection, inflammation, and immune-mediated
disorders
* Toxins/chemical agents
* Trauma, compression, thermal injuries
* Deficiencies in nutrients or growth factors

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7
Q

The cellular response to injury depends on:

A
  • type of injury
  • duration of the injury
  • the severity of the injury
  • The adaptability and the metabolism/phenotype of the cell

Big difference between cardiac cells and skeletal muscle cells re: vulnerability to ischemia

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7
Q

a state in which oxygen is not available in sufficient amounts at the tissue level to maintain adequate homeostasis

A

hypoxia

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7
Q

a condition in which blood flow (and thus oxygen) is restricted or reduced in a part of the body

A

ischemia

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8
Q

what types of pathophysiological consequences of the insult are clearly visible under the microscope?

A
  • cellular swelling
  • non-specific nuclear changes
  • Ribosomal detachment, membrane abnormalities due to cytoskeletal disassembly, accumulation of lipids
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9
Q

pathophysiological consequences that are more difficult to observe:

A

Damage to proteins (including misfolding), DNA, subtle changes in organelle function and size due to damaged membranes

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10
Q

Reversible injury that you can’t see under a light microscope

A

▪ Changes in calcium concentrations
▪ Unfolded proteins
▪ Damage to DNA or cytoskeletal elements
▪ Loss of membrane potentials or abnormal distribution of molecules across cell membranes
▪ ATP depletion

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11
Q

what is the pathophysiological consequences of loss of mRNA to the cell? Is this visible under a microscope?

A

a more eosinophilic cytoplasm. This is visible under a microscope

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12
Q

what are small “blebs”? Are they visible under a microscope?

A

bubble-like outpouchings in the membrane. These are visible under a microscope

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13
Q

what types of irreversible cellular injury would be visible under the microscope?

A
  • Serious loss of integrity – plasma membrane, lysosomal membranes, mitochondrial membranes, ER membranes
  • Destruction of cytoskeletal elements
  • DNA and nuclear “disruption”
  • Karyolysis
  • Pyknosis
  • Karyorrhexis
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14
Q

Describe karyolysis, an irreversible cellular injury that would be visible under the microscope.

A

– chromatin fades

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15
Q

Describe Pyknosis, an irreversible cellular injury that would be visible under the microscope.

A

chromatin condenses, more basophilic (purple), the nucleus shrinks

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16
Q

Describe Karyorrhexis, an irreversible cellular injury that would be visible under the microscope.

A

visibility of nucleus fragments

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17
Q

what are the two major categories of cell death?

A

necrosis and programmed cell death

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18
Q

The agents that have injured the physiology/biochemistry of
the cell → immediate loss of cellular viability

A

necrosis

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19
Q

in necrosis, is cell signalling involved?

A

If cellular signalling is involved in this process, it is disorganized and unregulated

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20
Q

Cell death is delayed and requires protein synthesis. This can be due to long-term, irreparable cellular damage or
loss of cell use

A

programmed cell death

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21
Q

is cell signalling involved in programmed cell death?

A

Cellular signalling is always involved and the cell proceeds through an orderly series of steps → death

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22
Q

what are the best examples of programmed cell death?

A

apoptosis and necroptosis

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23
Q

Necrosis – mechanisms of injury

A

▪ Depletion of ATP
▪ Mitochondrial damage
▪ Calcium accumulation
▪ Oxidative stress / free radicals
▪ Membrane damage
▪ Denatured proteins
▪ DNA damage

can occur in isolation or simultaneously
- one may lead to another

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24
Q

what does the reduction (5 – 10% of
normal) in ATP levels results in:

A
  • Na+/K+ pump dysfunction
    and swelling (Eventually leads to membrane damage)
  • Anaerobic metabolism decreases pH (lactic acid, inorganic phosphate)
  • Increased production of free radicals
  • Failure of calcium pumps
  • Reduction in protein synthesis, detachment of ribosomes, misfolding of proteins
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25
Q

what do high overall levels of cytosolic calcium do?

A

▪ Activate a variety of destructive enzymes
▪ Directly activate caspases
▪ Cause calcium release from mitochondria - would decrease ATP

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26
Q

what is the extracellular concentration of calcium (in mmol)

A

1– 2 mmol

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27
Q

what is the intracellular concentration of calcium (in mmol) at rest?

A

0.0001 mmol

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28
Q

Phospholipids are both _____________ and not synthesized during ischemic injury. This causes cytoskeleton damage which increases physical stresses on the membrane.

A

broken down.

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29
Q

Lipid breakdown (in the membrane) results in:

A

▪ Leaky membranes
▪ Lipid breakdown products that can have a detergent effect on cellular membranes

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30
Q

why is calcium considered a “special” ion?

A

Only ion that is a ubiquitous second messenger
- Interacts with a number of intracellular proteins (i.e. calmodulin) that can activate or inactivate intracellular processes

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31
Q

calcium can also activate enzymes that are particularly relevant to necrosis. These include:

A
  • Proteases
  • Phospholipases
  • Endonucleases (DNA, chromatin fragmentation)
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32
Q

what will the loss of cytosolic calcium (within cell) lead to?

A

▪ Loss of regulation → nonspecific overall activation of the enzymes specified above
▪ ATP deficiency disrupts appropriate calcium sequestration
▪ Cytosolic calcium accumulation opens the mitochondrial permeability transition pore (MPTP)

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33
Q

Mitochondrial membranes can be damaged by ____________

A

free radical attack

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34
Q

what does MPTP stand for

A

mitochondrial permeability transition pore

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35
Q

what are detergent-like effects:

A
  • unesterified free fatty acids
  • acylcarnitine
  • lysophospholipids
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36
Q

Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton. What does this lead to?

A

Lose the “anchoring” and stabilizing effect of the cytoskeleton on cell membranes

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37
Q

what are two causes of cytoskeleton absnormaltieis

A
  1. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton
  2. cell swelling which causes detachment of the membrane from the cytoskeleton
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38
Q

what does cell swelling causing detachment of the membrane from the cytoskeleton lead to?

A

membrane susceptible to stretching
and rupture

A “broken” cytoskeleton compounds this process

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39
Q

Injury to lysosomal membranes results in:

A
  • Direct enzymatic damage to cellular components
  • activation of enzymes by lysosomal enzymes
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40
Q

what are lysosomal enzymes?

A

Enzymes include RNases, DNases, proteases,
phosphatases, glucosidases and cathepsins

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41
Q

What needs to happen to the intracellular mileiu before lysosomal enzymes can be activated?

A
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42
Q

Unregeulated enzymatic degradation of cell
components leads to loss of ______ which causes death by ________

A

Unregeulated enzymatic degradation of cell
components → loss of DNA, RNA, glycogen,
cytoskeletal proteins → death by necrosis

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43
Q

what are free radicals generated by

A
  • normal metabolic processes
  • Metabolism of drugs or toxins
  • Radiation – UV light, x-ray
  • Fenton reaction
  • Leukocytes
44
Q

metals receive or donate electrons
(copper, iron) is a ________ reaction

A

Fenton reaction

45
Q

what is the role of leukocytes?

A

to kill pathogens in inflammatory reactions

46
Q

what types of cells do free radicals damage

A

▪ Lipids – leading to membrane damage
▪ Proteins – especially at disulfide bonds
▪ DNA – can cross-link and break strands

47
Q

formed when incomplete reduction of O2 during oxidative phosphorylation; By phagocyte oxidase in leukocytes

A

Superoxide O2

48
Q

Generated by SOD from
O2- and by oxidases in peroxisomes

A

Hydrogen peroxide H2O2

49
Q

Generated from H2O by hydrolysis, e.g., by radiation; from H2O2 by Fenton reaction; from O2-

A

Hydroxyl OH

50
Q

Peroxynitrite ONOO-

A

Generated by O2- and NO synthase in many cell types (endothelial cells, leukocytes, neurons, others)

51
Q

_____ is eliminated by the Conversion to H2O2
and O2 by SOD

A

Superoxide O2-

52
Q

_____ is eliminated by the Conversion to H2O and O2 by catalase (peroxisomes), glutathione peroxidase (cytosol, mitochondria)

A

Hydrogen peroxide H2O2

53
Q

_____ is eliminated by the Conversion to H2O by glutathione peroxidase

A

Hydroxyl OH

54
Q

_____ is eliminated by the Conversion to HNO2

A

Peroxynitrite ONOO-

55
Q

Mechanisms to remove free radicals include:

A
  1. Antioxidants: i.e. Vitamin E, A, C
  2. Enzymes
56
Q

which enzyme breaks down H202

A

catalyze

57
Q

which enzyme converts 02- to H202

A

Superoxide dismutase

58
Q

which enzyme decomposes H202

A

Glutathione peroxidase

59
Q

a tightly regulated intracellular program that requires synthesis and activation of signalling and effector proteins

A

apoptosis

60
Q

If you block protein synthesis, apoptosis is ______

A

blocked

61
Q

does the plasma membrane remain intact during apoptosis

A

yes
However, it is altered → better phagocytosis of cell remnants

62
Q

does inflammation occur after apoptosis or necrosis?

A

No, in apoptosis, dead cell remnants rapidly cleared → no inflammation

Inflammation is prominent after necrotic damage to tissue

63
Q

what are 3 scenarios in which apoptosis occurs due to physiological need?

A
  1. Programmed destruction of cells during
    embryogenesis
  2. Hormone-dependent involution in adult
  3. Cell deletion in proliferating cell populations
64
Q

what are examples of apoptosis due to Hormone-dependent involution in adult?

A

▪ Endometrial cell breakdown during the menstrual cycle
▪ Ovarian follicular atresia in menopause
▪ Regression of lactating breast after weaning
▪ Prostatic atrophy after castration

65
Q

why does apoptosis occur during embryogenesis?

A

The embryo forms many structures that are no longer required in the fetus

66
Q

what is an example of apoptosis due to Cell deletion in proliferating cell populations?

A

intestinal crypt epithelia in order to maintain a constant number of cells

67
Q

what is an example of apoptosis due to death of host cells that served their purpose?

A

▪ Neutrophils in acute inflammatory response

▪ Lymphocytes at the end of an immune response
* Cells undergo apoptosis because deprived of necessary
survival signals, e.g. growth factors

68
Q

what are 4 scenarios in which apoptosis as an adaptive response to pathology?

A
  1. Death of host cells that served their purpose
  2. Elimination of potentially harmful self-reactive lymphocytes
  3. Cell death induced by cytotoxic T cells
  4. Cell death produced by a variety of injurious stimuli
69
Q

what can ER stress be described as?

A

accumulation of misfolded proteins

free radical damage or genetic disease can result in the accumulation of misfolded proteins

70
Q
  • Proteins can ______ because of free radical damage, ATP depletion, of viral infection
A

misfold

71
Q

Microscopic pathology of apoptosis

A
  • cell shrinkage
  • chromatin condensation
  • formation of cytoplasmic blebs and apoptotic bodies
  • phagocytosis of apoptotic cells or cell bodies by macrophages
72
Q

what microscopic pathology of apoptosis is difficult to visualize

A

▪ not all cells in a tissue at risk undergo apoptosis at once
▪ no inflammation
▪ apoptotic bodies are quite small

73
Q

what are the two basic stages of apoptosis?

A
  • Initiation and execution
74
Q

the sequence of events involving the recognition of apoptotic signals or cellular damage and activation of intracellular “initiator” caspases

A

Initiation

75
Q

“executioner” caspases are activated by the
“initiator” caspases and cause the cellular changes of apoptosis

A

Execution

76
Q

what are the two major types of apoptosis? Where does each one occur?

A

Intrinsic (mitochondrial) pathway
Extrinsic (death-receptor) pathway

77
Q

The intrinsic pathway results from

A

cellular damage or from lack of growth factors

Results from increased permeability of the
mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules into the cytoplasm

78
Q

in the intrinsic (mitochondrial) pathway, the Release of pro-apoptotic proteins is tightly controlled by the ___ family of proteins

A

BCL2

79
Q

BCL2 family of proteins are composed of varying numbers of _____ domains

A

BH4 domains
It’s a good name → 4 X “BH” proteins

80
Q

what proteins are anti-apoptotic

A

Bcl-2, Bcl-X, and Mcl-1

81
Q

what proteins are pro-apoptotic

A

Bax and Bak

82
Q

what types of proteins prevent mitochondrial pore formation and leakage of cytochrome
c and other pro-apoptotic proteins into the cytosol

A

anti-apoptotic
Bcl-2, Bcl-X, and Mcl-1

83
Q

What increases Bim, Bid, and Bad, Puma, Noxa (BH3 only)?

A

▪ ER stress
▪ Lack of growth signals
▪ DNA damage

84
Q

What activates the mitochondrial leak channel (Bax/Bak)?

A

▪ Lack of BH4 molecules
▪ BH3-only molecules

85
Q

What happens if you open the mitochondrial leak channel?

A

▪ Cytochrome C leaks into the cytosol
▪ Cytochrome C directly activates a protein known as apoptosis-activating factor (APAF) → activation of caspases

86
Q

The anti-apoptotic and pro-apoptotic BH families counteract each other – the balance between the two determines whether a cell will

A

pursue apoptosis

87
Q

what family of receptors are death receptors a part of? which receptor is best known/studied?

A

▪ Part of the TNF family of receptors
▪ Fas receptor is best known/studied

88
Q

Intracellular death domains of these receptors (extrinsic) then activate caspases ___ and __

A

8 and 10

Caspases 8 and 10 then activate other caspases that are involved in the execution phase

89
Q

what allows the macrophages to recognize and phagocytose apoptotic bodies during the end of the execution phase?

A

Phosphatidylserine “flips” to the outer envelope of the cell membrane (flippase)

Normally present in the inner envelope of the cell membrane – during apoptosis it flips to the other side

90
Q

efferocytosis

A

Phagocytosis of apoptotic cells is so efficient that dead cells often disappear within minutes without leaving a trace

91
Q

describe the cellular adaption of the unfolded protein

A

recruit more chaperones to unfold and then refold proteins

92
Q

if a cell fails to adapt to unfolded protein what will happen?

A

as soon as the misfolded protein becomes a burden, caspase activation will occur which will result in apoptosis

93
Q

what does the following describe?
▪ loss of ATP, cell/organelle swelling, generation of free radicals, etc
▪ Does not involve caspase activation

A

Necroptosis

94
Q

why is Necroptosis sometimes called “programmed necrosis”

A

unlike necrosis, it is triggered by genetically
programmed signal transduction

95
Q

Necroptosis – when does it
happen?

A
  • (calcification) of the growth plate
  • fatty liver
  • ischemia-reperfusion injury (not enough blood then you reintroduce blood BUT not enough blood or too fast reintroduction)
  • Parkinson’s disease
  • a mechanism for cells infected by viruses that inhibit the activation of caspases
96
Q

increase in size of cells → increase in size of the organ

A

Hypertrophy
Can be physiologic or pathologic

97
Q

causes of Hypertrophy

A

Causes: increased functional demand, hormonal stimulation

98
Q

increase in the number of cells in an organ

A

Hyperplasia
Physiologic or pathologic, again

i.e. growth, regeneration, adaptation to mechanical stresses, hormones, growth factors

99
Q

decrease in the number and/or size of cells

A

Atrophy
Physiologic or pathologic, again

100
Q

What is the result of atrophy?

A

Usually pathologic – disuse, loss of growth factors, compression, loss of nerve supply, reduction of blood supply

101
Q

______ can be a mechanism for the development of atrophy

A

Autophagy
As the name suggests – cells “eat” or digest unused components

102
Q

Three major types of Autophagy

A
  • Chaperone-mediated lysosomal digestion of old proteins
  • lysosomes that “surround” old cellular components
  • macro-autophagy
103
Q

Abnormal tissue deposition of calcium salts. Can also include smaller amounts of magnesium and iron salts

A

calcification

104
Q

dystrophic calcification

A

Calcification in dying tissue
▪ No abnormalities in serum calcium or calcium metabolism

105
Q

metastatic calcification

A

Calcification in viable tissue
Almost always due to hypercalcemia (high calcium in the blood)

106
Q

where does Dystrophic Calcification happen?

A

Localized in areas of necrosis

107
Q

in dystrophic calcification, the calcium salts
appear

A

macroscopically as fine, white granules or
clumps often felt like gritty deposits

The final common pathway is the formation of crystalline calcium phosphate

108
Q

Calcium is concentrated in membrane-bound
vesicles in cells by a process that is initiated by membrane damage and has several steps:

A

(1) Calcium ion binds to the phospholipids present in the vesicle membrane
(2) Phosphatases associated with the membrane generate phosphate groups, which bind to the calcium
(3) The cycle of calcium and phosphate binding is repeated, raising the local concentrations and producing a deposit near the membrane
(4) A microcrystal is formed which can then propagate and lead to more calcium deposition

109
Q
A

BMS 100 (37 decks)

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