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Pathology > Cellular Reactions to Injury: Apoptosis and Adaptations > Flashcards

Cellular Reactions to Injury: Apoptosis and Adaptations Flashcards

1
Q

what is autophagy

A
  • cellular autodigestive system

- transfer of cytoplasmic contents to lysosomes for degradation

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2
Q

purpose of autophagy

A

rids cells of misfolded proteins, damaged organelles and microbes

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3
Q

autophagy is one of the most important survival responses to

A
  • starvation

- the starving cell reallocates nutrients from unnecessary processes to more essential ones

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4
Q

how are normal endogenous substances produced

A

at a normal or increased rate, but the rate of metabolism is inadequate to remove it (liver fatty change)

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5
Q

why would normal endogenous substances accumulate

A

because of defects in enzymes responsible for its metabolism (lysosomal storage disease)

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6
Q

how are abnormal substances accumulated

A
  • endogenous misfolded proteins are a produce by a mutated gene (alpha 1- antitrypsin)
  • exogenous ingestion of non-metabolizable materials (Silica, carbon, etc)
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7
Q

what is steatosis (fatty change)

A

the abnormal accumulation of triglycerides

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8
Q

what organ is steatosis seen in

A

liver bc it is the major organ involved in fat metabolism

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9
Q

what is the most common cause of steatosis

A
  • alcohol abuse
  • nonalcoholic fatty liver disease
  • obesity
  • diabetes
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10
Q

disorders in cholesterol metabolism leads to what

A

accumulation of cholesterol which is seen in multiple disease processes
ex. cholesterol granuloma, xanthomas

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11
Q

what happens with atherosclerotic plaques

A

-cholesterol and cholesterol esters accumulate in smooth muscle cells and macrophages within the intimal layer of large arteries

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12
Q

what is characteristic of advanced atherosclerosis

A

yellow cholesterol-laden atheromas

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13
Q

what is glycogen

A

an energy source

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14
Q

where is glycogen stored

A

in the cytoplasm of healthy cells

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15
Q

disorders in glucose or glycogen metabolism can lead to

A

excessive intracellular deposits of glycogen

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16
Q

in DM where is glycogen found

A

in renal, liver, heart muscle cells

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17
Q

glycogen storage disease can cause

A

massive glycogen accumulation and cause cell injury and death

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18
Q

in DM glycogen can accumulate in renal tubular epithelial cells and cause

A

nodular glomerulosclerosis

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19
Q

name 2 exogenous pigments

A
  1. carbon (coal dust)

2. Tattooing

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20
Q

what is the most common exogenous pigment

A

carbon (coal dust)

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21
Q

what is carbon (coal dust) pigment

A
  • present as air pollutants
  • inhaled and engulfed by macrophages within the alveoli and transported through lymphatic channels to the regional lymph nodes
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22
Q

what can carbon (coal dust) lead to

A

anthracosis of lung and lymph nodes

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23
Q

what are tattooing pigments

A
  • an exogenous pigmentation

- pigments are engulfed by macrophages but are not degraded

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24
Q

do tattooing pigments evoke an inflammatory response

A

Not usually

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25
Q

name 3 endogenous pigments

A
  1. lipofuscin
  2. melanin
  3. hemosiderin
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26
Q

what is lipofuscin

A
  • insoluble brown pigment
  • phospholipids in complex with protein
  • weak and tear pigments
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27
Q

what is melanin

A

-brown-black pigment

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28
Q

what is melanin formed by

A

melanocytes

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29
Q

what is hemosiderin

A
  • golden yellow-to-brown

- granular or crystalline

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30
Q

when does hemosiderin form

A

when there is local or systemic iron excess to bleeding in some area

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31
Q

what are Russel bodies

A

globs of immunoglobins that accumulate

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32
Q

what are dutcher bodies

A

accumulation of protein

appear are pale blue bodies

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33
Q

what is dystrophic calcification

A

when cells lose their ability to regulate intracellular calcium and crystalline calcium phosphate forms

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34
Q

when does dystrophic calcification occur

A

-in dead/dying tissues in absence of systemic hypercalcemia

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35
Q

what is metastatic calcification

A

-calcium salts deposit due to hypercalcemia (ie. increased parathyroid hormone, Paget’s disease)

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36
Q

where does metastatic calcification occur

A

in normal tissues

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37
Q

what causes biological aging

A
  • decreased cellular replication
  • defective protein homeostasis
  • environmental and metabolic insults
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38
Q

decreased cellular replication (replicative senescence)

A

-shortened telomers, short repetitive nucleotide sequences at 3’end of DNA

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39
Q

defective protein homeostasis

A
  • reduced protein translation

- defective chaperone activity

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40
Q

environmental and metabolic insults

A

-accumulation of DNA, protein, phospholipid damage

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41
Q

what are the diseases of premature aging

A
  1. Hutchinson-Guilford progeria

2. Werner Syndrome

42
Q

what is Hutchinson-Guilford progeria

A

-a disease of premature aging

43
Q

what is the mechanism of Hutchinson-Guilford progeria

A
  • mutation in LMNA gene (encodes lamin A protein)
  • defective lamin A precurson protein termed Progerin
  • Progerin accumulates in nucleus (no longer round, irregular shaped)
44
Q

what are the characteristics of Hutchinson-Guilford progeria

A
  • see features of aging (male pattern baldness, atheroscelrosis/coronary artery disease)
  • typical lifespan less than 10 yrs
45
Q

what is Werner Syndrome

A
  • a disease of premature aging
  • a mutation in WRN gene, which codes for a protein with multiple DNA-dependent enzymatic activities
  • increased cancer risk
  • typically die in 5th decade
46
Q

what is the function of the WRN gene

A

plays a role in telomere length maintenance and processing of DNA damage

47
Q

what are characteristics of Werner Syndrome

A

-early cataracts, hair loss, skin atrophy, osteoporosis and atherosclerosis

48
Q

what is apoptosis

A
  • programmed cell death in which activated enzymes degrade the DNA/proteins
  • ATP-dependent process
  • involves single cells or small groups of cells
49
Q

where does apoptosis occur

A

in both physiologic and pathologic situations

50
Q

what is the function of apoptosis

A
  • role in developing and maintaining health by eliminating old, unhealthy or unnecessary cells
  • apoptotic cells break up into apoptotic bodies, membrane-bound vesicles of cytosol and organelles
51
Q

what happens to apoptotic bodies

A

are rapidly extruded and phagocytosed

52
Q

does apoptosis produce inflammation

A

NO!

53
Q

what are 4 types of physiologic apoptosis

A
  1. embryogenesis
  2. hormone-dependent tissue
  3. maintaining adequate cellular number
  4. elimination of self-reactive (harmful) lymphocytes
  5. elimination of “no longer needed” cells
54
Q

define embyogenesis

A

Implantation, organogenesis, developmental involution

55
Q

define hormone-dependent tissue

A

endometrial cell breakdown (menstrual cycle), ovarian follicular atresia (menopause), regression of the lactating breast

56
Q

maintaining adequate cellular number includes

A

antigenic selection of lymphocytes in bone marrow and thymus

57
Q

when does elimination of “no longer needed” cells occur

A

at the end of the inflammatory response

58
Q

what is pathologic apoptosis

not physiologic apoptosis

A

eliminates cells that have been irreversibly damaged avoiding inflammation and additional damage to surrounding tissue

59
Q

what are the causes of pathologic apoptosis

A
  1. DNA damage
  2. Protein misfolding
  3. infections
60
Q

DNA damage

A
  • direct or indirect (ROS) damage caused by radiation, drugs, hypoxia
  • intrinsic cell destruction is started to avoid DNA mutation
61
Q

protein misfolding

A

improper protein expression of mutated genes leads to accumulation of misfolded proteins causing ER stress and apoptotic cell death

62
Q

infections

A

mediated by infections agent (virus) or host immune response (cytotoxic T lymphocytes)

63
Q

what are morphologic changes associated with Apoptosis

A
  1. cell shrinkage
  2. chromatin condensation
  3. formation of apoptotic bodies
  4. macrophage phagocytosis
64
Q

what are the biochemical features of apoptosis

A
  1. activation of caspases
  2. DNA and protein breakdown
  3. membrane alteration and recognition by phagocytes
65
Q

what triggers apoptosis to begin

A

activation of caspases (cleavage of pro-enzymatic inactive state)

66
Q

what are caspases

A

family of cysteine proteases cleaving after aspartic acid residues

67
Q

what are 2 functional groups of caspases

A
  • initiators (caspases 8,9)

- executioners (caspases 3,6)

68
Q

what can DNA be cleaved by in agarose DNA gels

A

Ca++ and Mg++ dependent endonucleases btwn nucleosomal subunits

69
Q

what will viable cells look like in DNA gels

A

intact DNA

70
Q

what will apoptotic cells look like in DNA gels

A

ladder pattern of DNA fragments, which represent multiples of oligonucleosomes

71
Q

what does necrotic cells look like in DNA gels

A

diffuse smearing of DNA

72
Q

describe how membrane alterations can contribute to apoptosis

A
  • Phosphatidylserine on the cell membrane move from the inner to outer leaflet where they are recognized by a number of receptors on phagocytes
  • Adhesive glycoproteins are expressed on some apoptotic bodies, recognized by phagocytes
73
Q

describe the main mechanism of Apoptosis

A
  1. intrinsic mitochondrial)
  2. extrinsic (death receptor-mediated)
  3. cytotoxic CD8+ T-cell (perforin/granzyme-mediated)
    Through distinct mechanisms, pathways converge to activate caspases, the actual mediators of cell death
74
Q

what are the main players of viable cells in the mitochondria that aid with apoptosis

A

-cytochrome c

Bcl family of pro- and anti-apoptotic proteins

75
Q

what are the main players of viable cells in the cytoplasm that defend against apoptosis

A

Bcl-2 and Bcl-x

76
Q

what are Bcl-2 and Bcl-x

A

are anti-apoptotic proteins present in cytoplasm and mt and prevent mitochondrial protein leakage

77
Q

when are Bcl damage sensor proteins activated

A

in the presence of ER stress of DNA damage

78
Q

what activates pro-apoptotic Bax and Bak

A

-damage sensors

79
Q

what forms when pro-apoptotic Bax and Bak are activated

A

oligomers and insert into mitochondrial membrane allowing leakage of contents

80
Q

what does Bcl-2 and Bcl-x anti-apoptotic proteins do

A

-prevent pores leakage of contents by preventing formation of pores

81
Q

when is cytochrome c released

A

when Bax-Bak activation and anti-apoptotic Bcl blockage

82
Q

death receptor-mediated (extrinsic) pathway is involved in

A

elimination of self-reative lymphocytes

83
Q

describe the death receptor-mediated pathway

A
  • activated T-lyphocytes express Fas ligand
  • target cell (self-reactive thymocyte) will express Fas death receptor CD95
  • Fa ligand binding to Fas receptor binds to and activates caspase 8
  • TNF receptor type 1 (expressed on most cell types) binding to soluble mediator TNF also activates extrinsic pathway for apoptosis
84
Q

what do cytotoxic T cells release

A
  • perforins, punching holes in target cells

- granzymes which can activate caspases

85
Q

how are apoptotic cells removed

A
  • lipid components of the cellular membrane (phosphatidulserine) hcange their configuration making itself available to macrophage receptors
  • formation of apoptotic bodes break cells up into small fragments allowing for easy phagocytosis
  • secretion of soluble factors that recruit phagocytes (thrombospondin by apoptotic bodies)
86
Q

why is it crucial that the clearance of apoptotic cells is fast

A

crucial in avoiding secondary necrosis, inflammation and further tissue damage

87
Q

what is growth factor withdrawal

A

an intrinsic (mitochondrial) initiation pathway of apoptosis

88
Q

when does growth factor withdrawal occur

A

in the absence of survival signals (eg. growth factors) decreased synthesis of Bcl-2 and Bcl-x and activation of pro-apoptotic members the Bcl family leads to apoptosis

89
Q

examples that can lead to growth factor withdrawal

A
  1. Hormone-sensitive cells without relevant hormone
  2. Lymphocytes without antigenic/cytokines stimuli
  3. Neurons deprived of nerve growth factor
90
Q

what happens when DNA damage (genotoxic stress) occurs

A

p53 protein accumulates and signals the cell to arrest the cell cycle in G1 phase (to allow time for repair)

91
Q

what happens if DNA damage is irreversible

A

p53 triggers apoptosis by activating transcription of Bcl pro-apoptotic proteins (eg. Bax, Bak)

92
Q

what can lead to genotoxic stress

A

-exposure to radiation, toxins (chemotherapeutic drugs), free O2 radicals

93
Q

where are p53 mutations often seen

A

in cancer (ie. uterine serous carcinoma)

94
Q

mutated p53 is incapable of

A

inducing apoptosis therefore cells with damaged DNA are allowed to survive, proliferate and undergo malignant transformation

95
Q

what is uterine serous carcinoma

A

aggressive type of endometrial cancer associated with rapid progression of disease and a poor prognosis

96
Q

both USC and precursor lesions demonstrate what

A
  • strong p53 overexpression by immunohistochemistry

- suggests alterations of the p53 gene in their pathogenesis

97
Q

what are misfolded proteins tagged with

A

Ubiquitine and targeted for proteolysis

98
Q

if misfolded proteins accumulate in the ER what happens

A

they trigger the unfolded protein response which increases ubiquitination, degradation and decreased translation of defective proteins

99
Q

what happens if accumulation of misfolded proteins is excessive in the ER (ER stress)

A

caspases are activated and aptoptosis ensues

100
Q

intracellular accumulation of abnormally folded proteins can causes what neurodegerative diseases

A
  • Alzheimer
  • Huntington
  • Parkinson
101
Q

how can defects in apoptosis DECREASE cell survival

A

increase risk of:

  • Neurodegenerative diseases
  • Ischemic injury
  • Death of virus-infected cells
102
Q

how can defects in apoptosis INCREASE cell survival

A
  • p53 is the most common genetic abnormality found in human cancers
  • Failure to eliminate harmful cells (self-reacting lymphocytes) and dead cells (source of self-antigens)
  • Thus, defective apoptosis may be the basis of autoimmune disorders

Pathology (18 decks)

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