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MOD1 > Chapter 2 > Flashcards

Chapter 2 Flashcards

1
Q

What are the four aspects of the disease process?

A

hypertorphy, hyperplasia, atrophy, metaplasia

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2
Q

What is hypertrophy?

A

an increase in the SIZE of cells, the results in an increase in size of the affected organ

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3
Q

What is the most common stimulus for hypertrophy of muscle?

A

increased workload

in the heart: stimulus for hypertrophy is usually chronic hemodynamic overload resulting from HTN or faulty valves

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4
Q

What is the mechanism of hypertrophy?

A

increased production of cellular proteins

increased workload triggers mechanical sensors (TGFB, IGF1 -> activate secondary pathways (IP3) -> activate transcription factors (GATA4, NFAT, MEF2) -> increase synthesis of muscle proteins

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5
Q

What is hyperplasia?

A

increase in the NUMBER of cells in an organ or tissue in response to a stimulus

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6
Q

When is the only time hyperplasia can take place?

A

if the tissue contains cells capable of dividing (thus increasing the number of cells)

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7
Q

What is physiologic hyperplasia?

A

when there is a need to increase functional capacity of hormone sensitive organs, and when there is need for compensatory increase after damage or resection

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8
Q

What causes pathologic hyperplasia?

A

excessive or inappropriate actions of hormones or growth factors acting on target cells

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9
Q

What is an example of pathologic hyperplasia?

A

endometrial hyperplasia, caused by an increase in estrogen relative to progesterone, leading to hyperplasia of the endometrial glands -> leads to abnormal menstrual bleeding

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10
Q

What are patients with hyperplasia at increased risk for developing cancer?

A

in cancer, growth control mechanisms become deregulated, and pathologic hyperplasia constitutes a fertile soil in which cancerous proliferations may eventually arise

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11
Q

What is the mechanism of hyperplasia?

A

it is the result of growth factor driven proliferation of mature cells and in some cases, by increased output of new cells from stem cells

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12
Q

What is atrophy?

A

a reduction in the size of an organ or tissue due to a decrease in cell size and number

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13
Q

What are the causes of pathologic atrophy? (6)

A

decreased workload (atrophy of disuse), loss of innervation (denervation atrophy), diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and pressure

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14
Q

What can accompany prolonged disuse of muscle?

A

muscle atrophy can be accompanied by bone resorption, leading to osteoporosis of disuse

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15
Q

What is senile atrophy?

A

in late adult life, the brain may undergo progressive atrophy, mainly because of reduced blood supply as a result of atherosclerosis (can also affect the heart)

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16
Q

What is marasmus and what is it associated with?

A

profound protein-calorie malnutrition

associated with the utilization of skeletal muscle proteins as a source of energy after other reserves (adipose) have been depleted

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17
Q

What is cachexia?

A

muscle wasting

note: also seen in patients with chronic inflammatory disease and cancer

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18
Q

What is thought to be responsible for appetite suppression in patients with chronic inflammatory disease?

A

tumor necrosis factor (TNF) is thought to be responsible for appetite suppression and lipid depletion, culminating in muscle atrophy

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19
Q

What is characteristic of atrophic cells?

A

fewer mitochondria, myofilaments, and RER

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20
Q

What is the mechanism of atrophy?

A

decreased protein synthesis and increased protein degradation in cells

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21
Q

What is the main pathway of atrophy?

A

ubiquitin-proteasome pathway

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22
Q

What does ubiquitin ligase do?

A

a cellular marker that attaches ubiquitin to cellular proteins and targets the proteins or degradation in proteasomes

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23
Q

What generally accompanies atrophy?

A

autophagy (self-eating to reduce nutrient demand), marked by appearance of autophagic vacuoles

note: some cell debris can resist digestion and persist in the cytoplasm as membrane-bound residual bodies (example: lipofuscin granules)

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24
Q

What is metaplasia?

A

reversible change in which one differentiated cell (epithelial or mesenchymal) is replaced by another cell type

note: often an adaptive response

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25
Q

What is the most common epithelial metaplasia?

A

columnar to squamous (as occurs in the respiratory tract in response to chronic irritation like smoking)

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26
Q

What can a deficiency of vitamin A induce in the respiratory tract?

A

squamous metaplasia in the respiratory epithelium

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27
Q

What is lost in metaplasia?

A

although squamous cells are tougher than fragile columnar cells, important mechanisms of protection against infection (mucus secretion and ciliary action) are lost

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28
Q

What are other common sites of metaplasia? (2)

A
  • Barrett esophagus: squamous to columnar, under the influence of refluxed gastric acid
  • connective tissue: formation of bone, adipose or CT in tissue that normally doesnt contain those elements
    note: myositis ossificans - occurs after intramusclular hemorrhage
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29
Q

What is the mechanism of metaplasia?

A

is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue

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30
Q

What affect does retinoic acid have on metaplasia?

A

there is a direct link between transcription factor disregulation and metaplasia with vitamin A deficiency

note: retinoic acid regulates gene transcription directly thru nuclear retinoid receptors, which can influence differentiation of progenitors derived from tissue stem cells.

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31
Q

What are the hallmarks of reversible injury?

A

reduced oxidative phosphorylation with resultant depletion of ATP, cellular swelling (caused by changed in ion concentration/H2O influx), and alterations in organelles (mitochondria/cytoskeleton)

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32
Q

What are the two principal types of cell death?

A

necrosis and apoptosis

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33
Q

Why is necrosis considered accidental?

A

it results from damage to cell membranes and loss of ion homeostasis
note: when damage is severe, lysosomal enzymes enter the cytoplasm and digest the cell

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34
Q

Why does necrosis cause inflammation?

A

cellular contents leak thru the damaged plasma membrane into extracellular space, where they elicit a host reaction

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35
Q

When does a cell undergo apoptosis?

A

when the cell’s DNA or proteins are damaged beyond repair, characterized by nuclear dissolution, fragmentation, and rapid removal of cellular debris

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36
Q

What are the causes of cell injury? (7)

A

hypoxia, physical agents, chemical agents, infectious agents, immunologic reactions, genetic derangements, nutritional imbalance

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37
Q

What can cause hypoxia? (4)

A

reduced blood flow (ischemia), inadequate oxygenation of blood d/t cardiorespiratory failure, decreased oxygen-carrying capacity, or severe blood loss

note: depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die

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38
Q

What are physical agents capable of causing injury? (5)

A

mechanical trauma, temp extremes, sudden changed in atmospheric pressure, radiation, electric shock

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39
Q

What are examples of simple chemicals that can cause injury?

A

glucose or salt in hypertonic concentrations, oxygen at high concentrations, trace amounts of poisons (arsenic, cyanide, mercuric salts)

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40
Q

How do genetic defects cause cell injury?

A

deficiency in functional proteins, such as enzyme defects in inborn errors of metabolism, accumulation of damaged DNA or misfolded proteins, or DNA sequence variations (polymorphisms)

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41
Q

What effect does an excess of cholesterol in the diet have on our cells?

A

excess cholesterol predisposes to atherosclerosis, and is associated with increased risk of diabetes and cancer

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42
Q

describe the features of necrosis:

cell size, nucleus, p.membrane, cellular contents, adjacent inflammation, physiologic or pathologic role

A

cell size: enlarged
nucleus: pyknosis -> karyorrhexis -> karyolysis
p.membrane: disrupted
cellular contents: enzymatic digestion (may leak out of cell)
adjacent inflammation: frequent
phys/pathologic role: invariable pathologic (culmination of irreversible cell injury)

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43
Q

describe the feature of apoptosis:

cell size, nucleus, p.membrane, cellular contents, adjacent inflammation, physiologic or pathologic role

A

cell size: reduced
nucleus: fragmentation into nucleosome-sized fragments p.membrane: intact, altered structure, especially orientation of lipids
cellular contents: intact, may be released in apoptotic bodies
adjacent inflammation: no
phys/pathologic role: often physiologic, means of eliminating unwanted cells
NOTE: may be pathologic after some forms of cell injury, especially DNA damage

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44
Q

What is the first manifestation of almost all forms of cell injury?

A

cellular swelling

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45
Q

What does cellular swelling cause at the macroscopic level? (3)

A

pallor (paleness), increased turgor (hydrostatic pressure), increased weight of the organ

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46
Q

What does cellular swelling cause at the microscopic level?

A

small clear vacuoles may be seen in cytoplasm (distended segments of ER), may also show increased eosinophillic staining (becomes much more pronounced with necrosis)

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47
Q

Where are the enzymes derived from that digest necrotic cells?

A

lysosomes of the dying cell and from lysosomes of leukocytes or inflammatory reaction

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48
Q

When can you see earliest signs of myocardial necrosis?

A

4-12 hours

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49
Q

When can you first detect cardiac specific enzymes and proteins in the blood after an MI?

A

as early as 2 hours after myocardial cell necrosis, because the plasma membrane loses its integrity so enzymes and proteins are rapidly released

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50
Q

What is the fundamental cause of necrotic cell death?

A

reduction in ATP levels

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51
Q

What is ATP depletion frequently associated with? (2)

A

hypoxic and chemical injury

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52
Q

What is the major cause of ATP depletion? (3)

A

reduced oxygen/nutrient supply, mitochondrial damage, and the action of some toxins (cyanide)

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53
Q

How does mitochondrial damage lead to necrosis?

A

decreased oxidative phosphorylation -> decrease in ATP:

  1. decrease in Na-pump activity -> ER swelling, cellular swelling, loss of microvilli, blebs (cytoplasmic swelling)
  2. increase in anaerobic glycolysis -> decrease in glycogen, decrease in pH -> clumping of nuclear chromatin
  3. detachment of ribosomes -> decrease protein synthesis
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54
Q

What are the three major consequences of mitochondrial damage?

A

mitochondrial permeability transition pore, reactive oxygen species, and caspase activation

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55
Q

What is a mitochondrial transition pore?

A

high-conductance channel in the mitochondrial membrane, that leads to the loss of membrane potential, resulting in failure of oxidative phos. and depletion of ATP -> necrosis

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56
Q

What is cyclophilin D, and why is it important?

A

it is a structural component of mitochondrial permeability transition pore and is one of several cyclophilins that is targeted by the immunosuppressive drug cyclosporine (used to prevent graft rejection)

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57
Q

How does increased intracellular Ca cause injury? (3)

A
  1. opens mitochondrial permeability transition pore
  2. activates enzymes with deleterious effects of cells (phospholipases, proteases, endonucleases, ATPases)
  3. activates caspases -> apoptosis
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58
Q

What pathologies can oxidative stress cause?

A

cell injury, cancer, aging and some degenerative diseases including Alzheimers

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59
Q

Superoxide anion:

  1. mech of production
  2. mech of inactivation
  3. pathologic effects
A
  1. incomplete reduction of O2 during ox.phos, by phagocyte oxidase in leukocytes
  2. conversion of H2O2 and O2 by superoxide dismutase
  3. stimulates rodcution of degradative emzymes in leukocytes ad other cells, may directly damage lipids, proteins and DNA (acts close to site of production)
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60
Q

Hydrogen peroxide

  1. mech of production
  2. mech of inactivation
  3. pathologic effects
A
  1. generated by superoxide dismutase from O2, and by oxidases in peroxisomes
  2. conversion of H2O and O2 by catalase (in peroxisomes), glutathione peroxidase (cytosol, mitochondria)
  3. can be converted to hydroxyl radical and OCl-, which destroy microbes and cells, can act distant from site of production
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61
Q

Hydroxyl radical

  1. mech of production
  2. mech of inactivation
  3. pathologic effects
A
  1. generated from H2O by hydrolysis (radiation), from H2O2 by fenton rxn, or from superoxide anion (O2)
  2. conversion from H20 by glutathione peroxidase
  3. ***most reactive oxygen-derived free radical, principal ROS responsible for damaging lipids, proteins and DNA
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62
Q

Peroxynitrite (ONOO-)

  1. mech of production
  2. mech of inactivation
  3. pathologic effects
A
  1. produced by interaction of superoxide anion and NO generated by NO synthase in many cell types (endothelial, leukocytes, neurons)
  2. conversion of HNO2 by peroxiredoxins (cytosol, mitochondria)
  3. damages lipids, proteins, DNA
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63
Q

What are the three relevant ROS reactions that are relevant to cell injury?

A
  1. lipid peroxidation in membranes
  2. oxidative modification of proteins (free radicals promote cross-links like disulfide bonds)
  3. lesions in DNA (free radicals can cause single and double strand breaks)
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64
Q

What are the four possible mechanisms of membrane damage?

A
  1. ROS
  2. decreased phospholipid synthesis (defective mitochondria)
  3. increased phospholipid breakdown (activation of Ca-dependent phospholipases -> leads to accumulation of lipid breakdown products)
  4. cytoskeletal abnormalities (activation of proteases by increased Ca may cause damage)
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65
Q

What are the most important sites of membrane damage during cell injury? (3)

A

mitochondrial membrane, plasma membrane, and lysosome membranes (enzymatic dissolution)

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66
Q

What happens if cellular damage is too severe to be corrected?

A

cell initiates apoptosis. a similar reaction is triggered by improperly folded proteins (d/t either inherited or acquired mutations)

67
Q

What two phenomena characterize irreversible damage?

A
  1. inability to reverse mitochondrial dysfunction (lack of ox.phos and ATP)
  2. profound disturbance in membrane function
68
Q

How can you detect tissue-specific cellular injury?

A

checking blood serum samples for leakage of intracellular proteins

cardiac: creatine kinase, troponin
liver: alkaline phosphatase, transaminases

69
Q

What is the most common type of cell injury?

A

ischemia, it results from hypoxia induced by reduced blood flow

70
Q

What are the two most common causes of ischemia?

A

mechanical arterial obstruction or reduced venous drainage

71
Q

Why does ischemia cause more rapid and severe injury than hypoxia?

A

Not only is aerobic metabolism compromised, but anaerobic energy generation stops after glycolytic substrates are exhausted
- also see an accumulation of metabolites that inhibit glycolysis (that are normally washed away by flowing blood)

72
Q

What is irreversible injury associated with?

A

severe swelling of mitochondria, extensive damage to p.membranes (giving rise to myelin figures) and swelling of lysosomes

73
Q

What are myelin figures?

A

large masses composed of phospholipids, that form as cellular components are degraded after ischemia. they are either phagocytosed by leukocytes or degraded further into FA’s
NOTE: calcification of the FA residues may occur, with the formation of calcium soaps

74
Q

When would you see a massive influx of Ca into myocardial cells in the injury process?

A

30-40 minutes after ischemia, particularly if the ischemic zone is reperfused

75
Q

What is hypoxia-inducible factor-1?

A

a protective response to deal with hypoxic stress, it promotes new blood vessel formation, stimulates several pathways and enhances aerobic glycolysis

76
Q

What is considered the most useful strategy for reducing ischemic injury to the brain and spinal cord?

A

transient induction of hypothermia (reducing the core temperature to 92 degrees)
NOTE: this treatment reduces metabolic demands of the stressed cells, decreases cell swelling, suppresses formation of free radicals, and inhibits host inflammatory response

77
Q

Why is ischemia-reperfusion injury important?

A

it contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow

78
Q

How does reperfusion injury occur?

A

new damaging processes are set in motion during reperfusion, causing death of cells that may have otherwise recovered

79
Q

What are the mechanisms of reperfusion injury? (4)

A
  1. oxidative stress (increased generation of ROS and nitrogen species)
  2. intracellular calcium overload (favors opening of the mitochondrial permeability transition pore)
  3. inflammation
  4. activation of complement system (IgM Ab’s have propensity to deposit in ischemic tissues)
80
Q

What is the most common reason for terminating theraputic drug therapies?

A

toxic liver injury

81
Q

What are the two general mechanisms of toxic injury?

A
  1. direct toxicity: chemicals can injure cells directly by combining with critical molecular components (ex: mercury poisoning, mercury binds to sulfhydryl groups of cell membrane proteins)
  2. conversion to toxic metabolites (metabolites cause membrane damage and cell injury mainly by formation of free radicals and lipid peroxidation)
82
Q

Where is the greatest damage in direct toxicity?

A

usually to the cells that use, absorb, excrete or concentrate the chemicals

83
Q

What are apoptotic bodies?

A

cell fragments that contain portions of the cytoplasm and nucleus -> are targets for phagocytes

84
Q

What pathologic conditions cause apoptosis? (4)

A
  1. DNA damage (radiation)
  2. accumulation of misfolded proteins (gene mutations, leads to ER stress)
  3. cell death in certain infections (viral infections -> T lymphocytes induce apoptosis)
  4. pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid gland, pancreas)
85
Q

What is the most common feature of apoptosis?

A

chromatin condensation

but also cell shrinkage, bleb and apoptotic body formation, and phagocytosis

86
Q

What is a cellular marker for cells undergoing apoptosis?

A

the presence of cleaved, active caspases

87
Q

What are the two phases of apoptosis?

A
  1. initiation: caspases become active

2. execution: other caspases trigger degradation of critical cellular components

88
Q

What two pathways converge on caspase activation?

A
  1. mitochondrial (intrinsic) pathway

2. death receptor (extrinsic) pathway

89
Q

What is the major mechanism of apoptosis in mammalian cells?

A

the intrinsic pathway

90
Q

What initiates the intrinsic pathway?

A

increased permeability of mitochondrial outer membrane causes release of cytochrome C molecules from intermembranous space into the cytoplasm

91
Q

What controls the release of mitochondrial pro-apoptotic proteins?

A

BCL2 family

92
Q

What are the three groups of BCL2 proteins?

A
  1. anti-apoptotic: BCL2, BCL-XL, MCL1 (they prevent leakage of cytochrome c into the cytosol)
  2. pro-apoptotic: BAX, BAK (form a channel in outer mitoch. membrane, allowing Cyt C leakage)
  3. sensors: BAD, BIM, BID, Puma, Noxa (sense cellular stress and damage)
93
Q

What does cytochrome C bind to once in the cytosol?

A

APAF-1 -> forms apoptosome and is able to bind caspase 9

94
Q

What is the critical initiator caspase of the mitochondrial pathway?

A

caspase 9

95
Q

What does caspase 9 cleavage trigger?

A

caspase cascade that activates other caspases and active enzymes . Smac/Diablo (other proteins) enter the cytoplasm where they bind and neutralize cytoplasmic proteins that function as apoptosis inhibitors (IAPs)

96
Q

What do IAPs do?

A

they block the activation of caspases (including caspase 3 executioner) and keep cells alive

97
Q

What does neutralization of IAPs permit?

A

the initiation of a caspase cascade

98
Q

What initiates the extrinsic pathway?

A

plasma membrane death receptors (members of TNF family)

99
Q

What are the best known death receptors?

A

type 1 TNF receptor and CD 95

100
Q

Where is FasL expressed?

A

on T cells that recognize self antigens (and some cytotoxic T lymphocytes)

101
Q

What happens when FasL binds FasR?

A

three or more molecules of Fas are brought together and their cytoplasmic death domains form a binding site for an adaptor protein FADD, which also has a death domain

102
Q

What happens when FADD attached to death receptors binds inactive caspase 8?

A

multiple pro-caspase-8 molecules are brought into proximity and they cleave one another to generate active caspase 8

103
Q

Where is phosphatidylserine usually found in healthy cells?

A

the inner leaflet of the plasma membrane

104
Q

Where is phosphatidylserine found in apoptotic cells?

A

the phospholipid flips out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors

105
Q

What is thrombospondin?

A

an adhesive glycoprotein that coats apoptotic bodies. it is recognized by phagocytes, targeting cells for engulfment

106
Q

What is C1q?

A

a natural antibody of the complement system that coats apoptotic bodies

107
Q

What is the unfolded protein response?

A

a number of cellular responses that increase the production of chaperones, enhance proteasomal degradation of abnormal proteins, and reduce the load of misfolded proteins in the cell

108
Q

What is ER stress?

A

if cytoprotective responses are unable to cope with the accumulation of misfolded proteins the cell activates caspases and induces apoptosis

NOTE: this is now recognized as a feature of a number of neurodegenerative diseases, including Alzheimers, Huntington and Parkinsons disease

109
Q

Cystic fibrosis

  1. affected proteins
  2. pathogenesis
A
  1. cystic fibrosis transmembrane conductance regulator (CFTR)
  2. loss of CFTR leads to defects in chloride channel
110
Q

Familial hypercholesterolemia

  1. affected proteins
  2. pathogenesis
A
  1. LDL receptor

2. loss of LDLr leading to hypercholesterolemia

111
Q

Tay-Sachs disease

  1. affected proteins
  2. pathogenesis
A
  1. hexosaminidase beta subunit

2. lack of the lysosomal enzyme leads to storage of GM2 gangliosides in neurons

112
Q

Alpha-1-antitrypsin deficiency

  1. affected proteins
  2. pathogenesis
A
  1. alpha 1-antitrypsin
  2. storage of nonfunctional protein in hepatocytes causes apoptosis, absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema
113
Q

Creutzfeldt-Jacob disease

  1. affected proteins
  2. pathogenesis
A
  1. prions

2. abnormal folding of PrPsc causes neuronal cell death

114
Q

Alzheimer disease

  1. affected proteins
  2. pathogenesis
A
  1. AB peptide

2. abnormal folding of AB peptides causes aggregation within neurons and apoptosis

115
Q

What do cytotoxic T lymphocytes secrete upon activation?

A

perforin (a transmembrane pore-forming molecule, which promotes the entry of CTL granzymes)

116
Q

What do granzymes do?

A

cleave proteins at aspartate residues and activate a variety of cellular caspases

117
Q

What is the most common genetic abnormality found in human cancers?

A

TP53 mutation (disorders associated with defective apoptosis)

118
Q

What might be the basis of autoimmune disorders?

A

defective apoptosis

119
Q

What disorders are associated with increased apoptosis/excessive cell death? (3)

A
  1. neurodegenerative disease
  2. ischemic injury
  3. death of virus-infected cells
120
Q

How does necroptosis resemble necrosis?

A

loss of ATP, swelling of cell and organelles, ROS generation, lysosomal enzyme release, p.membrane rupture

121
Q

How does necroptosis resemble apoptosis?

A

it is triggered by genetically programmed signal transduction events that culminate in cell death

NOTE: necroptosis sometimes calls programmed necrosis

122
Q

How is necroptosis different than apoptosis?

A

the genetic program that drives it does NOT result in caspase activation

NOTE: it is sometimes referred to as caspase-independent programmed cell death

123
Q

What are the two unique kinases involved in necroptosis?

A

receptor associated kinase 1 and 3 (RIP1 and RIP3)

124
Q

What recruits RIP1 and RIP3?

A

TNFR1 recruits them into a multiprotein complex that also contains caspase-8

125
Q

When does necroptosis occur physiologically?

A

in the mammalian bone growth plate, steatohepatitis, acute pancreatitis, reperfusion injury and neurodegenerative disease such as Parkinsons

126
Q

What is pyroptosis?

A

programmed cell death that is accompanied by release of fever inducing cytokine IL1

NOTE: this pathway shares some biochemical similarities with apoptosis

127
Q

What is the function of the inflammasome?

A

to activate caspase-1 (aka interleukin 1beta converting enzyme), which cleaves a precursor form of IL1 and releases the active form

128
Q

What is the end result of pyroptosis?

A

results in the death of some microbes that gain access to the cytosol and promote the release of inflammasome-generated IL1

129
Q

What are the three categories of autophagy?

A
  1. chaperone-mediated
  2. microautophagy (inward invagination)
  3. macroautophagy (major form, involves an autophagosome)
130
Q

What are the steps of autophagy? (3)

A
  1. formation of an isolation membrane (phagophore) and its nucleation
  2. elongation of the vesicle
  3. maturation of the autophagosome, its fusion with lysosomes and eventual degradation of the contents
131
Q

What are Atgs?

A

autophagy-related genes

132
Q

What human diseases does autophagy play a role in? (4)

A
  1. cancer
  2. neurodegenerative disorders (Alzheimers)
  3. infectious disease (mycobacteria, Shigella, HSV1)
  4. inflammatory bowel disease both Chrons and UC shown to have links to SNP’s in autophagy related genes
133
Q

What are the four main pathways of abnormal intracellular accumulation?

A
  1. inadequate removal of normal substance secondary to defects in packaging and transport (liver steatosis)
  2. accumulation of abnormal endogenous defects in folding. packaging, transport or secretion (alpha1-antitrypsin)
  3. failure to degenerate a metabolite d/t inherited enzyme deficiencies (storage diseases)
  4. deposistion/accumulation of abnormal exogenous substance when the cell has neither when the cell has neither enzymatic machinery to degrade nor the ability to transport it to other sites (accumulation of carbon or silica particles)
134
Q

What is the most common cause of significant fatty change in the liver?

A

alcohol abuse and nonalcoholic fatty liver disease (associated with diabetes and obesity)

135
Q

What are the four types of cholesterol accumulation pathologies? (4)

A
  1. atherosclerosis: cells have foamy appearance (foam cells), lipid vacuoles aggregate in intimal layer
  2. xanthomas: intracellular accumulation of cholesterol within macrophages, foam cells found in subepithelial connective tissue of the skin and tendons -> produce tumorous masses
  3. cholesterolosis: accumulation of cholesterol-laden macrophages in lamina propria of gallbladder
  4. Niemann-Pick disease, type C: lysosomal storage disease caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs
136
Q

How do intracellular protein accumulations usually appear?

A

rounded, eosinophilic droplets, vacuoles or aggregates in the cytoplasm

137
Q

What are the five types of protein accumulation pathologies?

A
  1. reabsorption droplets in proximal renal tubules (proteinuria: increased reabsorption of protein into vesicles)
  2. russell bodies: large, eosinophilic inclusions of distended ER
  3. defective intracellular transport and secretion of critical proteins (alpha1 antitrypsin deficiency: buildups aggregate in ERof liver and are not secretes, results in emphysema)
  4. accumulation of cytoskeletal proteins
  5. aggregation of abnormal proteins (deposits may be intracellular, extracellular, or both) ex: amyloidosis, proteinopathies, protein-aggregation diseases
138
Q

When are excessive intracellular gycogen deposits seen?

A

patients with glucose or glycogen metabolism abnormalities

139
Q

What is the prime example of a glucose metabolism disorder?

A

diabetes mellitus

140
Q

What is the most common exogenous pigment?

A

carbon (coal dust): when inhaled, is picked up by macrophages. accumulations blacken the lung tissue, can lead to coal worker’s pneumoconiosis

NOTE: tattooing is a form of localized exogenous skin pigmentation

141
Q

What are the two endogenous pigments discussed?

A
  1. lipofuscin (lipochrome): derived thru lipid peroxidation of polyunsaturated lipids
  2. hemosiderin (hemoglobin-derived, golden yellow to brown)
142
Q

When is lipofuscin seen and where?

A

in cells undergoing slow, regressive changes

is particularly prominent in the liver and heart

143
Q

What is the only black-brown endogenous pigment?

A

melanin, seen in alkaptonuria

144
Q

What does the body do with an excess of iron?

A

ferritin forms hemosiderin granules (micelles)

145
Q

Where can small amounts of hemosiderin be seen under normal conditions?

A

mononuclear phagocytes of bone marrow, spleen and liver, which are actively engaged in red cell breakdown

146
Q

What is an example of local excess of hemosiderin?

A

bruises, result from hemorrhages in tissues. red blood cells are phagocytosed over several days by macrophages, which break down hemoglobin and recover the iron. heme is then converted to biliverdin (green), then bilirubin (red). iron released is incorporated into ferretin and eventually hemosiderin

147
Q

What happens when there is a systemic overload of iron?

A

hemosiderin can be deposited in organs and tissues (hemosiderosis)

148
Q

What are the main causes of hemosiderosis?

A
  1. increased absorption of dietary iron d/t inborn error of metabolism called hemochromatosis
  2. hemolytic anemias
  3. repeated blood transfusions
149
Q

What is the hyaline change?

A

alteration within cells or in the extracellular space that gives a homogenous, glassy, pink appearence. it is produced by a variety of alterations and does not represent a specific pattern of accumulation

ex: reabsorption droplets, russell bodies, alcoholic hyaline

150
Q

What are the two forms of pathologic calcification?

A
  1. dystrophic (in areas of necrosis)

2. metastatic (normal tissues whenever there is hypercalcemia: usually a consequence of PTH excess)

151
Q

Where is calcification almost always present?

A

atheromas of advances atherosclerosis and aging/damaged heart valves

152
Q

What are serum calcium levels in dystrophic calcification?

A

normal

153
Q

What are the four principal causes of hypercalcemia?

A
  1. elevated PTH
  2. resportion of bone tissue
  3. vitamin D-related disorders
  4. renal failure
154
Q

What are the less common causes of hypercalcemia?

A

aluminum intoxication and milk-alkali syndrome (excessive ingestion of calcium and absorbable antacids)

155
Q

Where does metastatic calcification primarily affect?

A

gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins

156
Q

What are the mechanisms of cellular aging?

A
  1. DNA damage

2. cellular senescence

157
Q

What is Werner syndrome?

A

premature aging due to defective DNA helicase (causes rapid accumulation of chromosomal damage)

158
Q

What are the two types of cellular senescence?

A
  1. telomere attrition (shortening): results in cell cycle arrest
  2. activation of tumor suppressor genes (particullarly CDKN2A, is correlated with chronologic age in virtually all human tissues
159
Q

What is defective protein homeostasis?

A

the balance between maintaining proteins in correctly folded conformation and degradation of misfolded proteins by autophagy-lysosome and/or ubiquitin-proteasome systems

160
Q

What is deregulated nutrient sensing?

A

it is thought that caloric restriction increases lifespan in all eukaryotic species by reducing the signaling intensity of IGF1 pathway and increasing sirtuins

161
Q

What is IGF1?

A

mimics intracellular signaling by insulin and informs cells of the availability of glucose (promoting growth and replication)

162
Q

What are the downstream targets of IGF1?

A

AKT and mTOR

163
Q

What are sirtuins?

A

a family of NAD-dependent protein deacytlases (at least 7 types), they are located in various cellular compartments and are designed to adapt bodily functions to various environmental stresses (food deprivation, DNA damage)

NOTE: they are thoughts to promote longevity by inhibiting metabolic activity, reducing apoptosis, stimulating protein folding and inhibiting free radical damage

MOD1 (4 decks)

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