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BMS 460 > Cellular Pathology > Flashcards

Cellular Pathology Flashcards

1
Q

what is the overall cause of cell injury?

A

disruption of cellular homeostatic mechanisms

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2
Q

describe cellular injury as a consequence of calcium overload

A
  • first, some agent injures the cell and the result is increased Ca2+ (can come from injurious agent itself, the mitochondria, or the ER)
  • increased cytosolic Ca2+ has 4 major effects:
    1. affects ATPase: leads to decreased ATP
    2. affects phospholipase: decreased phospholipids
    3. affects proteases: disruption of membrane and cytoskeletal proteins
    4. affects endonuclease: results in nuclear chromatin damage!! probably clumping of chromatin/formation of heterochromatin
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3
Q

describe the cellular Ca2+ gradient

A
  • Ca2+ is way more abundant than extracellular fluid than it is in the cytosol
  • this gradient is maintained by 1) the passive impermeability of the plasma membrane to Ca2+ and 2) ATP - dependent extrusion of Ca2+ from the cell
  • disruption of these processes = critical event in lethal cell injury (causes dystropic calcification)
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4
Q

dystropic calcification

A

macroscopic deposition of calcium salts, results from disruption of Ca2+ permeability barrier and consequent increase in intracellular Ca2+

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5
Q

describe calcification as seen in chronic renal failure

A
  • increased intracellular Ca2+
  • impaired renal excretion of phosphate
  • result is calcium phosphate salts in the eye, heart, blood vessels
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6
Q

describe cellular adaptations

A

persistent but sub-lethal

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7
Q

describe reversible injury

A
  • mild and short-lived
  • will revert back to normalcy
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8
Q

describe irreversible injury

A
  • severe, doesn’t revert to normalcy
  • necrosis, apoptosis, pyroptosis
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9
Q

describe the ways that cell injury can be acquired

A
  • stress that results in unsuccessful adaptation (inability to adapt)
  • injurious stimulus
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10
Q

describe basic reversible vs. irreversible injury pathways

A
  • reversible: mild, transient, soon return to normal cell (homeostasis)
  • irreversible: severe, progressive, results in necrosis or apoptosis
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11
Q

atrophy

A

decrease in cell size

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12
Q

hypertrophy

A

increased cell size

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13
Q

hyperplasia

A

increased cell number

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14
Q

metaplasia

A

conversion of one cell type to another (remember how this happens in ADPKD!)

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15
Q

dysplasia

A

disorderly growth (most cancers start from a dysplastic cell!)

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16
Q

characteristics of normal epithelium

A
  • cadherins (cell-cell adhesion)
  • intact basement membrane
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17
Q

describe CIS

A
  • stands for carcinoma in situ
  • cadherins no longer functioning, cells are disorderly
  • still local, has not metastasized because the cells have not invaded the basement membrane, so they are still confined within the epithelial layer
  • therefore, this is treatable!!
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18
Q

describe the time scale of the series of biochemical and morphological that occur with cell injury that is severe enough to cause cell death (slide 15)

A
  • start at homeostasis
  • cell injury occurs
  • reversible changes:
    –> ATP depletion
    –> biochemical dysfunction
    –> early ultrastructural changes
  • cell death
  • irreversible changes:
    –> late ultrastructural changes
    –> early light microscopic changes
    –> late light microscopic changes
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19
Q

time scale of pathologic findings of cellular responses to injury (slide 15)

A
  • start: normal
  • seconds: no change
  • minutes: no change
  • 15-60 minutes:
    –> ER swelling and ribosome dissociation
    –> membrane rupture, mitochondrial inclusions
  • 4-8 hours
    –> hypereosinophilia of cytoplasm, other features variable depending on the involved tissue
    –> karyolysis, coagulative necrosis, influx of neutrophils
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20
Q

do acute injuries always show characteristic pathologic changes?

A

no, because when an injury is acute enough to cause rapid death of organism, there often isn’t sufficient time for typical cellular responses to develop

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21
Q

cell injury: decreased ATP

A

leads to multiple downstream effects

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22
Q

cell injury that involves mitochondrial damage

A

leads to leakage of pro-apoptotic proteins, as well as decreased ATP

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23
Q

cell injury that involves entry of Ca2+

A

leads to increased mitochondria permeability and activation of multiple cellular enzymes

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24
Q

what are the effects of cell injury that involves increased reactive oxygen species?

A

damage to lipids, proteins, and DNA

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25
Q

what are the effects of cell injury that involves membrane damage?

A

plasma membrane damage leads to loss of cellular components, lysosomal membrane damage leads to enzymatic digestion of cellular components

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26
Q

cell injury that involves protein misfolding, DNA damage

A

leads to activation of pro-apoptotic proteins

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27
Q

what does anoxia (or any other form of energy deprivation) cause?

A
  • reduction in ATP synthesis and malfunction of the ATP-dependent Na+/K+ pump
  • this causes Na+ and water to move into the cell, which = cellular swelling
  • this is hydropic or vacuolar degeneration!
  • organelles swell (including mitochondria), so less energy made
  • cell reverts to anaerobic glycolysis, then pH becomes acidic
  • organelles break and disentigrate, membranes curl up into concentric bodies
    –> myelin figures: rolled up phospholipid bilayers (need electron microscope to see)
    –> clumping of nuclear chromatin
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28
Q

what is the first manifestation of almost all forms of injury to cells?

A

cellular swelling!

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29
Q

how are myelin figures observed?

A
  • first of all, myelin figures are a manifestation of hydropic degeneration in which phospholipid membranes roll up as organelles break and disintegrate
  • they are observed with the electron microscope in the cytoplasm or as an inclusion in mitochondria and autophagic vacuoles
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30
Q

define ischemia

A

decrease in blood supply to a bodily organ, tissue, or part caused by constriction or obstruction of blood vessels

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31
Q

describe the pathway of cell injury caused by ischemia

A
  • MAIN IDEA: causes clumping of nuclear chromatin and lipid deposition!!!
  • ischemia (loss of blood supply) results in hypoxia
  • this decreases oxidative phosphorylation in the mitochondria, decreasing ATP production, which leads to 3 things:
    1. decreased Na+ pump activity, resulting in influx of Ca2+, H2O, and Na+. also increased efflux of K+. this results in ER swelling, cellular swelling, loss of microvilli, and blebs!
    2. increased anaerobic glycolysis, leading to decreased glycogen (b/c using it), and increased lactic acid which decreased pH, causing clumping of nuclear chromatin!
    3. detachment of ribosomes, causing decreased protein synthesis and lipid deposition!
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32
Q

what are intracellular inclusions and how can they come about?

A
  • reversible cell injury!!
  • accumulation of normal substances in excess caused by abnormal metabolism (ex: fatty liver)
  • abnormal substances because of faulty synthesis or transport. this could be the result of mutations causing defective protein folding/transport, or deficiency of critical enzymes for lysosomal degredation
  • accumulation of pigments and phagocytosed particles due to inability to degrade (indigestion of indigestible particles)
33
Q

examples of intracellular accumulations that are pigments that get phagocytosed due to inability to degrade

A
  • remember, this is classified as reversible cell injury!!
  • melanin: for example, UV exposure can cause increased melanin production to the point where it can’t be properly degraded
  • hemosiderin: toxic form of partially broken down ferritin in the blood
  • bilirubin: result of liver issues in which red blood cells are not properly broken down into bilirubin/bilirubin is not excreted
  • can be inorganic, like silicone dust that gets into lung that can’t get degraded
34
Q

caveat for reversible cell injuries resulting in intracellular inclusions?

A

some of these manifestations may not be reversible if the magnitude is severe, especially with genetic conditions!

35
Q

alpha1-antitrypsin (AAT) deficiency

A
  • hereditary disease that causes cell injury leading to intracellular inclusions
  • autosomal recessive disorder involving SERPINA1 gene
  • mutation in this gene impairs secretion of AAT (a serine protease inhibitor) from hepatocytes into serum!
  • AAT normally serves to inhbit proteases released from neutrophils at sites of inflammation
  • there are 3 alleles (M (normal), S, and Z, so several degrees of deficiency
  • all alleles inherited codominantly
36
Q

ATT deficiency variants (alleles)

A

from most severe to least severe:
ZZ, SZ, MZ, MS
- these show a selective defect in migration of this secretory protein (AAT) from the ER to the golgi (and therefore it cannot be secreted from hepatocytes into serum)

37
Q

what can AAT deficiency cause?

A
  • liver disease in infants, children, and adults
  • can lead to lung disease in adults
  • due to pathologic accumulation of AAT in hepatocytes, liver damage occurs and is the most common cause of cirrhosis in children
  • these individuals are at an increased risk for hepatocellular carcinoma
38
Q

describe AAT accumulation in the liver (histology)

A
  • need PAS stain, can see PAS positive globules in the liver
  • if they are PAS positive, we know that AAT is a glycoprotein!!
39
Q

describe neonatal hepatitis: cholestasis (histology)

A
  • hepatitis: liver inflammation
  • cholestasis: bile accumulation in the liver
  • can see intraheptic cholestasis (bile buildup) which is reddish
40
Q

describe emphysema in AAT deficiency

A
  • one of the functions of AAT is to protect the lungs from proteases
  • neutrophil elastase is a powerful enzyme secreted in the lungs (during inflammatory response) that disrupts connective tissue
  • when serum AAT is deficient (<15% of normal), elastase continues unopposed destruction of elastic fibers in the alveolar wall, which leads to emphysema
41
Q

how does cigarette smoke relate to AAT deficiency?

A
  • cigarette smoke induces alveolar macrophages to secrete proteases and chemoattractants to recruit neutrophils
  • the neutrophils will chronically release elastase, which no amount of AAT would be able to overcome
  • in this case, there is not a deficiency of AAT, but an excessive amount of the protease elastase that it inhibits
41
Q

what are proteases?

A

-enzymes normally secreted by neutrophils at sites of inflammation
- AAT is a protein that functions to protect tissues from overactive proteases, which can cause damage to cells and tissue

42
Q

panacinar emphysema

A
  • result of hereditary (autosomal recessive) AAT deficiency
  • walls of alveoli blend together because the protease elastase degrades the elastic walls of the alveoli
  • elastase should be inhibited by AAT, so in the absence of AAT this type of emphysema is the result
43
Q

main points on necrosis

A
  • a response to exogenous injury
  • often occurs with a group of cells
  • triggers inflammation (neutrophils) to the area
44
Q

steps of necrosis

A
  • start with a normal cell that becomes injured by an exogenous source
  • in response to injury, mitochondria and RER swell
  • pyknosis (nuclear clumping) occurs, forming heterochromatin
  • cell membrane ruptures
  • karyorrhexis (dying cell breaks down and fragments), triggering neutrophils to come to the area
45
Q

apoptosis main points

A
  • in response to suicide gene activation
  • often happens with a single cell
  • suicide genes can be triggered by nuclear changes or cytoplasmic fragmentation
  • cell creates apoptotic bodies, which macrophage engulfs
46
Q

big difference between necrosis and apoptosis

A
  • necrosis is a pathologic consequence of cell injury and inflammation
  • apoptosis is not always a pathologic process and occurs as a necessity of development and tissue remodeling
47
Q

what is pyroptosis?

A
  • an inherently inflammatory form of cell death triggered by pathological stimuli, such as stroke, heart attack, or cancer
  • crucial for controlling microbial infections
  • suggested that microbial infection was the main evolutionary pressure for this proinflammatory cell death
48
Q

major differences and similarities between pyroptosis and apoptosis

A
  • pyroptosis results in release of pathogen-associated molecular patterns (PAMPs) and cytokines that activate pro-inflammatory immune cell mediators (apoptosis does not do this)
  • both pyroptosis and apoptosis are characterized by early loss of plasma membrane integrity along with shedding of membrane vesicles
49
Q

what are some potential triggers for apoptosis and how do they affect caspases?

A
  • withdrawal of survival factors: regulatory proteins get inhibited, which activates caspases
  • various cell injuries: damages DNA, which activates p53, which activates caspases
  • binding to Fas ligand: initiates caspases and adaptor proteins with death domains that also initiate caspases
  • interaction with cytotoxic cells or intrinsic signals: activates granzyme B, which activates caspases
  • intrinsic embryogenic signals: activate caspases
50
Q

steps of apoptosis

A
  1. cell receives some sort of signal that activate suicide genes
  2. regulatory proteins inhibit or promote activation of caspases
  3. caspase activation starts the process of cellular degredation
  4. apoptotic cell fragments are internalized by phagocytic cells (macrophage or adjacent epithelial cell)
51
Q

define efferocytosis

A

process by which dying/dead (apoptotic or necrotic) cells are removed by phagocytic cells

52
Q

what is the role that mitochondria play in the disposal of dead cells?

A
  • mitochondria in a resting macrophage interact with ER to isolate Ca2+ to just the ER and mitochondria
  • when a macrophage encounters a dead cell, its mitochondria break it up into smaller pieces, a process called fission
  • during fission, the mitochondria and ER no longer interact, so calcium builds up in the cytosol allowing the macrophage to properly degrade the dead cells and restructure its membrane to wrap around them
53
Q

what is high-burden efferocytosis?

A

when a single macrophage eats multiple dead cells in a short period of time. this places a large burden on the macrophage, and is basically uncontrolled apoptosis

54
Q

what are the consequences of defects in efferocytosis?

A
  • autoimmune disease
  • chronic lung disease
  • neurodegenerative disease
  • atherosclerosis
    -etc.
55
Q

types of necrosis

A
  • coagulative
  • liquefactive
  • fat necrosis
  • caseous necrosis
56
Q

describe coagulative necrosis

A
  • first, whole pathway of ischemic injury occurs (you know this… loss of plasma membrane integrity, calcium overload, etc.)
  • the general tissue architecture of the coagulative area is preserved for weeks due to rapid inactivation of cellular hydrolytic enzymes
  • manifestations of coagulative necrosis are the same regardless of the cause of cell death
57
Q

describe liquefactive necrosis

A
  • this one starts with dead cells!!
  • stuff you know: dead cells –> acidic pH –> activates lysosomal enzymes, then liquefaction
  • occurs most often in the brain
  • when dissolution of dead cells occurs rapidly due to liquefied area of lysosomal enzymes, an abscess or cyst may form
  • coagulative necrosis can turn into liquefactive through white blood cells invading necrotic tissue to remove dead cells by releasing lytic enzymes (an example of this is that myocardial infarcts often intially show coagulative necrosis, followed by secondary liquefaction)
58
Q

describe fat necrosis

A

death of adipose tissue, usually resulting from trauma or pancreatitis (release of digestive enzymes that destroy adipose tissue?)

59
Q

describe caseous necrosis

A

characteristic of lung tissue damaged by necrosis (usually caused by some sort of bacteria)

60
Q

what is gangrene?

A

cellular death that involves a large area of tissue, REGARDLESS OF CAUSE (an extension of necrosis)

61
Q

describe dry gangrene

A
  • a form of coagulative necrosis
  • blackened, dry, wrinkled tissue that is separated from adjacent healthy tissue
62
Q

describe wet gangrene

A
  • results from liquefactive necrosis
  • usually found in internal organs
  • organs appear cold and black
  • may be foul smelling due to bacteria invasion (= gaseous gangrene)
  • take home: add bacteria to dry gangrene, = wet gangrene
63
Q

relate ischemia and hypoxia to each other

A
  • ischemia is a lack of blood supply
  • hypoxia is the result in which tissues to not get adequate blood supply
  • interruption of blood flow is the most common cause of hypoxia
  • reperfusion injury (from restoration of blood flow) a common part of this process, and produces free radicals
  • sudden onset of ischemia and hypoxia leads to necrosis
64
Q

define infarction

A
  • when a large area is involved in a process of ischemia and hypoxia
  • macroscopic area of necrotic tissue in some organ caused by loss of blood supply
65
Q

what are the two types of infarctions?

A
  • white infarctions (anemic infarcts): affect solid organs (heart, spleen, kidneys). occlusion often composed of platelets which turn the organ pale/white
  • red infarctions (hemorrhagic infarcts): usually affect the lungs, occlusion consists of red blood cells and fibrin strands
66
Q

what is a volvulus and how can it happen?

A
  • a volvulus occurs when a segment of gut twists on its mesentery, resulting in a loss of blood supply
  • the entire bowel becomes dilated, gangrenous, and hemorrhagic (can rupture as well)
67
Q

describe the pathway from ischemia to inflammation

A
  • ischemia results in decreased oxygen delivery to mitochondria, causing decreased ATP production and thus failure of Na+, K+, Ca2+ pumps (ATP-dependent)
  • this results in Ca2+ overload because the Ca2+ ATPase doesn’t work and the Na+/Ca2+ exchanger doesn’t work due to loss of Na+ gradient
  • this causes changes in metabolism of the phospholipid bilayer and cytoskeletal damage
  • these changes in the membrane trigger recruitment of neutrophils, which causes inflammation!!
68
Q

describe reperfusion as it relates to inflammation

A
  • changes in cell membrane result in inflammation due to neutrophils
  • these activated neutrophils release large quantities of activated oxygen species, which, upon reperfusion, injure previously ischemic cells
  • this results in more free radical production
69
Q

describe how free radicals can be released intracellularly and extracellularly during reperfusion

A
  • neutrophils (which respond to changes in cell membrane caused by ischemia) release free radicals extracellularly as part of the inflammatory response
  • upon reperfusion (reintroduction of oxygen to previously ischemic cells), the cells can produce free radicals intracellularly with an enzyme called xanthine oxidase, which is an abnormal enzyme created during ischemic conditions
70
Q

explain diagram of ischemia (slide 27)

A
  • lack of oxygen decreases ATP from mitochondria
  • this decreases phospholipid synthesis
  • this results in phospholipid loss, changes membrane composition
  • lack of oxygen also increases cytosolic Ca2+
  • this activates phospholipases and proteases
  • phospholipases increase phospholipid degregation, which leads to phospholipid loss and lipid breakdown products (all change membrane!)
  • proteases damage cytoskeleton
  • ALL OF THESE CHANGE ATTRACT NEUTROPHILS, WHIC RELEASE REACTIVE OXYGEN SPECIES!!!
71
Q

describe enzyme changes during ischemia

A
  • overall, ischemia causes proteolysis
  • specifically, xanthine dehydrogenase is converted to xanthine oxidase
  • another part of proteolysis is catabolism of ATP, GTP, and nucleic acids, resulting in abundance of purines
  • xanthine oxidase oxidizes purines to form uric acid (free radicals = byproducts) in the presence of oxygen during reperfusion
72
Q

during which process are the most toxic oxygen species generated?

A

during reperfusion, not during ischemia itself!

73
Q

describe normal cardiac tissue

A
  • branching and anastomosing striated cardiocytes with a central nucleus and intracellular contractile myofilaments
  • individual cardiocytes are joined by intercalated disks
74
Q

describe first 24 hours of myocardial ischemia

A
  • necrosis of cardiomyocytes
  • cardiocytes have an eosinophilic cytoplasm that lacks characteristic intracellular striations
  • shape of the nucleus is gone (pyknotic)
  • lactic dehydrogenase-1 and CK-MB are released from dead cardiocytes and detected in serum. serum levels of these enzymes remain elevated days after the myocardial infarction
75
Q

myocardial ischemia: 3 days later

A

necrotic cardiocytes are surrounded by neutrophils (can see granules)

76
Q

myocardial ischemia: 3 weeks later

A
  • capillaries, fibroblasts, macrophages, and lymphocytes are observed in the necrotic area
  • after 3 months, the infarcted region is replaced by scar tissue
77
Q

what is creatine kinase?

A
  • an enzyme composed of two dimers, M and B
  • CK-MM is found in skeletal muscle and heart
  • CK-BB is found in brain, lung, other tissues
  • CK-MB is characteristic of myocardium

BMS 460 (34 decks)

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