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Pathology Midterm > (part 1) Cell injury - Lecture 2 > Flashcards

(part 1) Cell injury - Lecture 2 Flashcards

1
Q

what are ROS?

A

partially reduced oxygen derivatives

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2
Q

name 6 ROS

A

hydrogen peroxide
superoxide anion
hydroxyl radical
peroxynitrile
lipid peroxide radicals
hydrochlorous acid

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3
Q

where can O2 be converted to O2-?

A

in the cytosol or mitochondria

if in the cytosol, O2- is reduced to H2O2 by superoxide dismutase (in the cytosol) and finally reduced to WATER

if in the mitochondria, O2- is reduced to H2O2 by mitochondrial SOD and then converted to H2O by glutathione peroxidase

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4
Q

cytosolic H2O2 can be detoxified to H2O by…

A

catalse enzyme in peroxisomes

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5
Q

where does the respiratory burst occur?

A

in neutrophils

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6
Q

explain the respiratory burst

A
  1. NADPH oxidase reduces O2 to O2- and SOD converts O2- to H2O2
  2. OCl- and OH. are produced from H2O2 by myeloperoxidase. O2- and H202 activate granules in neutrophil to release degradative enzymes
  3. bacteria are engulfed by neutrophils and destroyed by ROS nd degradative enzymes
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7
Q

name 6 factors leading to necrotic cells irreversible changes

A

-decreased ATP
-mitochondrial damage
-entry of calcium
-increased ROS
-membrane damage
-protein misfolding and DNA damage

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8
Q

how does protein folding and DNA damage lead to necrotic cells and irreversible changes?

A

pro apoptotic proteins are activated

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9
Q

how does ischemia injury lead to cell death

A

delivery of O2 decreases and so does energy and nutrients like glucose and fatty acids.

anaerobic glycolysis occurs which leads to lactic acidosis and decreased intracellular pH

pumps are distorted leading to ionic imbalance in the cell

PLA2 (phospholipase A2) is activated and proteases disrupt plasma membrane and cytoskeleton. calcium also activates proteases that attack cytoskeleton and attachment to membrane

-cell dies

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10
Q

what happens when blood flow is restored to an ischemic area?

A

can lead to exacerbated (worse) and accelerated injury

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11
Q

what is ischemia reperfusion injury

A

injury that occurs when blood flow to an ischemic area is restored

-may contribute to tissue damage in myocardial infarctions and cerebral infarctions

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12
Q

explain why the injury can be made worse when blood flow is restored to an ischemic area

A

-increases the generation of ROS

-inflammation may increase because of influx of WBC and plasma proteins

-some antibodies deposit in ischemic tissues and when blood flow is restored, complement proteins bind to the deposited antibodies and activate them - making injury worse

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13
Q

REACTIVE OXYGEN SPECIES

generated by ______
produced by _____
made by _____

A

generated by XANTHINE OXIDASE

produced by NEUTROPHILS

made by MITOCHONDRIA

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14
Q

How is ionic composition altered by ischemic reperfusion

A

rapid pH normalization when the pH was just very acidid

increased Na and Ca

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15
Q

true or false

there are multiple reactions that produce ROS

A

true

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16
Q

true or false

different oxidative radicals cannot be transformed from 1 to another

A

false - they can

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17
Q

name 3 detoxifying enzymes and what they detoxify

A

SODs = superoxide dismutases
-inactivate O2-

catalase = in peroxisomes. inactivate H2O2

GPX = glutathione peroxidase
-catalyzes H2O2 and lipid peroxidase reduction in mitochondria in cytosol

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18
Q

what enzyme produces the superoxide anion?

A

NADPH oxidase

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19
Q

what is lipid peroxidation

A

unsaturated fatty acids converted to lipid radicals by OH. which reacts with O2 to form lipid peroxides
LOOH

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20
Q

name 4 “scavengers of ROS.”
what is their purpose?

A

inactivates reactive oxygen species or products of their destruction

-vitamin e
-vitamin c
-retinoids
-no.

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21
Q

explain how vitamin E is a scavenger of ROS

A

it’s fat soluble and thus protects membranes from lipid peroxidation

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22
Q

what causes the formation of toxic protein aggregates

A

-normal proteins can become damaged by exposure to ROS and become misfolded

-genetic mutations or translational errors can result in misfolded proteins

-the hydrophobic regions of these molecules (usually hidden in the core) are polyubiquinated and can have hydrophobic and ionic reactions and aggregate, leading to degradation

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23
Q

explain a1-antitrypsin deficiency

A

mutations in a1-antitrypsin gene in the liver. causes liver production of an insoluble protein that is not exported and accumulates in HEPATOCYTES

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24
Q

Where do lewy bodies occur

A

in neurons of substantia nigra in parkinsons due to accumulation of abnormal proteins

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25
what are mallory bodies
hepatocellular inlusions in alcoholic liver injury
26
what is prion diseases
normal alpha helical structure becomes a beta pleated sheet. -- intracellular accumulation of abnormal proteins
27
what are the 2 types of cell death
necrosis and apoptosis
28
define necrosis
the death of a group of cells in a living tissue and complete lysis of these cells
29
as mentioned, necrosis is the death of a group of cells in a living tissue by complete lysis of these cells. what types of lysis can occur?
autolysis and heterolysis autolysis = lysis by the cell's own enzymes heterolysis = lysis by enzymes from recruited inflammatory cells (like neutrophils and macrophages)
30
NECROSIS IS ASSOCIATED WITH _______
INFLAMMATION
31
necrosis is the major pathway of cell death resulting from what occurrences?
ischemia exposure to toxins infections trauma
32
what can you say about necrotic cells
they are unable to retain the integrity of their membrane and their contents often LEAK OUT
33
what are some microscopic findings in necrotic cells
loss of basophilia (blue staining) when enzymes have digested the organelles, cytoplasm becomes vacuolated and appears "moth eaten" dead cells may be replaced by MYELIN (large phospholipid masses) that are derived from damaged cell membranes
34
cell death is a result of ____ injury
IRREVERISBLE
35
what nuclear changes occur as a result of coagulative necrosis? define them
pyknosis = chromatin continues to clump and nucleus becomes small and deeply basophilic (blue) karyorrhexis = pyknotic nucleus fragments into many small pieces and is scattered in cytoplasm karyolysis = pyknotic nucleus may become extruded from the cell or slowly lose chromatin stain
36
irreversible injury is marked by what 4 things
-nuclear changes -severe mitochondrial vacuolization -extensive damage to plasma membrane -leakage of lysosomal enzymes into the cytoplasm
37
explain the morphology of coagulative necrosis
the cells are dead, but they basic tissue architecture remains for several days
38
what is liquefactive necrosis
dead cells are digested (liquefied) by enzymes of recruited WBC
39
name 6 types of necrosis
coagulative liquefactive gangrenous caseous fat fibrinoid
40
in coagulative necrosis, the architecture of the dead tissues is preserved for several days. how
the injury denatures proteins and enzymes which blocks the proteolysis of the dead cells
41
ultimately, in coagulative necrosis, how are necrotic cells eventually removed?
by phagocytosis of cellular debris by incoming WBC
42
in coagulative necrosis, what cells may persist for weeks?
eosinophilic, anucleate cells (therefore, pic of coagulative necrosis would have little to no nuclei)
43
explain liquefactive necrosis
often occurs in pyogenic bacterial infections bc inflammatory cells are recruited and the enzymes of leukocytes digest (LIQUEFY) the tissue
44
_____ often brings about liquefactive necrosis
hypoxic death of cells within the CNS
45
explain the morphology of liquefactive necrosis
dead cells are completely digested, resulting in transformation of the tissue to a liquid, viscous mass - abscess. the abscess cavity is filled with polymorphonuclear leukocytes. (if the process was initiated by acute inflammation, the material is PUS)
46
explain the polymorphonuclear leukocytes
result from acute inflammatory reaction -- have hydrolases that are capable of complete digesting in dead cells -occurs in bacterial infection
47
gangrenous necrosis is a coagulative ISCHEMIC necrosis + _______
bacterial infection
48
gangrenous necrosis is a coagulative necrosis involving....
MULTIPLE TISSUE LAYERS
49
gangrenous necrosis may be.....
dry wet gas (in case of clostridia infectioN)
50
name 3 potential final outcomes of necrosis
-resolution - restoring normal tissue function and structure -organization - replacement of necrotic tissue by granulation tissue and fibrosis -calcification - DYSTROPHIC calcification. precipitation of calcium salts
51
necrosis may result in what kind of calcification
dystrophic
52
what is programmed cell death
apoptosis
53
true or false apoptosis is a passive process that does not require energy
FALSE active process that requires energy
54
inhibition of apoptosis can result in what 3 things
cancer progression autoimmune disease inflammatory disease
55
true or false in necrosis, the membrane is lost but in apoptosis it is not
TRUE
56
HYPERACTIVE apoptosis can lead to what
neurodegenerative diseases bone marrow aplasia skin disease
57
while necrosis is always a ______ process, apoptosis......
necrosis is always a PATHOLOGICAL PROCESS apoptosis serves many normal functions and is NOT necessarily associated with pathological cell injury
58
programmed cell death is also a ____ mechanism to eliminate:
self defense mechanism to eliminate -cells infected with pathogens -cells carrying genomic alteration
59
there are ___(how many) pathways for the initiation of apoptosis. name them
2 pathways: intrinsic (mitochondrial) extrinsic (death receptors)
60
mutations in _____ are considered to be important in tumor development and progression
p53
61
excessive apoptosis leads to what kind of disease?
neurodegenerative -- intracellular proteins accumulate within neurons and trigger apoptosis
62
differentiate between the type of control of apoptosis vs necrosis
in apoptosis, control is genetic in necrosis, there is no gene control
63
differentiate between the "lyses of cells" between apoptosis vs necrosis
in apoptosis, the cells do not lyse but only reduce in size in necrosis, the complete lyses of many cells occur (release of contents)
64
differentiate between the type of stimuli between apoptosis vs necrosis
the type of stimuli for necrosis is pathologic stimuli ONLY the type of stimuli for apoptosis is physiological or pathologic stimuli
65
differentiate between the number of cells affected between apoptosis vs necrosis
single or small groups of cells are affected in apoptosis in necrosis, large groups of cells are affected
66
differentiate between the tissue reaction of apoptosis vs necrosis
in apoptosis, there is NO inflammation around the dead tissue in necrosis, there are inflammatory cells around the dead tissue. inflammation is induced
67
________ viruses often inhibit apoptosis
oncogenic HPV inactivates p53 which increases chance that infected cells will progress to cancer
68
explain how the intrinsic pathway of apoptosis is INDUCED
intrinsic stress alters the mitochondrial membrane potential, increases ROS, and Ca, and decreases pH. this causes MPTP pore to open and breaks the MOM (mitochondrial outer matrix)
69
explain what happens in intrinsic apoptosis after the MOM is broken
molecules attached to the inner membrane or in the intermembranous space become detached and exit through the outer membrane holes. (SMACS, Cyt C, AIF) these molecules are what activate the caspases that cause apoptosis
70
name 3 proapoptotic proteins
cytochrome c SMACs AIF
71
how do the proapoptotic proteins leave the mitochondria?
proapoptotic Bak/Bax with antiapoptotic Bcl-2 family -- normally reside at the outer membrane. this association prevents apoptotic activity. when BH3 only members of the Bcl-2 clan are activated, Bak/bax proteins are freed and form a PORE (MAC) in the outer mitochondrial membrane where the proapoptotic proteins can exit
72
once the proapoptotic proteins (Cyt C, SMAC, AIF) enter the cytosol via the MAC pore, what happens
these proteins facilitate the activation of the CASPASE CASCADE
73
cytochrome c is a pro apoptotic protein. what 2 things does it activate?
Apaf 1 and caspase 9
74
what is the: -initiator -executioner -inhibitor of the intrinsic apoptotic pathway
initiator = caspase 9 executioner = caspase 3 inhibitor = IAPs -- bind caspases
75
what activates caspase 3? (intrinsic apoptosis)
caspase 3 is the executioner and is activated by caspase 9
76
what happens when caspase 3 is activated by caspase 9
procaspase 3 becomes caspase 3 and binds to IAPS. Smac/diablo binds IAPs and forces them to liberate the bound caspases, causing apoptosis
77
activated p53 goes where? how is it activated?
to the nucleus activated by stress/DNA damage
78
when activated p53 goes to the nucleus, what does it do?
if the DNA damage is irrepairable, p53 promotes transcription of proapoptotic proteins which then migrate to the mitochondria p53 also DECREASES the transcription of prosurvival (antiapoptotic) Bcl-2 the balance is altered so that proapoptotic outweighs anti because p53 is bound to Bcl-2 family. apoptosis occurs
79
the death receptor (extrinsic) apoptotic pathway is initiated by what
ligand binding to death receptors (members of TNF receptor family) ligand could be TNFa
80
the extrinsic apoptotic pathway is responsible for the elimination of what
self reactive lymphocytes and damage by cytotoxic T lymphocytes
81
explain the extrinsic pathway of apoptosis
ligans (TNFa is example) binds to death receptor to form DISC (death induced signaling complex) which binds and activates procaspase-8 to caspase-8 caspase 8 activates procaspases 3,6, and 7 to caspases 3,6, and 7 (EXECUTIONERS) caspase 3 activates endonucleases caspase 6 and 7 cleaves nuclear and cytoskeleton proteins, respectively
82
explain how the intrinsic and extrinsic pathways of apoptosis overlap
caspase 8 (from extrinsic pathway) activates Bid which yields a truncated derivative - tBid which transports to the mitochndria ACTIVATES THE INTRINSIC PATHWAY
83
what is necroptosis
a mix of apoptosis and necrosis. starts as extrinsic apoptosis and ends with loss of integrity of the plasma membrane and necroptosis
84
what is anoikis
when the cell's integrins lose attachment to the ECM, the survival signals are eliminated and apoptosis proceeds via death receptor (extrinsic) pathway AND intrisnic because their pathways are no longer blocked
85
under normal conditions.....
alpha and beta integrins of cells are bound to the ECM. these molecules activate survival signals and block both apoptotic signaling pathways. give survival signal and the cell survives
86
________ can be caused by granzymes of cytotoxic leukocytes (T cell)
a type of apoptosis that leads to nuclear fragmentation
87
what is a type of apoptosis caused by injurious agents - both infective and irritative
pyroptosis
88
explain how pyroptosis works
cell is exposed to injurious agents. inflammasomes recognize them. inflammasomes contain procaspase 1 and when inflammasome linked receptors are activated, procaspase 1 is converted to its active form - caspase 1 which forms pores in the plasma membrane, damages the nucelus, etc
89
explain netosis
neutrophils recognize pathogens and autophagy and NADPH oxidase are activated and NADPH oxidase produces ROS. chromatin disperses and cytoplasmic granule membranes disintegrate. antimicrobial molecules adsorb to the condensed chromatin and a CHROMATIN NET is released. the reactive oxygen species are concentrated within the trap so damage is limited. pathogens are trapped and destroyed in the net
90

Pathology Midterm (10 decks)

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