Test 3: 49 and 53 Flashcards
(78 cards)
1
Q
why do cells dies?
A
Internal and external signals
Trauma
Maintain homeostasis: cells divide and die at the same rate
Faulty cell function, such as loss of cell-cycle regulation
Developmental cues
2
Q
what is necrosis?
A
•Death of cells and living tissue, most often accidental
cytoplasm and nucleus change
cell swells and leaks out causing inflammation
3
Q
necrosis is caused by factors ___ to the cell
A
external
4
Q
what are some factors that can cause necrosis
A
trauma
damaged blood vessels, hypoxia/ischemia
toxins
infection
5
Q
what are some examples of trauma that can cause necrosis
A
•Extreme temperatures (burns, frostbite), radiation, electric shock, sudden changes in atmospheric pressure, mechanical trauma
6
Q
what causes ischemia that leads to necrosis
A
cardiopulmonary disease, carbon monoxide poisoning
7
Q
how does cell change during necrosis
A
cytoplasm becomes vacuolated and ER and mitochondria will swell
if cell can’t recover, cell will burst and will trigger an inflammatory response
8
Q
Necrosis: Cell death induces nuclear changes: swelling & DNA breakdown such as ___
A
–Pyknosis, karyorrhexis, karyolysis
9
Q
cytoplasm during necrosis will become ___
A
vacuolated (swells and little holes)
10
Q
nuclear shrinkage
A
pyknosis
11
Q
A
pyknois - nuclear shrinkage, DNA condenses into shrunken basophilic mass
12
Q
A
karyorrhexis
nuclear fragmentation
pyknotic nuclei membrane ruptures and nucleus undergoes fragmentation
13
Q
nuclear fragmentation
A
karyorrhexis
14
Q
nuclear fading
A
karyolysis- chromatin dissolution due to action of DNAases and RNAases
15
Q
A
karyolysis
nuclear fading
chromatin dissolution due to action of DNAases and RNAases
16
Q
which is necrotic?
A
smear of randomly cut up DNA pieces
17
Q
why is there a ladder?
A
apoptotic DNA gets broken into specific pieces (farther down means smaller moves faster)
18
Q
how do cells die from necrosis
A
- loss of cell membrane integrity
- cell death products are released into extracellular space
- initiates inflammatory response
19
Q
•Necrosis’ is a term used by ___ to designate presence of dead tissues or cells after death.
A
pathologists
20
Q
___ is the sum of changes that have occurred in cells after they have died.
A
necrosis
21
Q
•At cellular level, presence of necrosis tells us that a cell has died, but not ___ death occurred.
A
how
22
Q
Treatment for necrosis
A
treat cause of necrosis
prevent infection, anti inflammatory
remove dead tissue to promote healing
23
Q
summary of necrosis:
cell volume will ___
cell surface will become ___
response will be ___
A
swollen
leaky
inflammatory
24
Q
summary of necrosis:
organelles will ___
where does necrosis occur ___
what happens to chromatin___
A
swell and disintegration
localized: contiguous cells
broken clumps
25
summary of necrosis:
onset is usually \_\_\_
enzyme cascade will \_\_\_
biosynthesis will \_\_\_\_
DNA fragmentation will appear as a ___ on a gel
accidental
truncated
loss of ion homeostasis
random smear
26
SARDS
**sudden acquired retinal degeneration syndrome**
* Older animals (median age 8.5 yrs)
* Pugs, Brittany spaniels, maltese predisposed•60-70% **female bias**
* No inflammation, allergy, autoimmunity (?)
* Blood/urine analysis may suggest hyper-adrenocorticism (not **Cushing's Syndrome because low cortisol high estrogen**)
* Cells of the retina (rods & cones) undergo **apoptosis,** resulting in sudden irreversible blindness
* SARDS diagnosis is confirmed with retinal function test (electro-retinogram)
27
programmed cell death
apoptosis
28
why do we need apoptosis?
Development and differentiation during embryogenesis such as making fingers or deleting structure : frog tail
regulation cell numbers- Cell cycle regulation
remove defective cells or self reactive lymphocytes
Regulation and function of the immune system.
29
Adults lose ___ cells daily to apoptosis
kids lose 20-30 billion cells/day
50-70 billion
30
when is apoptosis inhibited
Cancer, developmental disorders, degenerative diseases
Autoimmune diseases (rheumatoid arthritis, lupus erythematosus) have defective apoptotic pathways
31
when is there overactive apoptosis
-neurodegenerative disorders, AIDS, ischemic damage
32
cellular changes with apoptosis
mild convolution (skinkage)
chromatin compaction and margination
condensation of cytoplasm
breakup of nuclear envelope
nuclear fragmentation
**blebbing**
cell fragmentation
33
what happens to apoptotic cells
they bleb into pieces and get eaten (phagocytosis)
34
what is happening?
**apoptosis**
nuclear gone
chromatin condensed
35
2 types of apoptotic induction
intrinsic inducers
extrinsic inducers
36
intrinsic inducers of apoptosis
* signals originate inside the cell
* When cell is **damaged beyond repair**, infected, stressed or starved
* Results from: defective DNA repair, cytotoxic drugs, irradiation, loss of survival signals, developmental cues
* Mitochondria
37
extrinsic inducers of apoptosis
signals originate outside the cell
Signal is transmitted via cell surface receptors “**death receptors"**
Toxins, cytokines, hormones, growth factors
Positive or negative induction
38
In extrinsic inducers of apoptosis, signal is transmitted via cell surface receptors “\_\_\_**"**
**death receptors**
39
what is shared in both extrinsic and intrinsic pathways of apoptosis
capases
40
\_\_\_ is a family of proteins that execute apoptotic process
caspases
41
Caspases
mediate cell death
14 different members
* Cysteine residue in catalytic site
* Cleave after Asp residue
* Synthesized as inactive zymogens (procaspases)
* Initiators: caspase-8, -9, -10
* Effectors: caspase-3, -6, -7
42
which caspases are initiators of apoptosis?
•Initiators: caspase -8, -9, -10
43
which caspases are effectors?
Effectors: caspase-3, -6, -7
44
caspases have ___ residue in catalytic site
cysteine
45
caspases cleave after ___ residue
aspartate
46
how does pro-caspase become activated
an active caspase comes in and cleave the prodomain
they two pieces left over change shape and form active caspase
47
explain caspase cascade
one active caspase can activate many other procaspases into active caspases
48
examples of death receptors
FasL, TNF
transmembrane receptors that transfer signal into cell
used for extrinsic pathway of apoptosis
49
2 pathways for extrinsic pathway of apoptosis (general)
type 1: death receptors - FasL, TNF
Type 2: mitochondria- will release cytochromeC into cytoplasm
50
Direct caspase activation
extrinsic pathway for apoptosis
Transduction from external signal to cell death through caspase cascade
Death receptors: cell surface receptor that transmit apoptotic signals, initiated by ligands. Fas, TNF-R
Ligands: Fas ligand, Tumor Necrosis Factor (TNF)-a
51
Mitochondria trigger apoptosis when \_\_\_
**Type 2 extrinsic pathway:** caspase signaling is not strong enough for execution of cell- caspase 8 will trigger mitochondria
**intrinsic pathway:** triggered mitochondria will release cytochromeC which which will trigger caspase 9 to cleave procaspase 3 into caspase 3 which leads to apoptosis
signal is routed through mitochondria for amplification
52
Transduction from external signal to cell death through caspase cascade is ___ and uses \_\_\_
type 1 extrinsic signal for apoptosis
Death receptors and ligands
53
caspase \_\_\_will trigger mitochondria to release cytochromeC which which will trigger caspase __ to cleave procaspase 3 into caspase 3 which leads to apoptosis
8
9
54
DISC apoptosis
death inducing signaling complex
55
explain how DISC is formed in apoptosis type 1
**in extracellular space**
Fas Receptor will bind to FasL (ligand)
**in cytoplasm**
DD( death domain) will bind to DD domain on FADD
DED (death effector domain) of the FADD will then bind to the pro-caspase 8
56
how does killer lymphocyte trigger extrinsic pathway for apoptosis
Fas Ligand binds to Fas death receptor
this triggers FADD to bind which triggers DED (death effector domain) to bind with procaspase 8 attached
this unit of FADD, DED and procaspase is called the DISC
procaspase will get cleaved into active caspase 8
57
how do mitochondria trigger apoptosis
**intrinsic pathway**
mitochondria gets injured or broken and **cytochrome c** breaks out
Apaf-1 will bind with cytochrome c
this will bind to procaspase 9 (apoptosome)
and activate it into
caspase 9 which will trigger a caspase cascade of 3,6,7 which will trigger apoptosis
58
apoptosome
cytochrome c, Apaf 1 and procaspase 9
intrinsic pathway of mitochrondria
59
how can mitochondria be injured
increased cytosolic Ca2+
oxidative stress
lipid peroxidation
60
what protein regulated the release of cytochrome C from the mitochondria
Bcl2 protein family
61
what blocks cytochrome c release from mitochondria?
Bcl-2 subfamily
Bcl2 and Bcl XL
(all have BH1, 2,3,4 domains)
62
what act to bind and inactivate apoptotic inhibitors of mitochondria
**Pro-apoptotic**
BH3
Bid
Bim
Bad
Puma
Noxa
63
what will stimulate cytochrome c release from mitochondria?
**pro-apoptotic**
Bax
Bak
(all have BH1, BH2 and BH3 domains)
64
how do B proteins act on mitochondria
**BH3 will inhibit Bcl-2 which will inhibit Bax**
**BH3:** pro apoptotic: bind and inactivate apoptotic inhibitors
**Bcl-2:** inhibit apoptosis: block cytochrome c release
**Bax:** pro apoptotic: stimulate release of cytochrome c
65
how are Bcl-2 and Bax similar
both have **BH 1, 2 and 3 domains** (Bcl-2 has BH4 as well)
tethered to outer mitochondrial membrane
66
how is BH3 subfamily different from Bcl-2 subfamily and Bax subfamily
BH3 **only has BH3 domain** and is not necessarily tethered or membrane associated- **missing membrane anchor**)
Bcl-2 have BH 1-4, Bax have BH 1-3: both are tethered to the outer mitochondrial membrane
67
stages of apoptosis that results in cell death
* Disruption of mitochondrial inner membrane (MIM) potential
* Opening of the permeability pore: small solutes leak out
* ATP synthesis is stopped
* Redox homeostasis is lost
* Formation of ROS: positive feedback on loss of MIM potential
* Influx of water ruptures mitochondrial outer membrane
* Release of pro-apoptotic proteins–Cytochrome C
* Nuclear DNA digestion
68
how do cells actually die during apoptosis
destruction of key cellular proteins
recognition by phagocytic proteins
69
destruction of key cellular proteins during apoptosis:
–Cleavage of actin & many other important targets
–DNAses cleave genomic DNA
70
what is the final step of apoptosis
gets eaten by macrophages:
**Engulfment has 5 stages**
1. sensing apoptotic cell
2. phagocytic recognition
3. internalization of target cell
4. Ingestion
5. post-engulfment response of phagocyte
71
compare and contrast necrosis vs apoptosis
72
compare necrosis vs apoptosis
cell volume
cell surface
response
73
compare necrosis vs apoptosis
organelles
incidence
chromatin changes
74
compare necrosis vs apoptosis
onset
enzyme cascade
biosynthesis
DNA fragmentation
75
how can necrosis be regulated
* Genetically controlled cell death
* Results in cellular leakage
* Cytoplasmic granulation
* Organelle/cellular swelling
_Examples:_
Necroptosis
Parthanatos
Oxytosis
Pyronecrosis
Pyroptosis
76
necroptosis
regulated necrosis
(usually accidentally but in necroptosis will happen on purpose by body)
77
SARDS induced by intrinsic or extrinsic pathway?
could be both
intrinsic- excess Calcium triggers mitochondria to release Cytochrome C
78
**Why would immunosuppressants be used for treating animals that have experienced necrosis? This seems counter-intuitive.**
A2. Yes, it does! Trauma, like toxin exposures, results in a rapid series of innate immune responses. Because necrosis results in the release of cellular molecules (which are classified as DAMPs: damage-associated molecule patterns) into the surrounding area, these molecules induce an inflammatory response. DAMPs include molecules from different cellular compartments: cytosol (e.g. uric acid, heat shock proteins, ATP), mitochondria (e.g. mtDNA, formyl peptides, ATP), nucleus (e.g. HMGB1, histones, DNA), plasma membrane (e.g. syndecans, glypicans), and endoplasmatic reticulum (e.g. calreticulin) …. The list of DAMPs is still growing. Thus, the immune system is ‘exposed’ to these DAMPs, which can escalate the innate immune response, resulting in greater inflammation, generating a viscious cycle of even more innate immune responses. This can result in organ dysfunction and systemic infection…thus its about a balance of using anti-inflammatory drugs and immune-suppressants.
