Chapter 2: Cell Death Flashcards
What are the main causes of necrosis?
Loss of oxygen supply (ischemia), exposure to microbial toxins, burns, and other forms of chemical and physical injury
How is necrosis characterized?
Denaturation of cellular proteins, leakage of cellular contents through damaged membranes, local inflammation, and enzymatic digestion of the lethally injured cell
What are two examples of the different types of DAMPs that are released from injured cells?
ATP (released from damaged mitochondria), uric acid (a breakdown product of DNA)
What is the purpose of the DAMPs that are released from injured cells?
They are recognized by receptors present in macrophages and most other cell types and trigger phagocytosis of the debris and the production of cytokines that induce inflammation
What is the basis for blood tests that detect tissue-specific cellular injury?
Necrosis-associated leakage of intracellular proteins through damaged plasma membranes and ultimately into the circulation
The necrotic cell may have a glassy homogenous appearance relative to normal cells. This is mainly as a result of what?
The loss of glycogen particles
In necrosis, dead cells may be replaced by large whorled phospholipid precipitates known as what?
Myelin figures
What is karyolysis?
When the basophilia of the chromatin fades
What is pyknosis?
Nuclear shrinkage and increased basophilia
What is karyorrhexis?
The pyknotic nucleus undergoes fragmentation
What nuclear change occurs in both necrosis and apoptosis?
Pyknosis
Why does karyolysis occur?
It reflects the loss of DNA because of enzymatic degradation by endonucleases
What two phenomena consistently characterize irreversibility?
The inability to reverse mitochondrial dysfunction and profound disturbances in membrane function
What is coagulative necrosis?
A form of necrosis in which the architecture of dead tissue is preserved for a span of at least some days
How are coagulative necrotic cells broken down?
By the action of lysosomal enzymes derived from infiltrating leukocytes
What is an example of something that may lead to coagulative necrosis?
Ischemia caused by obstruction in a vessel in all organs except the brain
What is a localized area of coagulative necrosis called?
An infarct
What is liquefactive necrosis characterized by?
The digestion of the dead cells resulting in transformation of the tissue into a vicious liquid
When is liquefactive necrosis seen?
In focal bacterial or occasionally fungal infections because the microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells
Why is the necrotic tissue in liquefactive necrosis frequently creamy yellow?
Because of the presence of leukocytes (called pus)
Hypoxic death of cells within the CNS manifests as what?
Liquefactive necrosis
What is gangrenous necrosis?
A term usually applied to a limb (generally the lower leg) that has lost its blood supply and has undergone necrosis (typically coagulative necrosis)
When bacterial infection is superimposed in gangrenous necrosis, what do you get?
Wet gangrene
What is caseous necrosis?
It is encountered most often in foci of tuberculous infection
What is fat necrosis referring to?
Focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity
When does fat necrosis occur?
Acute pancreatitis
What occurs during acute pancreatitis?
Pancreatic enzymes leak out of the damaged acinar cells and liquefy the membranes of fat cells in the peritoneum, releasing triglyceride esters that are split by pancreatic lipases
On histologic examination, what does fat necrosis look like?
The necrotic areas contain the shadowy outlines of necrotic fat cells, basophilic calcium deposits, and an inflammatory reaction
What is fibrinoid necrosis?
A special form of vascular damage usually seen in immune reactions involving blood vessels
When does fibrinoid necrosis typically occur?
When complexes of antigens and antibodies are deposited in the walls of arteries; the immunologically mediated vasculitis syndromes
What does the wall of a fibrinoid necrotic artery look like?
It shows a circumferential bright pink area of necrosis with inflammation
If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, what happens?
They provide a nidus for the deposition of calcium salts and other minerals, and thus become calcified (dystrophic calcification)
Although the “point of no return” at which the damage becomes irreversible and progresses to necrosis is still largely undefined, two phenomena consistently characterize irreversibility. What are they?
severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes
What are the 5 different causes of physiological apoptosis?
1) the removal of supernumerarary cell during development 2)involution of hormone-dependent tissues 3)cell turnover in proliferating cell populations 4) elimination of potentially harmful self-reactive lymphocytes 5) death of host cells that have served their useful purpose such as neutrophils in acute inflammatory response
What are 4 pathological causes of apoptosis?
1) DNA damage 2) accumulation of misfolded proteins 3) during certain infections, particularly viral infection like HIV 4) pathologic atrophy in parenchymal organs after duct obstruction
What are the 4 morphologic features associated with apoptosis?
1) cell-shrinkage 2) chromatin condensation 3) formation of cytoplasmic blebs and apoptotic bodies 4) phagocytosis of apoptotic cells or cell bodies
what is the most characteristic feature of apoptosis?
chromatin condensation
apoptosis results from the activation of what?
enzymes called caspases
What can be used as a marker for cells undergoing apoptosis?
the presence of active caspases
the process of apoptosis may be divided into what?
an initiation phase and an execution phase
Two distinct pathways converge on caspase activation, what are they?
the mitochondrial pathway and the death receptor pathway
because the cell shrinkage and formation of apoptotic bodies are rapid and the pieces are quickly phagocytosed, there is an absence of what in apoptosis?
an inflammatory reaction
which pathway is responsible for apoptosis in most physiologic and pathologic situations?
the mitochondrial (intrinsic) pathway
what does the mitochondrial pathway result from?
increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial intermembrane space into the cytoplasm
What are the anti-apoptotic molecules?
BCL2, BCL-XL, and MCL-1
what is the function of the anti-apoptotic molecules?
they keep the mitochondrial outer membrane impermeable to prevent leakage of cytochrome c and other death inducing proteins into the cytosol
What are the pro-apoptotic molecules?
cytochrome c, BAX, and BAK
what is the function of the pro-apoptotic molecules?
upon their activation, they oligomerize within the outer mitochondrial protein and promote permeability
what group is responsible for sensing cellular stress and damage and regulate the balance between the other two groups?
the regulated apoptosis initiators
what are the members in the regulated apoptosis initiators?
BAD, BIM, BID, Puma, and Noxa
What activates the regulated apoptosis initiators (aka the sensors)?
loss of survival signals, DNA damage, and other insults activate sensors
Once released into the cytosol, what happens to the cytochrome c that is released from the mitochondria?
it binds to a protein called APAF-1 which forms the structure called the apoptosome
what does the apoptosome bind to?
caspase 9
what is the critical initiator of the mitochondrial pathway?
caspase 9
what happens when the apoptosome binds to caspase 9?
it activates it, which causes there to be a cascade of caspase activation (such as caspase 3)
What is the executioner of the mitochondrial pathway?
caspase 3
What is the extrinsic (death receptor) pathway initiated by?
engagement of plasma membrane death receptors on a variety of cells with the ligand for the death receptor
what are the death receptors that are found on the plasma membrane?
TNFR and FAS
What cells express the ligand for Fas (Fas Ligand)?
T cells that recognize self antigens and on some cytotoxic T lymphocytes
What is the first thing that happens when FasL binds to Fas?
three or more molecules of Fas are brought together
What do the 3 Fas molecules’ cytoplasmic death domains form when they come together?
a binding site for an adaptor protein called FADD (Fas-associated death domain)
What happens once FADD binds to the cytoplasmic death domain of the Fas molecules?
FADD will bind inactive caspase 8, which then auto activates itself
what is considered to be the initiator of the extrinsic pathway?
caspase 8
the extrinsic pathway can be inhibited by what?
a protein called FLIP
what is the action of FLIP?
it binds to pro-caspase 8 (the inactive form), and this thereby blocks FADD binding, so it cannot be activated
Where does FLIP come from?
some viruses and normal cells produce FLIP as a mechanism to protect themselves from Fas-mediated apoptosis
Apoptotic cells and their fragments also undergo several changes in their membranes that actively promote their phagocytosis so they are most often cleared before they lose membrane integrity and release their cellular components; In healthy cells, what is present on the inner leaflet of the plasma membrane, but in apoptotic cells it flips out and is expressed on the outer layer of the membrane?
phosphatidylserine
apoptotic bodies may also become coated with natural antibodies and proteins of the complement system- most notably what?
C1q
What is the process of apoptotic cell phagocytosis called?
efferocytosis
What is pyroptosis? and where does it occur?
a form of apoptosis that is accompanied by the release of the fever-inducing cytokine IL-1; occurs in cells infected by microbes
How is pyroptosis different from classical apoptosis?
pyroptosis is characterized by the release of inflammatory mediators
How does necroptosis resemble necrosis?
there is loss of ATP, swelling of the cell and organelles, generation of ROS, release of lysosomal enzymes, and rupture of the plasma membrane
How is necroptosis similar to apoptosis?
it is triggered by signal transduction pathways that culminate in cell death
How is necroptosis largely different from apoptosis?
the signals leading to necroptosis do not result in caspase activation- it is a caspase-independent programmed cell death
What triggers necroptosis?
ligation of TNFR1 and by proteins found in RNA and DNA viruses
instead of caspases, what does necroptosis depend on?
RIPK1 and RIPK3 complex
What does RIPK1 and RIPK3 signaling lead to?
the phosphorylation of MLKL, which then forms pores in the plasma membrane
when does physiologic necroptosis occur?
during the formation of the mammalian bone growth plate
when does pathologic necroptosis occur?
steatohepatitis, acute pancreatitis, ischemia-reperfusion injury, and neurodegenerative diseases such as parkinson
What does necroptosis act as a backup mechanism for?
in host defense against certain viruses that encode caspase inhibitor such as cytomegalovirus
What is Ferroptosis?
a distinct form of cell death that is triggered when excessive intracellular levels of iron or ROS overwhelm the glutathione-dependent antioxidant defenses to cause unchecked membrane lipid peroxidation
what is the overall effect of ferroptosis?
the loss of the plasma membrane permeability, which ultimately leads to cell death resembling necrosis; however the process is regulated by specific signals and can be prevented by reducing iron levels
what has ferroptosis been linked to in pathological conditions?
cancer, neurodegenerative diseases, and stroke
What is autophagy?
a process in which a cell eats its own contents
what could activate an autophagy pathway?
cellular stresses such as nutrient deprivation
What are the different phases of autophagy?
initiation, nucleation, and elongation
what type of mechanism is autophagy?
a survival mechanism
when might dysregulation of autophagy occur?
inflammatory bowel diseases, cancers, and neurodegenerative diseases
