What are the stages of cellular response to injury?
Cell injury is reversible to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury and ultimately undergoes cell death.
What are the two principle pathways of cell death?
necrosis and apoptosis
What is necrosis?
Necrosis is accidental and unregulated form of cell death. It results from damage to the cell membranes after which lysosmal enzymers enter the cytomplasm and digest the cells. Cell contents also spill into the extracellular space and elicit inflammation. Necrosis occurs in response to many common injuries such as toxin exposure, infections, and trauma.
What is apoptosis?
Apoptosis is a type of programmed cell death, or self-killing. It occurs when the cell's DNA proteins are damaged byeond repaired and is characterized by nuclear dissolution, fragmentation of the cell with membrane statying intact, and rapid removal of cellular debris by macrophages. There is no inflammatory response becasue cell contents do not leak out, they are always contained within the cell membraen-bound apoptic bodies.
What happens to the cell size during necrosis?
During necrosis, the cell size becomes enlarged (swelling)
What happens to the cell size during apoptosis?
During apoptosis, the cell size becomes reduced (shrinkage)
What happens to the nucleus during necrosis?
Pryknosis (nuclear shrinkage and DNA condensation) then karyorrhexis (nuclear fragmentation) and then karyolysis (nuclear dissolution)
What happens to the nucleus during apoptosis?
Fragmentation into nucleosome-size fragments
What happens to the cellular components during necrosis?
enzymatic digestion, may leak out cell
What happens to the cellular components during apoptosis?
Intact, may be released in apoptotic bodies
What happens to the plasma membrane during necrosis?
During necrosis, the plasma membrane is disrupted
What happens to the plasma membrane during apoptosis?
During apoptosis, the plasma membrane is intact, but it coud have an altered structure, especially the orientation fo the lipids
Is there adjacent inflammation during necrosis?
Is there adjacent inflammation during apoptosis?
Is necrosis physiologic or pathologic role?
Invariably pathologic (culmination of irreversibel cell injury
Is apoptosis physiologic or pathologic role?
Often physiologic, means of eliminating unwanted cells, may be pathologic after some forms of cell injury, especially DNA damage
What are some causes of cell injury?
oxygen deprivation (hypoxia), physical agent, chemical agents and drugs, infectious agents, immunolgic reactions, genetic derangments, nutrional imbalances
What are the two types pathways of apoptosis?
The intrinsic pathway (mitochondrial) and the extrinsic pathway (death receptor). These pathways differe in initiation and regulation but both activate the same effector caspases.
What group of proteins is anti-apoptotic and stimulated by growth factors?
The Bcl-2 family, which block pore formation by pro-apoptotic Bax and Bak
What happens durign the intrinsic pathway?
When there is a loss of survival signals, DNA damage or other insults activate sensors that antagonize the anti-apoptotic proteins that activate the pro-apoptotic proteins Bax and Bak, which form pores or channesl in the mitochondrial membrane. The resulting leakage of cytochrome and anti-IAPs (other proteins) leads to caspase actiavation and apoptosis. The combined activities of Bcl-2 family proteins, IAPs (inhibitor of apoptic proteins) and anti-IAPs (smac/diablo - anti inhibior (activator) of apoptic proteins) determine a cell's sensitivity to apoptosis.
What happens during the extrinsic pathway?
FasL(death receptor ligand) binds Fas(death receptor) which oligomerizes and binds the adaptor protein FADD. FADD binds the initiator protein caspase 8 or 10, causing autocleave and activate, and to activate downstream executioner caspases.
How is the intrinsic pathway initiated?
Cellular stress, DNA damage, unfolded proteins, etc
How is the extrinsic pathway initiated?
Signaling pathways involving "death receptors" and their ligands
How is the intrinsic pathway transduced?
mitochondrial pore formation by pro-apoptic, effector BH1-3 decreases membrane potential and release cytochrome c and anti-IAPs , cytochrome c/APAF-1 (apoptosome) binds to pro-caspase 9 promoting autocatalytic cleavage
How is the extrinsic pathway transduced?
Fas-associated death domain protein (FADD) binds the death receptor, pro caspase 8/10 binds FADD-death receptor comples forming the DISC, and induces autocatalyic cleavage
What is the execution of the intrinsic and extrinsic pathway?
Downstream capsases 3,6,7 activated, proteolytic cleavage of cytoskeletal and nucleoplasmic proteins, cytoplasmic Dnase (CAD) is activated and cleaves DNA in a specific ladder-sized protein