Cell Injury and Death Flashcards
types of cell death
necrosis and apoptosis
major causes of cell injury and death
hypoxi/anoxic injury, physical agents, chemical agents, infectious agents, immune system, genetic disease, nutritional abnormalities
necrosis
local death of groups of cells in a living organism, all forms are pathologic
cells die quickly after the “tipping point” 4-12 hours after injury
Identify the variants of necrosis.
coagulative, liquefaction, caseous, fat, gangrenous, tumor
cellular changes in necrosis
cell swelling
increased eosinophilia due to loss of RNA
glassy homogeneous pattern due to degradation of protein/organelles
loss of nuclear material: random DNA breaks, DNase activity, karyolysis, pyknosis, karyorrhexis (fragmentation)
ghost like appearance
inflammatory response
coagulative necrosis
most commonly after a severe cell injury from ischemia, due to exposure of toxic agents
opaque and drier than surrounding normal tissue, nuclei may be absent, but cell outlines and cytoplasm are still discernible
liquefaction necrosis
a form of coagulative necrosis
necrotive area rapidly liquiefied due to extensive lysis
most fequently seen in the brain after ischemic injury from arterial occlusion
necrotic area is soft and the center becomes liquefied as the result of release and activation of hydrolytic enzymes
caseous necrosis
commonly associated with foci of tuberculous infection in tissues, whitish-gray, sharply demarcated from surrounding non-necrotic tissue
reminiscnent of dry cheese, center of these lesions undergo liquefaction
hallmark is granuloma formation
fat necrosis
almost exclusively found in adipoe tissue contiguous to the pancreas and more rarely at distant sites
result of leakage of lipase and other hydrolytic enzymes form acutely injured acinar cells of the pancreas
calcium sinks due to saponification, which leads to hypocalcemia and tetany
process of pancreatic fat necrosis
gangrenous necrosis
a variant of coagulation necrosis, localized to soft tissue of lower limbs that have been compromised by protracted hypoxia and ischemia
tumor necrosis
tumors may outgrow their blood supply and create hypoxic zones, these cells will die through necrosis
therapy can lead to necrosis as well as abnormal production of pro-angiogenic factors secreted by the tumor cells causing the tration of immune system cells
apoptotic factors produced by dying cells can also trigger necrosis
Name the general mechanisms that can lead to necrosis
ATP depletion, loss of calcium homeostasis, free radical generation, loss of membrane permeability, damage to DNA and protein
ATP depletion
absence of oxygen, ATP synthesis stops, allowing the emitochondreal permeability transition pore to open
drop in pH leads to lactate and NADH accumulates, inhibiting anaerobic glycolysis
membrane damage, leakiness and cell swelling
early changes can be reversible
loss of calcium homeostasis
dead cells accumulate calcium due to influx of calcium into the cell and the mitochondria
uncontrolled calcium entry can cause death by activating degradative enzymes
prevents contraction in contractile cells such as heart muscle
free radical generation
adding electrons to molecular oxygen as well as modifications to L-Arginine can cause ROSs to form
can cause significant damage to proteins, nucleic acids, and lipids
anit-oxidants and recuding enzymes help reduce ROS buildup under normal conditions
anti-oxidants lost during ATP or nutrient depltion, and a pulse of free radicals can occur during reperfusiuon/reoxygenation
loss of membrane permeability
increase of intracellular calcium levels in the cytoplasm triggers phospholipase activation, resulting phospholipid loss would result in membrane damage
three “vital systems” of cell structure and function
boundary functions
energy metabolism
protein synthesis
mechanisms of free radical damage
DNA damage and lipid peroxidation
apoptosis
death of a signle cell, programmed and responsible for many developmental processes
activated through the intrinsic and extrinsic pathways
dysregulation is critical for cancer development and tumor cell survival
processes during apoptosis
loss of contact with adjacent cells, loss of water and electrolytes (dehydration), chromatin condensation and DNAfragmentation, blebbing of cytoplasm, fragmentation of the nucleus, phagocytosis
no inflammatory response
physiologic causes of apoptosis
developmental programming, hormone withdrawal, removal of self-reactive lymphocytes
pathologic causes of apoptosis
DNA damage, misfolded protein accumulation, infections, immune-related
caspases
important set of cystein proteeases with specificity for aspartic acid residues
the ones known are 3,7,8, and 9, reside in cells as procaspase precursors until needed
intrinsic pathway of apoptosis
triggered by p53 in response to DNA damage and other types of severe cell stress
p53 activates pathway by upregulating proteins such as PUMA and BAX
BAX causes the release of cytochrome c which activates caspase 9, activating other caspases that destroy the cell
extrinsic pathway of apoptosis
TNFr and Fas receptors are pro-apoptotic when activated
pathway stimulates apoptosis independently of p53
assembly of death-inducing signaling complex (DISC) and recruitment of initiator caspases 8 and 10 through the Fas-associated death domain (FADD)
caspases 8 and 10 activate effector caspases 3, 6, and 7, leading to apoptosis
fatty liver disease
alcoholic and non-alcoholic, caused by alcohol or obesity
macrovesicular change - fat deposits large in comparison to hepatocyte size, many hepatocyte replaced
microvesicular change - lipid droplets are smaller than hepatocytes
