cell injury, cell death, and adaptations Flashcards
4 adaptation responses
hypertrophy
hyperplasia
atrophy
metaplasia
hypertrophy
increase cell SIZE
hyperplasia
increase NUMBER of cells
*uterus during pregancy
metaplasia
transfer one cell group to another cell type
atrophy
cell shrinks
vitamin A deficiency may induce squamous metaplasia in ____ epithelium
respiratory
define reversible cell injury
in early stages or mild forms of injuries, functional and morphological changes are reversible IF the damaging stimulus is removed
define irreversible cell injury
as stimulus continues, the injury persists and cellular damage become irreversible
- *inability to reverse mitochondrial dysfuntion
- *development of profound disturbances in membrane function and integrety resulting in necrosis
necrosis is pathologic or physiologic?
pathologic only
apoptosis is pathologic or physiologic?
can be either pathologic or physiologic
necrosis
- need ATP
- cells SWELL
- affects larger areas of cells/tissues
- has immune rxn
- not regulated
- only pathologic
- leakage of enzymes/cell contents ocurs
- not a normal regulation method
- many cells affected
apoptosis
- NO ATP
- cell itself is degraded
- minimal disruption of surrounding tissues
- inner leaflet flips out causing BLEBING
- regulated, organized, programmed
- normal mechanism to regulate organs
- patho and physiologic
- single cell affected and SHRINK
pyknosis
shrink
karyorrhexis
fragment
karyolysis
disintegrate
inability to reverse mitochondrial dysfunction causes irreversible injury how?
results in lack of oxidative phosphorylation and ATP generation
4 major factorss required for maintaining the ion permeability of the cell
1) considerable amounts of ATP
2) structural integrity of phospholipid bilayer/cell membrane
3) intact ion channel proteins
4) normal association of membrane with cytoskeletal elements
what color are necrotic cells?
pale pink. Bc eosin binds to denatured proteins
blue=DNA/RNA=H
signs of reersible cell injury
1) cellular swelling
- -ion pumps fail causing altered homeostatsis
- failure of ATP generation= failed sodium pump
2) fatty change (steatosis)
- -hypoxic, toxic, metabolic injury
- liver affected commonly
- increase eosin staining
- alcohol COMMON cause
patterns of tissue necrosis
coagulative liquefactive gangrenous caseous fat fibrinoid
coagulative necrosis
- structure maintained, cells dead
- in solids organs EXCEPT the brain
- phago removes
- persists for days/weeks
liquefactive necrosis
- bacterial or fungal infections
- function and structure lost
- hypoxic death of cells within CNS evokes liquefactive necrosis known as BRAIN INFARCTS
gangrenous necrosis
- in limbs!
- usually due to small or large artery occlusion
wet gangrene
when a bacterial infection is superimposed then coagulative necrosis is modified by liquefactive pattern known as ‘wet’
caseous necrosis
- CHEESE LIKE
- associated with tuberculosis
- rements become GANULAR (not solid like coagulase or liquid like liqufactive)
- often enclosed by a granuloma
fat necrosis
- white color
- pancreus
- FA bind to Ca+
fibrinoid necrosis
- immune reactions involving BV= Polyarteritis nodosa
- antigen/antibody complexes depositied within the walls of arteries
- Ag-Ab immune complexes together with fibrin
early vs late lesions of arteries with fibrinoid necrosis
early= PMNs and eosinophils
late= lymphocytes, plasma cells, GRANULOMATOUS INFLAMMATION does NOT occur
what happens id Ag-Ab immune complexes together with fibrin are not removed from artery walls
they attract Ca+ and cause blockages
what are 4 subcellular responses to injury?
1) autophagy
2) induction (hypertrophy) of smooth ER
3) mitochondrial alterations most important
4) cytoskeletal abnormalities
autophagy
**subcellular responses to injury
process of self survival in nutrient deprivation
- preserves heath of cells by replacing damaged ones with fresh cells
- starved cells lives by eating its own contents
cancer and autophagy
autophagy has a downside bc cancer cells exploit it to survive in nutrient-poor tumors
autophagicavuoles vs autophagolysosomes
autophagicavuoles= form from the ribosome free region of the ER
autophagolysosomes= upon fusion with lysosome itself
heterophagy
process of cell consuming material from its environment. the mechanisms that takes place in the macrophages to destruct ingested substances
residual bodies
when some lysosomes with undigested debris persist within a cell after autophagy
induction (hypertrophy) of smooth ER
**subcellular responses to injury
- smooth ER involved
- response to chemicals causing ER hypertrophy
- BARBITURATES are metabolized in liver and its tolerance is due to in INcrease of
P-450 enzyme
detoxifiers of chemicals, process may also render more injurious (CCl4) by resulting in reactive oxygen species (ROS ) that can injure cell
mitochondrial alterations
**subcellular responses to injury
-alterations in #, size, shape, and function
cellular hypertrophy vs cellular atrophy
- cellular hypertrophy= increased # of mito
- cellular atrophy= decreased # of mito
**mitochondrial alterations– subcellular responses to injury
mitochondrial myopathies
defect in mito metabolism associated with increased # unusually large mitochondria, containing abnormal cristae
**mitochondrial alterations– subcellular responses to injury
cytoskeletal abnormalities
**subcellular responses to injury
interfere with assembly and function of cytoskeletal filaments, may results in abnormal accumulations of filaments, aberrent movement or organelles
vinca alakaloids
bind to MT and decrease tototic spindles during replication (cytoskeleton abnomality)
cardiac or skeletal muscle take longer to die after ischemia?
skeletal= 2-3 hours cardiac= 20-30 minutes
major causes of ATP depletion?
1) decreased oxygen and nutrients
2) mitochondrial damage
3) toxins (cyanide)
depletion of ATP to ____% of normal has widespread effects on critical cellular systems
<5-10%
glycolytic pathway can generate?
ATP in the absense of oxygen using glucose!
*Liver can survive longer than other organs with limited glycolysis, like the brain
Na+/K+ pump… how many in and out?
3 Na+ OUT
2 K+ IN
*uses ATP to get Na+ out, becomes ADP allowing the pump to open letting K+ in, once K+ is in the pump ditches ADP and restarts with ATP
damage to mitochondria
- mito needed to ATP production, and cell energy/death
- damaged by increased INtracellular Ca++, ROS and O2 deprivation (hypoxia/toxins)
- damage causes MPTP formation and pH changes
- Either ATP depletion leading to necrosis OR apoptosis due to leakages (like cytochrome c)
increased Ca++ in a cell can cause?
apoptosis (activates caspases and mito permeability)
*activation of phopholipase, protease, endonuclease, ATPase
Reactive Oxygen Species (ROS) is produced and removed where?
produced in mito and removed by degradation
what is oxidative stress?
when there is an increased ROS production or the scavenger system fails to remove them which results in increased free radicals
*ROS production is greater than body’s ability to remove
what are some triggers that cause excess ROS production?
UV light exposure, pollution, smoking, eating an unhealthy diet, excessive exercise, certain medications and/or treatments
Vitamins A, C, E, and B-carotene are all examples of?
antioxidents that block the formation o f free radicals or scavenge them
3 main reactions that are particularly relevant to cell injury mediated by free radicals?
1) lipid peroxidation of cell membranes
2) cross-linking of proteins (increases protein degradation)
3) DNA fragmentation (single strand breaks)
examples of cell injury and necrosis
1) ischemic and hypotoxic injury
2) ischemica-reperfusion injury
3) chemical (toxic) injury)
root word of apoptosis?
“falling away from”
In regards to the cellular membrane, how does necrosis and apoptosis differ?
- apoptotic cell membrane remains intact (except for blebing) and becomes a target for phago so there is no leakage or inflammation
- necrosis has loss of membrane integrity, enzymatic digestion of cells and leakage of cellular contents frequently causing inflammation or host reaction
the fundamental event in apoptosis is the activation of enzyme called?
caspase
Cysteine proteases that cleave protein after ASPartic residues
activation of caspases causes activation of?
nucleases that degrade DNA and other enzymes that destroy nucleoproteins and cytoskelatal proteins
**activation of apoptosis depends on a balance between pro and anti apoptotic molecules
what are the 2 distinct pathways that activate appoptosis that do interact?
1) mitochondrial/intrinsic pathway
2) death receptor/extrinsic pathway
anti-apoptotic molecules?
BCL-2 BCL-XL BCLW MCL BCLB \+viral homologs
BCL-2 vs BCL-2 superfamily
BCL-2 protein is ANTI ONLY
*BCL-2 superfamily is both pro and anti
executioner caspases cause (caspase 3)?
1) endonucleases activation
2) breakdown of fcytoskeleton
phagocytic clearance of apoptotic cells may be considered to consist of 4 distinct steps
1) accumulationof phagocytes
2) recognition of dying cells- bridge molecules and receptors
3) engulfment
4) processing
what molecule is in both apoptosis and necrosis (coexist)?
poly-ADP polymerase
*DNA damage, during apoptosis, activates poly-ADP polymerase, which depletes nicotinamide adenine, leading to fall of ATP, resulting in necrosis
p53
causes BOTH a helt in the cell cycle and repair of damaged DNA!! If unsuccessful, activates Bax and Bak for apoptosis
growth hormones, lymphocytes and nerves, typically activate what pathway for apoptosis?
mitochondrial
accumulation of misfolded proteins causes ___ stress
ER stress; resulting in apatosis
*common in neurodegenerative diseases
cytotoxic T lymphocytes (CTL) granule protease called ______ cleaves proteins at aspartate residues and can activates?
*may induce what?
called Granzymes
- activate caspases, effector phase of apoptosis, without involving tradittional pathways (death receptor or mitochondria)
- may also induce apoptosis by ligation of Fas receptors on target cells
describe autophagy
self eating
*intracellular stuff is first sequestered in autophagic vacuole, and THEN fuses with lysosomes to form an autophagolysosomes for digestion
5 common intracellular accumulations?
1) fat
2) cholesterol and cholesteryal esters
3) proteins
4) glycogen
5) pigments
fatty change (intracellular accumulation)
- accomulation fo triglycerides within parenchymal cells
- cause FATTY LIVER
- apoproteins form lipoprotein complex
most common causes of fatty liver?
alcohol consumption and diabetes mellitus
cholesterol and cholesteryal esters (intracellular accumulation)
- cholesterol metabolism is tightly regulated but may become overloaded with lipids
- macrophages become “FOAMY macrophages” upon contact
- artherosclerosis
- hyperlipidemic syndrome
artherosclerosis
smooth muscle cells and macrophages filled with lipid vacuoles giving the plaque their characteristic yellow appearance
hyperlipidemic syndrome
hereditary or acquired
*forming of masses of foamy macrophages celled xanthomas
protein (intracellular accumulation)
- less common than lipid accumulation
- due to excess synthesis
- pinocytic vesicle containing proteins fuse with lysosomes resulting in PINK hyaline cytoplasmic droplets
- Nephrotic syndrome
- Russell bodies
- Mallory body (alcoholic hyalin)
- neurofibrillary tangle
Nephrotic syndrome
when heavy protein (albumin) leaks, there is an increased reacsorption of albumin by pinocytosis in the proximal convoluted tubules
Russell bodies
accumulation of immunoglobulins in the RER of some plasma cells
Mallory body (alcoholic hyalin)
eosinophilic cytoplasmic inclusion in the liver cells composed of aggregated intermediate filaments that presumably resist degradation
*seen in alcoholic liver disease
neurofibrillary tangle
seen in brain of Alzheimers patient
*aggregation of microtubule-associated proteins and neurofilaments that disrupt neuronal cytoskeleton
glycogen (intracellular accumulation)
indiabetes, glycogen may accumulate in renal tubular epithelium, hepatocytes and cardiac myocytes and B cells of Islets of Langerahnds
*enzyme myophosphorylase is needed
B cells in liver produce?
insulin
myophosphorylase
enzyme needed for breakdown of glycogen into sugar in muscles
*in hereditary glycogen storgae disease you LACK this enzyme
pigments (intracellular accumulation) of CARBON
exogenous or endogenous
- Carbon most common exogenous; causes black streaking in lungs called ANTHRACOSIS
- not harmful unless it accumulates which would induce emphysema and coal workers pneumonocniosis
lipofusion
an endogenous pigment for “wear and tear”
*in large amounts cause ‘brown atrophy’ which is PERINUCLEAR and accumulate in many tissues (heart, lung)
melanin
brown-black endogenous pigment that protects against UV radiation
*causes freckles, benign moles and melonoma
Hemosiderin
hemoglobin-derived pigment from breakdown of erythocytes, golden to brown.. CAUSES BRUISES
*is the iron complex to apoferrin forming ferritin micelles
SIR2 proteins
activated by calorie restriction
- activate DNA repair mechanisms
- gets worse with aging
p16
inhibits cell cycle
*reduced regeneration capacity of tissue in stem cells
telomeric DNA is composed of ____ repeats
tandem repeats of guanine rich sequence TTAGGG in a single stranded overhang at the 3’ end
telomerase and its proteins
enzyme that replicates telomer
**exclusive proteins are TRF1, TRF2, POT1
senescence
a potent anti-carcinogenic regulatory program that is important for telomerase and telomers; will disappear with cell age
1) superoxide dismutases (SODs)
2) glutathione peroxidase
3) catalase (in peroxisomes)
4) vitamine A, C, E and B-carotene
5) transferrin, ferritin, lactoferrin, and ceruloplasmin
1) spontaneousy decay superoxide
2) catalyze free radicals
3) degenerate hydrogen peroxide
4) antioxidants that block formation of free radicals
5) bind iron and copper to catalyze formation of ROS
