T23 - Cell Injury II Flashcards
What are the eight common causes of cellular injury?
radiation
infections/toxins
chemicals
immune-mediated damage
oxygen
genetic defects
aging
physical agents
[RICIOGAP]
What are the six most common effects of cellular injury?
mitochondrial damage
depletion of ATP
disturbance in calcium homeostatis
damage to cell membranes
damage to DNA
misfolding of proteins
[MACCDP]
What are the four effects of ATP depletion?
(1) decrease in ATP-dependent proton pumps → retention of Na+ → efflux of K+ → cell swelling
(2) increase in anaerobic glycolysis → lactic acid buildup → pH increase → decreased enzyme activity
(3) failure of ATP-dependent Ca2+ pumps → influx of Ca2+
(4) disruption of protein synthesis → detached of ribosomes from RER → decreased protein synthesis
What are the four mitochondrial responses to mediate cell injury?
(1) failure in OxPhos → ATP depletion → necrosis
(2) abnormal OxPhos → ROS production
(3) formation of mitochondrial permeability transition pores
(4) release of internal proteins that initiate apoptosis
Compare intracellular and extracellular calcium concentrations.
intracellular calcium is 10,000x lower than extracellular calcium
List the five enzymes that are activated as a consequence of calcium homeostasis disturbance.
(1) phospholipases: membrane damage
(2) proteases: breakdown of membrane/cytoskeletal proteins
(3) endonucleases: DNA/chromatin fragmentation
(4) ATPases: hasten ATP depletion
(5) caspases: initiate apoptosis
What are the four pathways by which ROS are generated?
normal metabolism
inflammation
radiant energy
toxic chemical metabolism (of CCl4, for example)
[NIRT]
How are ROS removed? (3)
spontaneous decay
antioxidant scavengers
enzymatic removal
Give four examples of antioxidant ROS scavengers.
vitamin A
vitamin E
vitamin C
beta-carotene
Give three examples of enzymes that remove ROS.
superoxide dismutases
catalases (peroxidases)
gluthiatione peroxidase
What are the three ROS effects on cells?
lipid peroxidation
cross-linking proteins
DNA fragmentation
Describe the effects of ROS on lipid peroxidation.
free radicals break double bonds of membrane polyunsaturated lipids, yielding peroxides
Describe the effects of ROS on cross-linking proteins.
free radicals promote sulfhydryl-mediated protein cross-linking, leading to loss of enzyme activity
Describe the effects of ROS on DNA fragmentation.
free radicals interact with thymine and produce single-stranded breaks
What are the five pathways that give rise to membrane damage?
(1) decreased phospholipid synthesis because of lower ATP
(2) phospholipase breakdown of membranes
(3) ROS damage
(4) protease breakdown of cytoskeletal proteins
(5) liberated lipids (like free fatty acids) that act as detergents
What kinds of damage lead to apoptosis? (3)
damage by:
ROS
calcium-activating proteases
DNAses
What kinds of damage lead to necrosis?
membrane damage
Differentiate between apoptosis and necrosis.
apoptosis = programmed cell death
necrosis = unprogrammed cell death
What is physiologic apoptosis?
normal apoptotic phenomenon that eliminates cells no longer needed
Give an example of physiological apoptosis.
embryogenesis: apoptosis of cells between fingers
What is pathologic apoptosis?
elimination of cells genetically altered or injured beyond repair, without eliciting a severe host reaction to keep tissue damage to a minimum
Give three examples of pathologic apoptosis.
apoptosis in response to DNA damage
apoptosis in response to misfolded proteins
apoptosis due to viral infection
What are the two pathways of apoptosis?
extrinsic = death receptor pathway
intrinsic = mitochondrial pathway
What are caspases?
apoptosis-associated enzymes that are cystine proteases which cleave substrates after an aspartyl residue
Describe the steps of the extrinsic pathway of apoptosis. (3)
Death signals (FasL, TRAIL, TNF-alpha) bind to Death Receptors (TNFR1)
formation of Death Inducing Signaling Complex (DISC), which contains FADD adaptor protein + pro-initiator caspase 8
DISC converts procaspase 8 into active caspase 8, which cleaves effector caspases to induce apoptosis
Describe the steps of the intrinsic pathway of apoptosis. (3)
stimuli (growth factor withdrawal, DNA damage, etc.) cause release of cytochrome c from mitochondria
CytC binds Apaf-1 + pro-caspase caspase-9 = forms apoptosome
apoptosome cleaves pro-caspase 9 into caspase 9, which cleaves effector caspases
Which protein family mediates the extrinsic pathway of apoptosis?
TNF-superfamily
Which protein family mediates the intrinsic pathway of apoptosis?
BCL2 family
Describe the roles of the BCL2, BAX, BAK, and BH3 proteins in the intrinsic/mitochondrial pathway of apoptosis.
BCL2: anti-apoptotic
BAX/BAK: pro-apoptotic
BH3: inhibit BCL2 and therefore pro-apoptotic
How do BAX and BAK serve as proapoptotic proteins in the intrinsic pathway of apoptosis? (2)
increase permeability of mitochondrial membrane
release cytochrome c
What is autophagy?
lysosomal digestion of cell’s own components
Why would autophagy be useful?
survival mechanism in times of nutrient deprivation
Describe how autophagy and apoptosis are related. (3)
autophagic vacuoles form w/ intracellular organelles and cytosolic contents
vacuole fuses w/ lysosomes to form autophagolysosome
starved cell can no longer survive by eating itself, so apoptosis is initiated
Describe the relationship between autophagy and neurodegenerative disease.
defective autophagy means misfolded proteins aren’t properly cleared, leading to neurodegenerative disease
What are intracellular inclusions?
aggregates of nuclear or cytosolic material due to inadequate removal of the substance, secondary to defects in transport or packaging
What are four pathways to intracellular inclusions?
packaging/transport defects
accumulation of abnormal endogenous substance
failure to degrade metabolite due to inherited deficiences
deposition/accumulation of abnormal exogenous substance
What is anthracitic pigment? (2)
carbon dust
air pollutant that aggregates in lymph nodes and pulmonary parenchyma as black pigment
What is lipofuscin? (3)
pigment that accumulates as a result of “wear and tear”
function of age or atrophy
appears as granular brown-yellow intracellular pigment
What is melanin? (2)
endogenous brown-black pigment synthesized by melanocytes
found in basal keratinocytes (freckles) or in dermal macrophages
What is hemosiderin? (3)
hemoglobin-derived granular pigment
golden yellow-brown color
accumulates in tissue with excess iron
What are four pigments that commonly accumulate in cells?
anthracitic pigment
lipofuscin
melanin
hemosiderin
Differentiate between striated and cardiac muscle in terms of how they can tolerate ischemia.
striated muscle can tolerate ischemia for 2-3 hours
cardiac muscle can tolerate ischemia for 30 minutes
(T/F) Morphological changes in cells precede loss of function.
False. It’s the other way around — loss of function precedes morphological changes.
In terms of damage to cellular membranes, which organelle membranes are the most critical?
mitochondrial (decreases ATP)
plasma membrane (loss of osmotic balance)
lysosomes (leakage of contents)
What is hepatic steatosis?
accumulation of TGs in liver parenchymal cells (i.e. hepatocytes)
What are two causes of hepatic steatosis?
alcohol abuse
diabetes associated with obesity
In a hemorrhage, RBCs are observed outside vessels. Describe how RBCs are then degraded.
RBC → hemoglobin → bilirubin → biliverdin
(T/F) Lipofuscins are dangerous to cells.
False. Lipofuscin is not dangerous to cells.
The presence of lipofuscin in a cell indicates
oxidative damage
What is hemosiderosis? (4)
increased iron presence in cells, due to:
increased absorption of dietary iron
impaired utilization
hemolytic disease
red blood cell transfusion
Give an example of an antioxidant scavenger.
glutathione
