Mechanism of Cell Injury Flashcards
4 intracellular systems are particularly vulnerable to injury
° cell membrane
° mitochondria
° protein synthesis
° genetic apparatus
are common consequences of both ischemic and toxic injury
ATP depletion and ATP synthesis
Cell Membranes
especially ionic/osmotic homeostasis
mitochondria
oxidation phosphorylation/ATP production
Protein synthesis, folding and packaging
Structural and functional proteins
genetic apparatus
DNA/RNA
ATP required;
✓membrane transport
✓protein synthesis
✓protein stability
✓lipogenesis
are chemical species with a single unpaired electron in outer orbit readily react with organic or inorganic chemicals, avidly attack/degrade membranes, proteins and nuclei acids
free radicals
free radical-induced injury, particularly that induced by activated oxygen species, is an important mechanism of cell damage in many disease processes, what are these?
chemical, radiation, O2 toxicity, inflammation, reperfusion
it occurs when the free radical generation overwhelms antioxidant defense mechanism
cell injury
Generation of free radicals
✓ cellular metabolism
✓ enzymatic metabolism of exogenous chemicals
✓ ionizing radiation
✓ divalent metals
small amounts produced from cell detox (loss of electrons) reactions
cellular metabolism
some intermediary metabolites of chemical/drugs are highly reactive free radicals
enzymatic metabolism of exogenous chemicals
hydrolyzes water into hydroxyl and hydrogen free radicals
ionizing radiation
the transition metals, accept or donate free electrons during certain intracellular reactions
divalent metals
important reactants
✓ superoxide anion (O2) hydroxyl radical (OH), hydrogen peroxide (H2O2) and peroxynitrite (ONOO)
✓ H2O2
✓ ferric (Fe3+)
not a free radical. is a frequent by-product of oxidative metabolism that can generate hydroxyl radicals from reactions with copper or ferrous ions
H2O2
main sites of damage
✓ damage of membranes (lipid peroxidation)
✓ damage of proteins
✓ damage to DNA
Protective mechanism of the Cell
✓ storage and transport proteins
✓ antioxidants
✓ enzyme that involve in neutralizing free radicals
biochemical mechanism
✓ ATP depletion
✓ Free radical induced injury
✓ intracellular calcium and loss of calcium homeostasis
✓ mitochondrial damage
✓ defects in membrane permeability
can catalyze formation of reactive oxygen forms
iron and copper
Mechanisms of cell injury
✓ general consideration
✓ biochemical mechanisms
✓ chemical (toxic) injury
all cells are depending on oxidative metabolism for long term survival
mitochondrial damage
catalyzes that breaks down H2O2 to O2+H2O
catalase
catalyzes the conversion of O2 to H2O2
superoxide dismutase (SOD)
defects in membrane permeability
✓ damage to membranes often critical
✓ indirect damage
✓ direct damage
chemicals and certain drugs/toxins produce damage in one of two ways
✓ direct interaction
✓ conversion to reactive toxic metabolites
in humans and dogs, it is detoxified in liver to glucuronide and sulfate conjugates
acetaminophen (tylenol) toxicity
binds to molecules in hepatocytes and causes necrosis
electrophilic
it released from the liver cells and results in oxidative damage to hemoglobin
para-aminophenol
is highly reactive and causes lipid peroxidation (autocatyzing)
CCl3
