Mechanisms Of Cell Injury Flashcards
What is a cell’s sensitivity to hypoxia dependant upon?
The energy demands of the cell and/or its ability to utilize anaerobic glycolysis as a source of energy.
What are 3 functions of a cell’s membrane?
Part of the structure
Transport
Enzymatic
Which cell types have a high, intermediate, and low susceptibility to irreversible cell damage and how long would it take for each type?
High > neurons; 3-5 min.
Inter. > hepatocytes, myocardium, and renal epithelium; 30 min to 2 hours.
Low > fibroblasts, epidermis, skeletal muscle; many hours.
Brain and heart cells are sensitive to which type of cell injuries?
Hypoxia and ischemia
Liver cells are susceptible to which type of cell injury?
Drugs and chemicals
What are some biochemical mechanisms of cell injury (6).
1) ATP depletion
2) Mitochondrial damage
3) Intracellular Ca and loss of Ca homeostasis
4) Free radical induced injury (oxidative stress)
5) Defects in membrane permeability
6) DNA damage
What type of cell injury could cause ATP depletion?
What are some functions of ATP?
ATP depletion and decrease in ATP synthesis are common consequences of both ischemic and toxic injury.
ATP is required for membrane transport, osmotic balance, protein synthesis, protein stability (proper folding), lipogenesis, etc.
What effects could depletion of ATP have on critical cellular systems?
1) Na pump activity is reduced (pump is energy dependant)
2) Increased activity of cellular enzymes
3) Effects on the Ca pump (influx of Ca)
4) Disruption of protein synthesis (misfolded protein may cause cell injury or death) (also seen with heat and free radical exposure)
5) Cell deprivation of energy sources (Glu, O2)
Mitochondria are damaged directly and indirectly. What are examples of each?
Directly: toxins (eg. cyanide)
Indirectly: increased cytosolic Ca, free radicals, phospholipases, etc
What are some deleterious effects of the loss of cytosolic Ca [C] homeostasis? (eg. Increase in [C])
1) Activation of ATPase which leads to decrease in ATP.
2) Increased activation of phospholipases > decrease phospholipids > membrane damage.
3) Increased activity of proteases > disruption of membrane and cytoskeletal proteins > membrane damage.
4) Increased activity of endonucleases > DNA / chromatin damage
5) Induces apoptosis by activating cascades and by increased mitochondrial permeability.
What are the main sites of free radical damage?
Membranes (lipid peroxidation)
Proteins
DNA
What are free radicals?
Single unpaired electron in outer orbital, extremely unstable, reacts with organic and inorganic chemicals.
They are by-products of normal oxidative metabolism.
What are the sources of free radicals in tissues and cells?
1) absorption of radiant energy (UV light)
2) reduction-oxidation rxns during normal physiologic processes:
A. Respiratory chain enzymes and O2 (in mitochondria)
B. Xanthine oxidase (in the cytosol)
C. Cytochrome p450 mono-oxygenase activity (in ER and mito)
D. NADPH oxidase (in plasma membrane)
E. Fenton reaction
3) exposure to toxins (O2, carbon tetrachloride, acetaminophen)
What damage can free radicals cause?
1) Lipid peroxidation of membranes
» loss of membrane function and increased permeability
» generate lipid autoperoxidation rxn
2) DNA damage leading to mutations and death
3) Cross linking of proteins
What are 3 catalytic/enzymatic ways to inactivate free radicals?
1) Superoxide dismutase (SOD): Catalyzes the bd of superoxide onto H2O2 and O2.
2) Glutathione peroxidase: Conversion of hydroxyl free radicals to H2O.
3) Catalase: Catalyzes conversion of hydrogen peroxide into H2O and O2.
Free radicals are also neutralized by? Name 6 of them.
Antioxidants! Vit E, A, and C. B-carotene Ceruplasmin Ferritin
What are 6 examples of damage by free radicals?
1) Ischemia-reperfusion
2) Chemical and radiation injury
3) Toxicity from O2 and other gases
4) Cellular aging
5) Microbial killing by phagocytic cells
6) Tissue injury by inflammatory cells
What is ischemia-reperfusion?
It is a combination of hypoxic and free radical injury.
During ischemia cells die, but when reperfusion occurs the surviving cells will die.
What is the pathogenesis of ischemia-reperfusion injury?
1) Reduction of blood flow leads to hypoxic damage to tissues.
2) This leads to Ca-activated protease»_space; increased Xanthine oxidase activity»_space; generation of more free radicals in the cytosol.
3) Re-establishment of blood flow brings O2 and inflammatory cells to the hypoxic tissue: O2 converted to superoxide anion and hydroxyl radical; inflammatory cells > inflammatory mediators.
The plasma membrane can be damaged by? 4 examples.
1) ischemia
2) various microbial toxins
3) lyric complement components
4) variety of physical and chemical agents
What does damage to DNA and proteins culminate in?
What could improperly folded proteins be caused by?
Cellular death by apoptosis.
Caused by inherited mutations or by external triggers such as free radicals.
Define cellular aging
A progressive decline in cellular viability caused by genetic abnormalities, and cumulative effect of cellular and molecular damage due to the effects of exposure to exogenous influences.
List some age-related diseases in animals.
Renal failure Osteoarthritis Muscle atrophy Cerebral atrophy (due to loss of cortical neurons) Cessation of growth teeth (horses)
