Rr 01 Cell Injury Part 2

Front 1

Define free radicals

Back 1

Unstable chemical compounds with a single unpaired electron in their outer orbital

Front 2

Describe how ionizing radiation produces free radicals

Back 2

Produces hydroxyl FRs

Front 3

Describe how damaged mitochondria produce free radicals

Back 3

Produce superoxide FRs

Front 4

Describe how high concentrations of O2 produce free radicals

Back 4

1. Produces superoxide and hydroxyl FRs
2. Produces hydrogen peroxide (H2O2)
-A reactive oxygen species that produces hydroxyl and peroxide FRs

Front 5

Describe how oxidase reactions produce free radicals

Back 5

1. NADPH oxidase in the neutrophil and monocyte cell membrane
a. Myeloperoxidase in the phagolysosome combines hydrogen peroxide with chloride to form bleach (hypochlorous acid)
2. Xanthine oxidase acting upon xanthine (degradation product of ATP)
-Produces superoxide FRs

Front 6

Describe how drugs can produce free radicals

Back 6

-e.g. acetaminophen
-Converted to acetaminophen FRs in the liver

Front 7

Describe how CCl4 leads to production of free radicals

Back 7

Converted to CCl3 FRs in the liver

Front 8

Describe how cigarette smoke leads to production of free radicals

Back 8

1. Produces quinone/hydroquinone FRs produced from tar
2. Produces NO, a FR gas
-NO reacts with other reactive species to produce additional FRs

Front 9

Describe how pollution leads to free radical production

Back 9

Nitrogen dioxide in car exhaust and ozone produce nitrate FRs

Front 10

Describe how metals (eg iron, copper) produce free radicals

Back 10

Produce hydroxyl FRs (called the Fenton reaction)

Front 11

Describe how NO produces free radicals

Back 11

FR gas that is produced by macrophages and endothelial cells

Front 12

Describe how the intima of elastic and muscular arteries produces free radicals

Back 12

1. Small dense subtypes of LDL enter the intima and are oxidized by FRs produced by macrophages, smooth muscle cells, and endothelial cells

2. Oxidized LDL contributes to formation of fatty streaks, which are progenitors of fibrous caps, the pathognomonic lesion of atherosclerosis

Front 13

Describe how free radicals attack a molecule and "steal" its election

Back 13

1. The attacked molecule becomes a FR that begins a chain reaction leading to cell death
2. FRs primarily target nucleic acids and membrane molecules
a. FRs produce DNA fragmentation and dissolution
b. FRs initiate lipid peroxidation of polyunsaturated lipids in cell and mitochondrial membranes
i. Lipid FRs combine with molecular O2
ii. Increases membrane permeability leading to increased cytosol Ca concentration
3. FR damage accumulates with age; important in the aging process

Front 14

Describe the neutralizers of FRs

Back 14

1. Superoxide dismutase
2. Glutathione peroxidase
3. Catalase
4. Vitamins
5. Selenium

Front 15

Describe superoxide dismutases

Back 15

1. Neutralize FRs
2. Converts superoxide free radicals to peroxide and O2

Front 16

Describe glutathione peroxidase

Back 16

1. Enhances glutathione, GSH
2. Located in the pentose phosphate pathway
3. Neutralizes H2O2 and acetaminophen FRs

Front 17

Describe catalase

Back 17

1. Present in peroxisomes
2. Degrades peroxide into O2 and water

Front 18

Describe vitamins as antioxidants

Back 18

1. Antioxidants neutralize FRs by donating one of their own electrons
a. Stops the electron stealing of FRs
b. Antioxidants remain stable and do not become a FR
2. Vitamin E (fat soluble vitamin)
a. Prevents lipid peroxidastion in cell membranes
b. Neutralizes oxidized LDL
3. Vitamin C (water-soluble vitamin)
a. Neutralizes FRs produces by pollutants and cigarette smoke
-Smokers have decreased levels of vitamin C because they are used up in neutralizing FRs derived from cigarette smoke
b. Best neutralizer of FRs

Front 19

Describe selenium

Back 19

Neutralizes FRs in the cytosol

Front 20

Describe acetaminophen FRs

Back 20

1. May cause diffuse chemical hepatitis
a. Liver cell necrosis initially occurs around the central veins (zone III)
i. Can occur at nontoxic levels in alcoholics
ii. Produces transient decrease in functional factor VII
-Prolongs the prothrombin time
b. Treatment with N-acetylcystine
-Increases synthesis of glutathione for neutralization of drug FRs
2. May cause renal papillary necrosis
-Necrosis occurs in association with the use of NSAIDs

Front 21

Describe carbon tetrachloride free radicals

Back 21

Produce liver cell necrosis with fatty change

Front 22

Describe ischemia/reperfusion injury in acute MI

Back 22

1. Occurs with restoration of blood flow to ischemic myocardium
2. Intracellular iron produces hydroxyl FRs, which damage parenchymal cells
-Examples of injury: cirrhosis, exocrine.endocrine pancreatic dysfunction

Front 23

Describe copper overload (Wilson's disease)

Back 23

1. Inability to excrete copper into bile
2. Copper excess in hepatocytes increases production of hydroxyl FRs
-Damage to hepatocytes produces cirrhosis

Front 24

Describe injury to mitochondria

Back 24

1. Release of cytochrome C from injured mitochondria
-Initiates apoptosis by activating caspases in the cytosol
2. Injurious agents include alcohol, salicylates, and increased cytosolic Ca
-Salicylates and alcohol produce megamitochondtria with destruction of the cristae

Front 25

Describe smooth ER injury and the induction of enzymes of the liver cytochrome P450 system

Back 25

1. May be caused by : Alcohol, barbiturates, phenytoin
2. Causes SER hyperplasia
-Increased drug detoxification with lower-than-expected therapeutic drug levels

Front 26

Describe smooth ER injury and the inhibition of enzymes of the cytochrome P450 system

Back 26

1. May be caused by
a. Protein receptor blockers (eg omeprazole)
b. Macrolides (eg erythromycin)
c. Histamine blockers (eg cimetidine)
2. Results in decreased drug detoxificiation
-Decreased drug detoxification with higher-than expected therapeutic drug levels

Front 27

Describe how enzymes enter lysosomes

Back 27

1. Hydrolytic enzymes synthesized by the RER are transported to the Golgi apparatus for post-translational modification
2. Modification involves attaching phospate to mannose residues on hydrolytic enzymes to produce mannose-6-phosphate
3. Marked enzymes attach to specific M6P receptors on the Golgi membrane
4. Vesicles containing the receptor-bound lysosomal enzymes pinch off the Golgi to form primary lysosomes in the cytosol
5. Fusion of addition vesicles to the primary lysosome further increases their content of hydrolytic enzymes
6. Small vesicles containing only the receptors pinch off primary lysosomes and return to the Golgi apparatus to bind more marked lysosomal enzymes so the cycle can repeat itself

Front 28

Describe the function of lysosomes

Back 28

1. Fusion with phagocytic vacuoles containing bacteria
-These lysosomes are designated secondary or phagolysosomes
2. Destruction of cell organells (autophagy)
3. Degradation of complex substrates (eg sphingolipids, glycosaminoglycans)

Front 29

Describe Inclusion I disease

Back 29

-Rare inherited condition
-There is a defect in post-translational modification of lysosomal enzymes in the Golgi membrane
-Mannose residues on newly syntehsized lysosomal enzyumes comring fromt he RER are not phosphorylated because of a deficiency of phosphotransferase
-Without M6P to direct the enzymes to lysosomes, vesicles that pinch off the golgi membrane empty into the extracellular space there the enzymes are degraded in the blood stream
-Undigested substrates (eg carbs, lipids, proteins) accumulate as large inclusion in the cytosol

Front 30

Describe the symptoms of Inclusion I disease

Back 30

-Psychomotor retardation
-Early death

Front 31

Describe lysosomal storage diseases

Back 31

1. Characterized by deficiency of lysosomal enzymes involves in degradation of complex substrates
2. Incompletely degraded complex substrates accumulate in lysosomes

Front 32

Describe Gaucher's disease

Back 32

Deficiency of glucocerebrosidase causes accumulation of glucocerebrosides in the lysosomes

Front 33

Describe Ppmpe's disease

Back 33

Deficiency of alpha-1,4--glucosidase causes an accumulation of glycogen in the lysosome

Front 34

Describe Chediak-Higashi syndrome

Back 34

-Autosomal recessive
-Defect in lysosomal transport proteins that affects the synthesis, maintenance, and storage of secretory granules in various cells (lysosomes in leukocytes, azurophilic granules in neutrophils, dense bodies in platelets)
-Granules in these cells tend to fuse together to become megagranules
-There is a defect in microtubule function in neutrophils and monocytes that prevents the fusion of lysosomes with phagosomes to produce phagolysosomes
-This produces a bactericidal defect, in particular, there is increases susceptibility to developing S. aureus infections
-Microtubular dysfunction also produces defects in chemotaxis which further exacerbates the susceptibility to infection

Front 35

Describe the normal functions of the cytoskeleton

Back 35

1. Network of protein filaments in the cytosol
-Maintains shape of the cell and, in some cases, motility of the cell
2. Composed of microtubules, actin filaments, intermediate filamens
3. Microtubiles are polymers composed of the protein tubulin
4. Actin thick and thin filaments are involved in the contractile process
5. Intermediate filaments are important in the integration of cell organelles

Front 36

Describe what can cause defects in synthesis of tubulin in the G2 phase of the cell cycle

Back 36

-Etoposide
-Bleomycin

Front 37

Describe the mitotic spindle defects in the M phase of the cell cycle

Back 37

1. Vinca alkaloids and colchicine bind to tubulin in microtubules
-Interferes with the assembly of the mitotic spindle
2. Paclitaxel enhances tubulin polymerization
-Interferes with disassembly of the mitotic spindle

Front 38

Describe intermediate filament defects

Back 38

1. Ubiquitin, a stress protein, binds to damaged intermediate filaments
-Marks them for degradation in proteasomes and lysosomes in the cytosol

2. Mallory bodies
-Damaged ("ubiquinated") cytokeratin intermediate filaments in hepatocytes in alcoholic liver disease
3. Lewy bodies
a. Damaged neurofilaments in idiopathic Parkinson's disease
b. Eosinophilic cytoplasmic inclusions in degenerating substnatia nigra neurons

Front 39

Describe rigor mortix

Back 39

Myosin heads become locked to actin filaments as a result of lack of ATP

Front 40

Describe intracellular bilirubin accumulations

Back 40

-Kernicterus: fat-soluble unconjugated bilirubin derived from Rh hemolytic disease of newborn
-Bilirubin enters basal ganglia nuclei of brain, causing permanent damage

Front 41

Describe intracellular cholesterol accumulations

Back 41

-Xantehlasma: yellow plaque on eyelid; cholesterol in macrophages

-Atherosclerosis: Cholesterol-laden smooth muscle cells and macrophages (foam cells); components of fibrofatty plaques.

Front 42

Describe intracellular glycogen accumulations

Back 42

Diabetes mellitus: Increased glycogen in proximal renal tubule cells (cells are insensitive to insulin and become overloaded with glycogen)

Von Gierke's glycogenosis: Deficiency of glucose-6-phosphate; glycogen excess in hepatocytes and renal tubule cells

Front 43

Describe intracellular hematin accumulations

Back 43

Melena: when blood is exposed to gastic acid, Hb is converted to a black pigment called hematin, which is responsible for black, tarry stools called melena, a sign of an upper GI bleed

Front 44

Describe intracellular hemosiderin and ferritin accumulations in iron overload disorders

Back 44

-eg Hemochromatosis
-Excess hemosiderin (breakdown product of ferritin) deposition in parenchymal cells, leading to FR damage and organ dysfunction (eg cirrhosis)
-Increase in serum ferritin

Front 45

Describe intracellular hemosiderin and ferritin accumulations in pulmonary congestion

Back 45

-In L sided heart failure there is pulmonary hemorrhage with phagocytosis of RBCs by alveolar macrophages.
-Hemosiderin is the breakdown product of RBC degradation in the macrophage (called "heart failure" cells)
-Responsible for rusty colored sputum

Front 46

Describe intracellular hemosiderin and ferritin accumulations in iron deficinecy

Back 46

Decrease in ferritin and hemosiderin

Front 47

Describe intracellular hemosiderin and ferritin accumulations in anemia of chronic disease

Back 47

Increase in ferritin and hemosiderin

Front 48

Describe intracellular melanin accumulations

Back 48

Addison's disease: destruction of the adrenal cortex; hypocortisolism leads to an increase in ACTH (melanocyte-stimulating properties) causing excess synthesis of melanin and diffuse pigmentation of the skin and mucosal membranes

Front 49

Describe intracellular protein accumulations

Back 49

Amyloid: derives from different properties (eg light chains, amyloid precursor proteins). Stains red with Congo red and when polarized has apple green birefringence

Front 50

Describe intracellular triglyceride accumulations

Back 50

Fatty liver: triglyceride in hepatocytes pushes the nucleus to the periphery

Front 51

Describe intracellular anthracotic pigment accumulations

Back 51

Coal worker's pneumoconiosis: phagocytosis of black anthracotic pigment (coal dust) by alveolar macrophages ("dust cells")

Front 52

Describe intracellular lead accumulations

Back 52

Lead poisoning: Lead deposits in nuclei of proximal renal tubular cells (acid-fast inclusion) contribute to nephrotoxic changes in the proximal tubule