Goljan- Cell Injury And Cell Death

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Hypoxemia- Definition, Causes (4)

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Decrease in "PaO2"-

1) Resp. Acidosis,
2,3) V/Q mismatch,
4) Diffusion defects (interstitial fibrosis, pulmonary edema)

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Anemia- what are values of PaO2, SaO2, O2 content

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Anemia

Normal PaO2, Normal SaO2, low total O2 content

Front 3

Methhemoglobinemia- what is it, what it is caused by, what it looks like clinically

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MetHb is oxidized Hb (Fe+3) (oxidized heme group)

can be caused by oxidizing agents or deficiency of met Hb reductase.

Chocolate-covered blood and cyanosis

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Methemoglobinemia- treatment

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methylene blue (activates Hb reductase) and Vit C (reducing agent)

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Pathogenesis of Hypoxia (3 ways)

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1) CO competes with O2 for binding sites on Hb (decrease Sat. but does NOT decrease PaO2)

2) Inhibits Cyt Ox. (ETC)

3) Left shift

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Part of brain affected by CO poisoning

Back 6

necrosis of Globus pallidus

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What causes left-shift in O2 curve? (6 things)

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LEFT-shift O2 curve

this means INCREASED affinity

1) decreased BPG
2) lower temperature
3) higher pH
4) CO poisoning
5) Fetal Hb
6) Methemoglobin

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Going to higher altitudes, what it does to your resp.

Back 8

Lower P-atm --> hypoxemia stimulates peripheral chemoreceptors (carotid bodies) --> resp. alkalosis ---> so this causes a left shift.....HOWEVER:

Alkalosis ---> PFK-1 ---> increased prdxn of 1,3 BPG ---> 2,3 BPG ---> shifts curve to the right

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Cyanide poisoning- causes and rx

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Cyanide poisoning (like CO poisoning) inhibits Cytochrome Oxidase, this can result from drugs (nitroprusside) and combustion of polyurethane (house fires).

Treat with- Amyl nitrate (produces MetHb which combines with CN) follwed by Thiosulfate (CN converted to thiocyanate)

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Example of an uncoupling agent (3 of them)

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Dinitrophenol (in TNT synthesis). Alcohol and slicylates damage IMM, causing protons to move into the matrix. Hyperthermia happens with uncoupling

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Examples of two major watershed areas

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1) Between ACA and MCA (brain)
2) Splenic flexure (between SMA and IMA)

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Layer of heart that receives LEAST amount of O2

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Subendocardial tissue (Angina, ST DEPRESSION)

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Hypoxic cell injury- changes considered probably reversible (~3 or 4 things)

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Anaerobic glycolysis-- causes the activation of PFK (caused by low citrate and inc. AMP). So 2 more ATP from glycolysis, but lactate causes decrease in intracellular pH
---> Impaired Na+/K+ pump
(so Na+ more now diffusing into cell ---> swelling)

Detachment of ribosomes (decreased protein synthesis)

Front 14

The role of calcium in hypoxic cell injury

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Impaired Ca2+/ATPase---> increased Cytosolic calcium

1) Enzyme activation--- PHOSPHOLIPASES damage membrane

2) Enzyme activation-- PROTEASES damage cytoskeleton

3) Enzyme activation-- ENDONUCLEASES causing karyolysis


4) Increased mito membrane permeability ---> calcium goes into mitochondria, causes release of cytochrome C (causes Apoptosis)

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Lipid peroxidation- what kind of lipids are acted on by free radicals

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POLYUNsaturated lipids in cell membranes are affected by free radicals

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Superoxide

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O2 (-)

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Peroxides

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free radical. H2O2

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SOD

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Superoxide dismutase. Neutralizes Superoxide (O2-) free radicals

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Glutathione peroxidase

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1) Enhances glutathione, which
--Neuatralizes free radicals from:::
-- peroxide
hydroxyl
acetaminophen

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Catalase

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neutralizes PEROXIDE free radicals

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Tylenol causing hepatic necrosis- which part of liver

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Liver cell necrosis from acetaminophen toxicity occurs around CENTRAL VEINS

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Tylenol causing kidney damage- which part of kidney

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may cause renal PAPILLARY NECROSIS from too much tylenol

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Difference between carbon tetrachloride liver damage and tyenol liver damage

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CCL4 causes liver cell necrosis with FATTY CHANGE.

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How Iron overload disorders cause intracellular damage

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Intracellular damage produces hydroxyl radical. Happens in Cirrhosis, pancreatic, skin pigmentation

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How/where enzymes marked for lysosome?

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In the golgi apparatus, hydrolytic enzymes marked by mannose-6-phosphate

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Inclusion (I) Cell disease

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Lysosomal enzymes lack man-6-PO4 marker, so primary lysosomes do NOT contain hydrolytic enzymes. Cytosol accumulation

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Gaucher's disease (very simply)

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Lysosomal storage d/o

Lack glucocerebrosidase causes their accumulation IN the lysosome

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Secondary Lysosomes (Phagolysosomes)

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arise from fusion of primary lysosomes with phagocytic vacuoles

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Chediak Higashi syndrome (Inheritance-- Defect -- Result --- Clinical)

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Autosomal Recessive

Defect in phagolysosome membrane fusion

Causes fusion of azuro granules in primary lysosome (leukocytes) and they cant fuse with phagosomes (to make 2' Lysosomes)

Susceptibility to Staph Aureus

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Mallory Bodies

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Ubiquinated cytokeratin intermediate filaments in hepatocytes in alcohlic liver disease

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Fatty Change in Liver (mechanisms --6)

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Accumulation of TGs- pushes nucleus to periphery

Mechanisms :

1) More NADH converts DHAP to Glycerol-3-phosphate

2) More FA synthesis (acetyl CoA is end product of alcohol metabolism)

3) Decreased B-oxidation of FAs

4) Inc. mobilization of FAs from adipose

5) Decreased synthesis of apo B-100 (comes from CCL4, kwashikior)

6) Decreased hepatic release of VLDL (same cause as #5)

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Von Gierke's glycogenosis (Cause, result)

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Deficiency of Glucose-6-Phosphatase

--> Glycogen excess in hepatocytes and rental tubular cells

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Glycogen excess and DM?

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YES. in DM, inc. glycogen in PT cells (sensitive to insulin)

Front 34

Lead accumulation and kidney

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Lead deposits in nuclei of PT cells-- nephrotoxicity

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FERRITIN- where it is found, what it represents, what it's measurement means

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Ferritin- (SOLUBLE) Iron storage protein

Stored in bone marrow macrophages mostly

Some ferritin stores in hepatocytes too

Small amount of ferritin that circulates in serum directly correlates with the bone marrow stores!!!

Front 36

Hemosiderin- what is it

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INSOLUBLE product of ferritin degradation in lysosomes

Front 37

DIfference between dystrophic and metastatic calcification

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Dystrophic calcification- NORMAL serum calcium and phosphate

Metastatic Calcification-- Elevated serum calcium and OR phosphate (excess phosphate drives calcium into normal tissue)

Front 38

Brown Atrophy

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Undigested lipids stored as residual bodies, results from lysosomal accumulation of lipofuscin (wear and tear). Lipofuscin is indigestible lipid coming from lipid perxidatin of membranes (occurs in atrophy or ROS-induced damage)

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Unilateral nephrectomy causes what in the other kidney

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hypertrophy AND hyperplasia

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Examples of stable (Resting) cells that must be stimulated to undergo hyperplasia

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Hepatocytes, astrocytes, SMCs

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Examples of permanent cells (nonreplicating)

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Neuron
Skeletal Muscle
Cardiac Muscles

the latter two can undergo hypertrophy, but none of these three can do hyperplasia

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"cell progression" in dysplasia

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disordery proliferation of cells with loss of cell maturation as cells progress to the surface

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What is preserved in Coagulative necrosis?

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Coagulation Necrosis- preservation of the structural outline of dead cells

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Microscopic features of coagulative necrosis (2)

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(1) Indistinct outlines of cells within dead tissue

(2) Karyolysis or absent nuclei

Front 45

Pale Infarct- Happens in what kinds of tissues?

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Pale Infarct is more for ISCHEMIC infarct (not hemorrhagic).
Ex) Heart
Kidney
Spleen

This is a type of coagulative necrosis

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Hemorrhagic Infarct- Happens in w hat kinds of tissues?

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Loose-textured tissue- Lungs, Small Bowel (RBCs can diffuse through necrotic tissues)


This is a type of coagulative necrosis

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Mechanisms of liquefactive necrosis, examples of when it happens

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Mechanism of Liquefactive Necrosis-- lysosomal enzymes released by necrotic cells or neutrophils

Happens in CNS (enzymes generated by neuroglial), Abscess in bacterial infection

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Dry gangrene vs. wet gangrene

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Dry Gangrene is primarily COAGULATIVE necrosis, while wet gangrene occurs when maybe superimposed infection causing Liquefactive necrosis to be the primary pattern seen

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Caseous Necrosis

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variant of COAGULATIVE necrosis

release of lipid from cell walls by TB or fungi

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Fat necrosis mechanisms

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Activation of pancreatic lipase (alcohol excess) causing hydrolysis of TGs in fat cells

Conversation of FAs into sap (FAs and calcium)

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BAX, Cyt C, BCL2

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BAX & Cyt C- PRO APOPTOTIC

BCL2- ANTI APOPTOTIC
(prevents leakage of Cyt C into cytosol)

Front 52

Which is more specific for liver disease, ALT or AST

Back 52

ALT is more specific for liver cell necrosis than AST

Front 53

Which is more specific for pancreatic disease, lipase or amylase?

Back 53

Lipase is more specific than amylase for pancreatitis (amylase can be elevated in mumps!)