Cell Injury 1 Terms
- Hypoxia – inadequate oxygenation of tissue (same definition as shock). o Oxygen is needed for the oxidative phosphorylation pathway.
Oxidative Phosphorylation Pathway
• It’s where we get ATP from; it’s specifically in the inner mitochondrial membrane. • The last reaction is oxygen (to receive the electrons). Protons are kicked out the electron
transport system and they end up going back into the membrane forming ATP. - Oxygen content
o Hemoglobin (Hb) x oxygen saturation (the oxygen attached to the heme group) + partial pressure of arterial oxygen (PaO2) (the amount of oxygen dissolved in plasma)
o Oxygen saturation
There’s 4 heme groups on hemoglobin and iron has to be +2.
If all 4 heme groups on hemoglobin are occupied by oxygen in everyone of the RBCs, the oxygen saturation is 100%.
This is measured with a pulse oximeter. o Partial Pressure
The amount of oxygen dissolved in plasma. Flow of oxygen
• The oxygen flows from the alveoli to the interface.
• It dissolves in the plasma and increases the partial pressure of oxygen.
• It then diffuses through the RBC membrane and attaches to the heme group on the RBC (oxygen saturation).
If the partial pressure of oxygen is decreased, the oxygen saturation also has to be decreased. Tissue Hypoxia
- Ischemia
o The most common cause of tissue hypoxia.
o
It is a decrease in arterial blood flow.o
The most common cause of ischemia is a thrombus in a muscular artery. It’s also the most common cause of death in the U.S. (myocardial infarction).o A decrease in cardiac output (hypovolemia, cardiogenic shock, …) could also cause ischemia b/c you have a decrease in arterial blood flow.
- Hypoxemia
o The second most common cause of tissue hypoxia.
o
It’s not the same as hypoxia (the big term). Hypoxemia is a cause of hypoxia. Hypoxemia deals with the partial pressure of arterial oxygen (the oxygen dissolved in plasma); hypoxemia is when the partial pressure of oxygen is decreased.o Respiratory Acidosis
Dalton’s law = the sum of the partial pressures must equal 760 mmHg at atmospheric pressure. When you retain CO2, that’s respiratory acidosis. What has to happen to the PO2 when the CO2
goes up is it has to go down (b/c you still have to maintain 760).
Everytime you have respiratory acidosis from any cause, you have hypoxemia (low PO2). • If CO2 goes down (respiratory alkalosis), PO2 goes up.
You have normal hemoglobin, oxygen saturation is decreased, and PO2 is decreased. Oxygen saturation is decreased b/c PO2 is decreased.
o Ventilation Defect
Best example is respiratory distress syndrome (aka hyaline membrane disease); the adult counterpart is called adult respiratory distress syndrome.
You have lost ventilation to the alveoli, but you still have perfusion (you’ve created an intrapulmonary shunt). Scenario
•
Patient has hypoxemia. They gave him 100% oxygen for 20 minutes. The PO2 didn’t increase. What does it mean?• It means you have a shunt (intrapulmonary shunt). • This is how you tell whether you have a shunt or not. o Perfusion Defect
This means you knock off blood flow.
The most common perfusion defect is pulmonary embolus.
We have ventilation, but no perfusion. This causes an increase in dead space.
If you give 100% oxygen to someone with a perfusion defect, you will get the PO2 up; b/c every vessel in the lung is not perfused so other areas of the lung can make up for the difference. o Diffusion Defect
You have something in the interface that oxygen can’t get through. An example is fibrosis; the best example is sarcoidosis. Another example is pulmonary edema or fluid from heart failure.
In heart failure you activate the J reflex. It’s integrated by the tenth nerve. Fluid or anythinginnervates the J receptor, then you get dyspnea. - Hemoglobin related problems can cause hypoxia.
o Anemia
Anemia would obviously be a cause.
In anemia, there is not a decrease in PO2. You don’t have hypoxemia when you have anemia.
You have normal gas exchange in a patient with anemia so the PO2 should be normal. The oxygen saturation should be normal, but the hemoglobin is decreased. Because of the tissue hypoxia, they have exercise intolerance. o Carbon monoxide and methemoglobinemia
Carbon Monoxide • Scenario
o A heater in the winter time. You’re in a closed space in a room heater.
o These heaters often have combustible material in them and you can get carbon monoxide from that.
o
Other situations are automobile exhaust and house fires. In a house fire two things produce tissue hypoxia: carbon monoxide poisoning and cyanide poisoning (upholsteries made of polyurethane products).• It’s very diffusible and has a high affinity for hemoglobin. The problem is going to be a decrease in oxygen saturation.
• Hemoglobin is normal, and so is the PO2 (oxygen in plasma) is normal. The problem is when it diffuses into the RBC, carbon monoxide is in its place.
• Treatment is 100% oxygen.
•
When you have a decrease in oxygen saturation, you have clinical evidence of cyanosis. However, in carbon monoxide poisoning you don’t see this b/c you have a cherry red pigment masks it.• The most common and first symptom of carbon monoxide poisoning is headache. Methemoglobin
• It’s iron (+3). If iron is +3 on the heme group, then oxygen can’t bind to it. • Oxygen saturation is decreased again b/c iron is +3 instead of +2.
• Scenario
o Patient with history of methemoglobinemia. They draw blood and it’s chocolate colored.
o It’s chocolate colored b/c there’s no oxygen on the heme groups.
• PO2 is normal and hemoglobin concentration is normal. The oxygen saturation is what’s decreased.
• RBCs have a methemoglobin reductase (change +3 to +2). • Scenario
o
A person comes out of the rocky mountains and he was cyanotic. They gave him oxygen and he was still cyanotic.o He was probably drinking water up there (the water up in the mountains may have nitrites and nitrates; oxidizing agents). Hemoglobin is oxidized and the iron becomes +3.
o Oxygen wouldn’t correct the cyanosis b/c.
• Treatment is intravenous methylene blue. An ancillary, but not the primary treatment is Vitamin C (it’s a reducing agent).
• Scenario
o
Dapsone (used in treating leprosy) is a sulfa drug. Sulfa and nitro drugs produce methemoglobin and have the potential for producing hemolytic anemia in G6PD deficiency.o Hemolysis in G6PD deficiency indicates oxidizing agents causing an increase in peroxide (destroys the RBC). Drugs that can produce this are nitro and sulfa drugs; they also produce methemoglobin.
o Drug candidates include dapsone, primaquine, trimethoprim-sulfamethoxazole, nitro…
o These drugs can cause both hemolytic anemia and methemoglobinemia b/c they’re oxidizing agents.
• Methemoglobinemia is common in HIV b/c they’re on trimethoprim-sulfamethoxazole for treatment of pneumocystis carinii.
o Shift of curves
Right-shifts have decreased affinity for oxygen. It will release oxygen to tissues. • 2,3-BPG, fever, acidosis (low pH), and high altitude shift it this way.•
In high altitude you have respiratory alkalosis and you have to hyperventilate. The right shift comes from the synthesis of 2,3-BPG. Left-shifts
• Carbon monoxide, methemoglobin, HbF, decrease in 2,3-BPG, and alkalosis. • This is bad b/c it produces tissue hypoxia.
• Carbon monoxide decreases oxygen saturation and also causes a left-shift on oxygen dissociation.
- Problems related to the oxidative pathway
o Cytochrome oxidase is the last enzyme before it transfers the electron to oxygen (acts as an electron acceptor).
o 3C’s: cyanide, and carbon monoxide inhibit cytochrome oxidase
o Carbon monoxide now has three ways to produce hypoxia: it increases O2 saturation (can’t carry a lot of oxygen), left-shifts curve, and inhibits cytochrome oxidase.
- Uncoupling
o Normal “Coupling”
The mitochondria and the inner mitochondrial membrane have the ability to synthesize ATP. The inner mitochondrial membrane is permeable to protons.
Protons should only go through ATP synthase; protons can’t randomly go into the mitochondrial matrix (this is what uncoupling agents do).o Examples of uncoupling agents are: dinitrophenol (a chemical used for preserving wood), alcohol, and salicylates.
o Pathogenesis
Protons end up going through the membrane and little ATP is retrieved from it.
The reactions that were generating the protons to begin with (reactions making NADH and FADH) are going to be revved up.
When you increase the rate of a chemical reaction, the temperature goes up, so you have a risk of hyperthermia (in salicylate toxicity, one of the complications is hyperthermia).• If you’re an alcoholic on a hot day, you have a good chance of developing a heat stroke (you already have uncoupling).
Decrease in ATP (in hypoxia) - Anaerobic glycolysis
o If you have a decrease in ATP, you have to go to anaerobic glycolysis.
o
The end product is lactic acid (pyruvate is converted into lactate b/c of an increase in NADH). o Anaerobic glycolysis is used when you have hypoxia b/c it can provide energy without involving themitochondria.
o Anaerobic glycolysis only provides 2 ATP/glucose; unfortunately you get a build up of lactic acid inside and outside the cell.
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A buildup of acid (lactic acid) in a cell produces coagulation necrosis.o An increase in acid in a cell will denature proteins and enzymes (can’t even autodigest itself). This is called coagulation necrosis. This can occur when you have tissue hypoxia w/in a cell.
o
From a gross point of view, coagulation necrosis is termed infarction. - ATP pump dysfunctiono All ATPase pumps do not function due to the decrease in ATP.
Sidenote: Digitalis• Digitalis can block an ATPase pump to allow sodium to go into the cardiac muscle to open up calcium channels so you can get an increase in force of contraction.
o Since there’s no ATP, sodium can get into the cell and bring water with it (you get cellular swelling); due to the dysfunction of the sodium potassium pump. Swelling is reversible (get oxygen again and you can pump it out).
- Calcium influx
o There’s a calcium ATPase pump that pumps calcium out of the cell. If ATP is decreased, calcium can then enter the cell.
o When calcium is in the cell, it activates numerous enzymes (phospholipases in the membrane – causes damage to the cell membrane; enzymes in the nucleus – you get nuclear pyknosis and nuclear chromatin disappears).
o
Sidenote: Hypercalcemia produces pancreatitis (the enzymes in the pancreas are activated). - When the cell membrane is destroyed, you have irreversible damage.- Cell enzymes can be released:
o CK and CK-MB (in myocardial infarction) o Transaminases (GOT, AST, ALT)
o Amylase (pancreatitis) Free Radicals
- A free radical is a compound with an unpaired electron in its outer orbit. This makes it very unstable and it can damage things.
- Brownish pigment
o
Lipofuscin is commonly seen in older people. It requires a history.o Could be hemosiderin, hemochromatosis, and hemosiderosis. Could also be billirubin.
o When you have free radical damage, one of the end products is lipofuscin. Certain things in the cell aren’t digestible; this includes lipids (lipofuscin is lipids that you can’t break down all the way). - Oxygen can produce free radicals
o
Excess oxygen (> 50%) for any period of time can cause them to get superoxide free radicals. o Reperfusion injury
This is what’s behind reperfusion injury. When you give a tissue plasminogen activator to someone who has a coronary thrombus to try and dissolve it, most of the time, oxygenated blood goes into the damaged heart muscle and damages it even further.
o Pulmonary damage
Kids with respiratory distress can end up with oxygen related free radical injury.
•
They can go blind (free radicals and free oxygen can destroy the retina: calledretinopathy of prematurity).
Free radicals can also produce damage to the lungs (called bronchopulmonary dysplasia) and you get fibrosis in your lungs.- Water can produce free radicals
o
Water in our tissues can be converted into hydroxyl free radicals. This is what ionizing radiation does (not UVB light); it occurs in cancer for example.o These OH- radicals can produce mutations in tissues.
The most common complication of radiation therapy is cancer: the most common cancer in radiation is leukemia.- Iron can produce free radicals
o Iron also can make free radicals (fentin reaction). This is why iron overload disease is so dangerous. o Wherever tissue iron is located, you’re going to get hydroxyl free radicals and they’ll damage that tissue
Cirrhosis in the liver
Restrictive cardiomyopathy in the heart Dysfunction in the pancreas
Cell Injury 2
Free Radicals (cont.)
- Tylenol (Acetominophen)
o
Tylenol is the number one cause of fulminant hepatitis due to a drug b/c of free radicals. o Scenario Where in the liver does acetominophen toxicity manifest itself? Around the central vein.
o Treatment = N-acetylcysteine
Sidenote: Superoxide free radicals are neutralized by superoxide dismutase (SOD).
o
Glutathione (comes from the hexose [or pentose] phosphate shunt; NADPH is also generated from this shunt). NADPH is the main substance used for all anabolic biochemical reactions (synthesizing steroids, cholesterol, etc.). Mechanism (glutathione)
• Glutathione’s main function is to neutralize free radicals (any free radical derived from peroxide).
•
Glutathione gets used up in the acetaminophen free radicals. When you give it acetylcysteine (aka mucames), you replenish glutathione (it’s made out ofN-acetylcysteine). You basically give the substrate to make more glutathione to keep up with neutralizing the acetaminophen free radicals.
• Methotrexate-Leucovorin analogy
o It’s like methotrexate and leucovorin rescue so you don’t get folate deficiency. The leucovorin makes a substrate that you can still make your DNA even with a block of dihydrofolate reductase.
- Carbon tetrachloride
o
Is seen in the dry cleaning industry.o
It can also be converted into a free radical in the liver. It forms CCl3 and you get fulminant liver failure.- Acetominophen and Aspirin effect on the kidneys
o This combination if prolonged is destructive to the kidneys.
o
Free radicals from acetaminophen annihilate the renal medulla (it only gets 10% of the blood supply). Aspirin inhibits the vasodilator of the kidneys (PGE2) in the afferent arteriole; this leavesangiotensin II (a vasoconstrictor in charge of the renal blood flow). Your ability to concentrate urine in the loop is decreased (analgesic nephropathy).
Apoptosis
- It’s programmed cell death.
- We have apoptosis genes involved in cell death. - It has normal functions.
o Embryology
Organs initially used to be solid. They got to have lumens because of apoptosis. Y chromosome
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Mullerian inhibitory factor in the germinal ridges of the testicles.• All the mullerian structures (uterus, cervix, and upper 1/3 of vagina) are gone b/c of apoptosis working through mullerian inhibitory factor (it signaled apopotsis through caspases).
X chromosome
• The absence of a Y chromosome causes germinal ridge to go the ovarian route. They have a factor that knocks off Wolfian duct structures.
Thymus
• It’s atrophied in older people and active in children.
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If it was absent, they’d have DiGeorge’s syndrome and tetany with it as well. • It involuted b/c of apoptosis.o Mechanism
• A signal (hormone or a chemical) activates the caspases (enzymes).
•
Caspases destroy everything (membrane damage and DNA fragmentation) and results in membrane-bound cell cleavage products called apoptotic bodies, which are easily phagocytosed by surrounding macrophages with no tissue necrosis.•
It ends up destroying the cell w/o any inflammatory infiltrate. What is left over that can’t be digested is lipofuscin.o It’s also a major mechanism in killing cancer cells and atrophy of cell mass or tissue mass. It is also involved in hepatitis.
o Hepatitis:
A virally infected cell is destroyed by cytotoxic T-cells by apoptosis. o Apoptosis could be related to ischemia as well.
Necrosis
- When we damage tissue and it dies. - Coagulation Necrosis
o When we have ischemia or tissue hypoxia and we have no oxygen, lactic acid builds up in a cell and it denatures everything in it and we end up with coagulation necrosis.
o
The gross manifestation is called infarction. o Infarctions The consistency of the tissue determines whether the tissue will be pale or hemorrhagic in appearance after infarction (via coagulation necrosis).
Hemorrhagic (Red)
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Bowel, which has a loose texture consistency.•
A testicle, if it underwent torsion.•
The lungs will also be red, b/c it has a loose consistency. When the blood vessels rupture, the RBCs can easily trickle out into the damaged tissue and produce a hemorrhagic appearance.• Bowel infarction
o The second most common cause of bowel infarction is getting a piece of small bowel trapped in an indirect inguinal hernia sac.
o
The most common causeis adhesions from previous surgery.•
In lungs, you would have a wedge-shape infarction near the pleural surface. You would have an effusion (it’s an exudate). It would be hemorrhagic with neutrophils in it. If you inflame the pleura, you have pleuritic chest pain (a knife-like pain oninspiration). Pale
•
If it’s good consistency and when the tissue dies including the blood vessels, then when the blood vessels die and the RBCs are released, they can’t diffuse out into the tissue (b/c the tissue has good consistency). It will grossly look pale.•
Organs expected to be pale are heart, kidney, spleen, and liver (rarest to infarct b/c of a double blood supply).•
Most are due to embolization.o
Most emboli in the systemic circulation arise from the left side of the heart. o A spleen could produce a pale infarct from an embolus from a vegetation. Vegetations
• Rheumatic fever wouldn’t produce an embolism, the vegetations in acute rheumatic fever rarely embolize (they’re too small) • Infective endocarditis can produce embolisms large enough to
produce an infarction.
o
Mitral stenosis can predispose to clots and thrombi in the left atrium and then get atrial fibrillation (the worst arrhythmia). The arrhythmia most associated with embolisation in the systemic circulation is atrial fibrillation b/c it produces stasis in the atria, clot formation, and when the atria vibrates, bits and pieces can come off and embolize.o Gangrene Dry
• You don’t have pus.
•
Dry gangrene of the foot is common in diabeticso
The problem is in the popliteal artery (it can have atherosclerosis in it and possibly even be thrombosed).o The most common cause of non-traumatic amputation in the U.S. is diabetes (b/c it enhances atherosclerosis).
o The popliteal artery has a small lumen and if it has atherosclerosis in it, it can pose a serious problem.
• It is related to coagulation necrosis related to ischemia (decrease in arterial blood flow). o Brain Infarction
It is the one exception to the rule that coagulation necrosis is the underlying type of necrosis in infarctions. Brain infarctions have liquefaction necrosis instead of coagulative necrosis.
The most common infarction occurs in the internal carotid; you listen with the stethoscope•
This is the place where a platelet thrombus develops over an atherosclerotic plaque, blocks it, and you end up with a stroke.•
It is also the place where bits and pieces of atherosclerotic plaque chip off and produce transient ischemic attacks (produces motor or sensory abnormalities that go away w/in 24 hours). The brain has little meshwork.
• The astrocyte is analogous to the fibroblast in the brain b/c of its protoplasmic processes. • When we infarct the brain, it doesn’t have any structure and liquefies.
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You don’t see vague outlines of what used to be there (coagulation necrosis); it forms a cystic space (liquefactive necrosis).o Liquefactive nerosis It liquefies tissue.
Neutrophils play a dominant role. Neutrophils main purpose is to phagocytose and destroy things with its enzymes (liquefy them). Liquefactive necrosis in most cases refers to an infection when neutrophils are involved (usually an acute inflammation) producing an abscess or some type of inflammatory condition.
The one exception to the rule of is an infarction of the brain (not an inflammatory condition). Staph. aureus vs. Streptococcus
•
In abscesses with Staph. aureus, you would see gram positive cocci in clusters (b/c of coagulase). Coagulase is why you see abscesses; it converts fibrinogen into fibrin, so itlocalizes the infection (neutrophils can’t get out b/c of the fibrin).•
Streptococcus releases hyaluronidase; this breaks down the glycosaminoglycans in tissues (this is why the infection spreads through tissues; this is called cellulitis). o Granulomatous necrosis (aka Casseous necrosis) Tuberculosis • Scenario
o Patient presents with fever, night sweats, and weight loss. Casseous means you have a cheesy consistency.
It means you either have a mycobacterium infection (any, including atypical) or systemic fungal infection.
The lipid in the cell wall is what gives the granuloma its cheesy appearance.
Sarcoidosis has granulomas, but it’s not casseous (b/c it’s not related to mycobacteria or systemic fungi).
In Crohn’s you also get granulomas, but they’re not casseous (not related to mycobacteria or systemic fungi).
o Fat necrosis
Pancreas (enzymatic fat necrosis) • Scenario
o Person has epigastric distress with pain radiating to the back. What is it? o Pancreatitis
• The pancreas is retroperitoneal and when it gets inflamed, the pain is referred to the back. • It has an enzymatic fat necrosis. It’s fat necrosis due to enzymes.
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The enzymes are breaking down fat into fatty acids. The fatty acids then combine with calcium salts to produce chalky areas of enzymatic fat necrosis (calledsuponification; forming a soap-like salt). These can be seen on x-ray b/c they have calcium in them.
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It tends to occur in a patient who is an alcoholic.• Wherever you see blue on a histologic section (ex. a coronary vessel and you know it’s atherosclerotic) it’s always calcium.
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In hemorrhagic pancreatitis, amylase is elevated as well as lipase (lipase is more specific b/c it’s only found in the pancrease; amylase is found in the parotids, small bowel, and fallopian tubes). Breasts (traumatic fat necrosis) • Scenario
o A woman with pendulous breasts damages them from running without support and she gets fat necrosis.
o This is not enzymatic, but traumatic fat necrosis.
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It can calcify and look like cancer on a mammogram. The difference between this and calcification in a cancer is it’s painful vs. painless (the cancer).o Fibrinoid necrosis
It looks like fibrin, but it isn’t.
It’s a necrosis of immunologic disease .• Some examples are palpable purpura (small vessel vasculitis; immune complex type III), henoch-schonlein purpura (which has palpable purpura).
• Rheumatic fever also has type III hypersensitivity. If it had vegetations on the mitral valve, they would be found to be sterile and to be composed of fibrin-like material in them.
It’s the necrosis of immunologic diseases; immune complexes can be found in them. Pathogenesis of immune complexes• Damage is from type III hypersensitivity.
• It’s an antigen-antibody complex that travels in the circulation. It deposits in places available to the circulation (glomerulus, small vessel, etc.).
•
It works by activating the alternative complement system which produces C5a. C5a is chemotactic to neutrophils.•
Neutrophils are the one that do the damage in type III hypersensitivity. o Livero Sidenote: Triad
Triad = portal vein, hepatic artery, and bile duct
The hepatic vein, hepatic artery, and portal vein will dump their blood into sinusoids.
The liver is an example of a sinusoid organ; other examples of sinusoid organs are bone marrow and spleen.•
Gaps are characteristic of sinusoids; gaps are between the endothelial cells so that things like RBCs, inflammatory cells, etc. can fit through them (this is unlike the glomerulus basememnt membrane that is fenestrated). Congestion
•
If you have right heart failure and blood builds up behind the failed heart, the liver is going to get congested with blood and you get the “nut-meg” liver (congestive hepatomegaly).• If you block the portal vein, nothing happens to the liver because it’s before the liver.
•
If you block the hepatic vein (Budd-Chiari syndrome; involves blockage bythrombosis), your liver gets congested.
The central vein is the part of the liver normally susceptible to injury. It’s susceptible to injury because it is furthest away from the sinusoids (zone 3).•
Zone 2 is where “midzone necrosis” occurs due to yellow fever (transmitted by the Aedes aegyptii mosquito).• Scenario
o In acetaminophen toxicity, which part of the liver is most affected? o The part around the central vein b/c it gets the least amount of oxygen.
Fatty change
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The most common cause is alcohol. - Alcohol Metabolismo
In alcohol metabolism, NADH and acetyl coA is all over the place.o Acetyl coA can be converted into acetate (a fatty acid) in the cytosol and also to ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone).
o NADH causes pyruvate to form lactate in anaerobic glycolysis.
Lactic acidosis is the metabolic acidosis always seen in alcoholics because the increase in NADH drives it in that direction.o Alcoholics have fasting hypoglycemia
If pyruvate is forced to become lactate, an alcoholic in a fasting state is going to have trouble making glucose by gluconeogenesis (you need pyruvate to start it off). In a fasting situation, liver glycogen stores are depleted and maintenance of blood glucose depends entirely on gluconeogenesis.
o
In alcoholics, of the two ketoacids (acetoacetic and beta-hydroxybutyrate) beta-hydroxybutyrate is what you will see because it’s an NADH driven reaction.-
Two types of metabolic acidosiso
You see lactic acidosis (b/c you’re driving pyruvate into lactate).o
You get ketoacidosis because of the excess of acetyl coA (shunted to produce ketone bodies . The main ketoacid is beta-hydroxybutyrate (b/c of the excess of NADH).- Increased VLDL and fatty liver
o
In glycolysis, around reaction four, you get dihydroxyacetone phosphate gets driven by NADH (b/c of the increase of NADH in alcoholics) to form glycerol-3-phosphate. Glycerol-3-phosphate is also the carbohydrate backbone for making triglyceride (just have to add 3 fatty acids to it).
o
The abundance of glycerol and free fatty acids (reduction in the citric acid cycle leads to shunting of acetyl coA and to increased fatty acid synthesis) results in an increased production of triacyl-glycerol, with increased export from the liver as very-low-density-lipoprotein (VLDL), and a fatty liver. o The fatty liver comes from impaired protein synthesis preventing assembly and secretion of VLDL,causing triacylglycerols to accumulate in the liver). - How diet affects synthesis of VLDL
o Restricting fat wouldn’t decrease the synthesis of VLDL.
o
Restricting carbohydrates would reduce the synthesis of VLDL (it’s a glucose intermediate that it’s madefrom – glycerol-3-phosphate [a product of glycolysis]).Inflammation 1
Liver and Fatty Change - Kwashiorkor
o Mechanism
When you make VLDL, and you want to get it out of the liver, you need a protein (apoproteins)
o
In Kwashiorkor, the problem is a decrease in protein intake. They have an adequate amount of calories,but it’s all carbs; they can’t get the VLDL out b/c they have no apolipoprotein to cover it and put it out into the blood stream and solubilize it in water.
o The reason for the protuberant abdomen is because:
They have decreased protein, which decreases oncotic pressure and you get ascites.
The main reason is they have huge livers b/c of fatty change (the mechanism is different than an alcoholic [they have increased in synthesis of VLDL]). In Kwashiorkor, it’s due to lack of protein to put around the VLDL to get out of the liver so it accumulates; this is the reason for the fatty change.Ferritin – is a soluble form of circulating iron; it’s a good marker for the amount of iron you have in your bone marrow. It’s also the test of choice for diagnosing any iron-related problem like iron deficiency, anemia of chronic disease, or iron overload diseases (hemochromatosis or hemosiderosis).
Types of Calcification - Dystrophic
o Abnormal calcification
o
It means you’ve had damaged tissue and it gets calficified. o Enzymatic fat necrosis is an example.o
Serum calcium is totally normal except that you have damaged tissue and it may be calcified.o
It can happen in an atheromatous plaque. This makes it hard to dissolve the plaques. The only way to get rid of dystrophically calficied blood vessels is to be on a diet called the Ornish diet (pure vegan diet).
o
It’s the most common cause of aortic stenosis.o It’s the most common cause of a certain hemolytic anemia. - Metastatic
o
Sometimes if you have hypercalcemia or hyperphosphatemia, calcium could be made to deposit in normal tissue that hasn’t been damaged.o If someone had hypercalcemia, the most common cause would be primary hyperparathyroidism. o If it was in a hospital, the most common cause would be malignancy-induced calcemia.
o Because you have hypercalcemia, you can put calcium in normal tissue (metastatic calcification). o When you deposit calcium in bone, it’s the phosphorous part of the solubility product that drives
calcium into bone.
If you have high phosphate levels, it’s dangerous b/c it’ll take calcium and drive it into normal tissue.
This is why when they have renal failure and they have high phosphate levels, they have to dialyze the phosphate because it’s going to be driving calcium into normal tissue like the heart, renal tubules, and the basement membrane (called nephrocalcinosis).Aortic Stenosis
- The most common cause is a congenital bicuspid valve (it should be tricuspid). Spherocytosis
- If you can’t see a central area of pallor, then it’s a spherocyte. Cell Membrane Defects
- Absence of spectrin
o
It causes the RBC not to be able to form a biconcave disc. If spectrin is defective, then it forms a sphere. - Ubuquitino It’s a stress protein; it helps to destroy misfolded proteins.
o In some of the intermediate filaments (like keratin, desmin, vimentin,…) are part of the superstructure of our cells. They keep our cells from collapsing on themselves and being a big protoplasmic mass. o When intermediate filaments get damaged, then ubiquitin tags them for destruction.
o Examples of ubiquinated products
Mallory bodies are found in liver and are an example of ubiquinated keratin; they’re used to say that a patient has alcoholic hepatitis.
Neurofibrillary tangles are also an example of an ubiquinated neurofilament.•
Neurofibrillary tangles (in a silver stain) are not just found in Alzheimer’s disease, but in Huntington’s chorea and Jakob-Creutzfeldt disease.•
Remember the Tau protein is associated with neurofibrillary tangles.
Lewy bodies are an example of ubiquination.•
Seen in Parkinson’s Disease• The neurotransmitter deficient is dopamine. • It’s also a damaged neurofilament.
- Cell Cycle
o Three types of cells Labile cells
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A cell whose division is via a stem cell.•
Three tissues that have stem cell are bone marrow, basement membrane of skin, and the base of the crypts in the intestine.•
These cells are in the cell cycle the most.• These cells are most likely affected by pharmacology that affects the cell cycle. • There are different drugs that affect the cell cycle and cause bone marrow suppression,
diarrhea, excess mucous, and rashes on the skin. These occur because these tissues have labile cells.
Stable Cells
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Are in the Go (resting) phase.•
Most are in parenchymal organs such as the liver, spleen, kidney, andonly smooth muscle .•
They’ll undergo division, but most of the time they’re resting in the Go phase;something (a hormone for example) has to stimulate them to get into the cell cycle and divide.
o Example is a estrogen and a woman.
If a woman is in the proliferative phase of her menstrual cycle, then her endometrial cells would have been initially in the Go phase; when estrogen came up, it stimulated the Go cells to go into the cell cycle. • Most of the time, the stimulus is a growth factor or a hormone.
Permanent Cells
• Can’t get into the cell cycle.
• They’ve been permanently differentiated.
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Muscles other than smooth muscle (striated and cardiac) fit into this category.•
Neurons are also permanent cells. Hypertrophy and Hyperplasia
• The only muscle that is not a permanent tissue is smooth muscle.
• Hypertrophy involves an increase in size, whereas hyperplasia has an increase in number. • A permanent cell could not undergo hyperplasia, but could undergo hypertrophy.
Smooth muscle can undergo both hyperplasia and hypertrophy. G1 phase
•
The most variable phase of a cell cycle is the G1 phase.o In women, the most variable phase of the menstrual cycle is the proliferative. o It’s analogous to the G1 phase of the cell cycle; it can be shortened or lengthened
(none of the other phases like S, G2, or M can vary in the cell).
o Most cancer cells have a longer cell cycle (takes them longer to get through a cell cycle). What’s responsible for this is a longer G1 phase. The inverse is true; if you had a cancer cell that had a shorter cell cycle than normal it’s because it had a shorter G1 phase.
Kinase – always means phosphorylation. Phosphorylation usually involves sending a message to something. Usually when you phosphorylate something, you activate it; when you
dephosphorylate, you deactivate.
• Glucagon is more likely to activate protein kinase whereas insulin would dephosphorylate and deactivate it.
Cyclin-D dependent kinase • Cyclin D activates it. • G1 makes Cyclin D
• Once Cyclin D is made in the G1 phase, then it activates the Cyclin-D dependent kinase. • The key area in the cell cycle to control is going from G1 to S phase.
o If you had a mutation and you went into the S phase and you duplicated it, then you have the potential for cancer.
o There are two suppressor genes that control this:
Rb suppressor gene (on chromosome 13); it makes a protein called Rb protein. It prevents the cell from going from the G1 to the S phase .•
The active cyclin-D dependent kinase phosphorylates the Rb protein (andinactivates it); when it phosphorylates it, it can go from the G1 phase into the S phase.
•
This enzyme is checked by p53 suppressor gene (on chromosome 17).o
It makes a protein product that inhibits the cyclin-D dependent kinase ; this would prevent phosphorylation of the Rb protein and it’s going to remain in the G1 phase.o The p53 suppressor gene is the most important gene for cancer. o Sidenote: Human Papilloma Virus
The human papilloma virus inactivates the Rb suppressor gene and the p53 suppressor gene; it makes two gene products E6 and E7. E6 knocks off the p53 and E7 knocks off the Rb suppressor gene.•
If an Rb suppressor gene is knocked off by a point mutation, nothing is there to stopthe cell from going into the S phase.
o
You run the risk of cancer: retinoblastoma (what Rb stands for), osteogenic sarcoma (Codman’s triangle, a sunburst appearance on X-ray). If you’re a woman and you had a breast cancer, Rb suppressor gene can be involved in that too.• By knocking off the p53 suppressor gene, the kinase would always be active and it would always be phosphorylating the Rb protein and you’d always be going into the S phase. • If you knock off either one of the genes, then the G1 phase goes into the S phase. • The p53 is actually called the “guardian of the cell”.
o It inhibits the cell from going into the S phase and gives the cell time to detect if there’s any abnormalities in DNA (splicing defects, codon,…).
o There are DNA enzymes that can splice out the abnormality and the cell is then ready to go into the S phase.
o If the cell has been damaged too much in its DNA, then it is removed by apoptosis.
S phase
• The S phase means the synthesis phase.
•
This is where everything is doubled (includes DNA, chromosomes [you’re 4n at this point; you were 2n in G1]). G2 phase
•
G2 phase is where you make tubulin (the protein from which you make the microtubules for the mitotic spindle); it’s blocked by etoposide and bleomycin. M phase•
M for mitosis; it’s where the cell divides into 2n cells.• The cell can either go into a Go resting phase or continue going on in the cycle and divide again or it can be permanently differentiated.
Drugs and where they work in the cell cycle
• Vinca alkaloids work at the mitotic spindle – M phase. • Paclitaxel affects the M phase.
• Colchicine – M phase. • Etoposide – G2 or S. • Bleomycin – G2 • Methotrexate – S phase. • Grieseofulvin – M phase. • Scenario
o
A patient has rheumatoid arthritis has macrocytic anemia. The drug responsible does what and is located where?o
Methotrexate – it blocks dihydrofolate reductase and it works at the S phase. • Scenarioo You have an HIV positive person that has dyspnea, tachypnea, and something out of the lung. He’s put on a drug and ends up with cyanosis. Where would the drug have worked?
o Dapsone (has nothing to do with the cell cycle). • Scenario
o
This drug used to be used in the treatment of acute gouty arthritis, but because of side effects is no longer used. Where would it work?o
M phase; it’scolchicine. • Scenarioo
This drug is a chemotherapy agent made from a yew tree. What drug is it and where?o
Paclitaxel in the M phase.•
Vinca alkaloids are made from periwinkle plants Growth Alterations- Atrophy
o The diagnosis is a decrease in tissue mass; the cell actually decreases in size. It has enough organelles to survive; it has less mitochondria than normal. It’s waiting for whatever it needs to stimulate it so it can come back.
o Hydronephrosis
The thinning of the cortex of the medulla is due to compression atrophy.
The most common cause of hydronephrosis is a stone in the ureter. Scenario
• What’s the growth alteration?
• Atrophy; because of the increased pressure on the cortex and medulla, this will produce ischemia. Blood flow will decrease and it will produce atrophy of the renal tubules. o Brain atrophy
Could be because of atherosclerosis (the most common cause) or because you have knocked off the neurons (in layers 3, 5, and 6).• An example is Alzheimer’s disease (you have degeneration of neurons).
o The cerebral cortex has its neurons in layers 3, 5, and 6; if they get destroyed, it would reduce the overall mass of the brain.
• Atherosclerosis could be a cause or Alzheimer’s disease (related to the beta amyloid protein – toxic to neurons).
o Muscle atrophy
Could be due to Lou Gehrig’s disease (amytrophic lateral sclerosis). If you knock off the nerve to the muscle, you would get atrophy. A leg in a cast could lead to muscle atrophy. Endocrine could also be related.
•
In hypopituitarism, the adrenal gland would be atrophied (in particularly the fasiculata and reticularis; not the zona glomerulosa).o
ACTH has nothing to do with stimulating aldosterone release (fasiculata is where you make cortisol and glucocorticoids; reticularis is where you make sex hormones [17-keto steroids]).• If someone’s taking thyroid hormone, the thyroid atrophies b/c the thyroid hormone decreases the thyroid stimulating hormone (TSH).
o Nothing is stimulating the gland and therefore it undergoes atrophy. o Pancreas
Scenario
• Biopsy of a pancreas from a child with cystic fibrosis. What’s the growth alteration present?
• Atrophy; The biopsy shows tubules filled with a reddish stuff like concrete. Cystic Fibrosis
• In cystic fibrosis the transmembrane regulator on chromosome 7 is defective, then you have problems with secretions; they become thicker. It blocks the ducts and then the glands which are making the fluids in the pancreas (exocrine part).
•
If you block the lumen, there’s a backpressure on them. Just like there was atrophy of the renal cortex and medulla from a backpressure related to urine, the same thing happens if you block the lumen of the duct; you get atrophy of the glands. This is why you get malabsorption in all children with cystic fibrosis.o Kidney
Renal vasculature hypertension causes renal atrophy.
• The renin level is high in the atrophied kidney. The other kidney would have a hypertrophy alteration.
Scenario
• The growth alteration noted in this patient (renal atrophy) is similar to a growth alteration in…
o Cardiac hypertrophy
In hypertrophy of a cardiac muscle, the muscle is permanent.
The supposed block is before the G2 phase (after the S phase and everything is doubled); the number of chromosomes would be 4n.• 1n is something like a sperm, 2n is a normal diploid cell, 3n means you probably have cancer or a trisomy disease, and 4n is this situation.
Hypertrophy is an increase in size of a cell, not number. - Hyperplasia
o It has increased mitosis.
o In the proliferative phase, you have increased mitosis. You end up getting endometrial mucosa with increased mitosis. The number of endometrial glands is increased by increasing cell division.
o
If you had unopposed estrogen, you could end up with cancer because if you didn’t have progesterone to undo what estrogen did, you would get cancer (you would go from hyperplasia to atypical hyperplasia to endometrial cancer).o
In hyperplasia left unchecked, you run the risk for cancer with one exception; the prostate. Prostate hyperplasia does not predispose to prostate cancer; you will have an increase in micturation frequency.o
Gravid uterus – a woman’s uterus after delivery. This is an example of 50% hypertrophy of the smooth muscle cells in the wall of the uterus and 50% related to hyperplasia. Normally, you should have 3x as many white blood cells as red blood cells.
A bone marrow aspirate from a bone marrow with RBC hyperplasia would not be expected in iron deficiency (you lack iron to make RBCs), nor thalassemia (you have a defect in making globin chains).•
You would expect it in someone with chronic obstructive pulmonary disease (COPD) because they have hypoxemia releasing erythropoietin (it’s made in the endothelial cell of the peritubular capillary).•
A bone marrow showing RBC hyperplasia is an erythropoietin stimulated marrow; erythropoietin is made in the endothelial cell of the peritubular capillary.o Psoriasis
It’s an example of hyperplasia.
It’s an unregulated proliferation of squamous cells in the skin; you get a raised red plaque with silvery scales on it (corresponding to the excess in stratum cornea; hyperplasia).
Methotrexate can work for psoriasis b/c it’s cell cycle specific to the S phase and prevents the basal cells from proliferating.o Prostate and Bladder
Prostate only demonstrates hyperplasia of glands and smooth muscle, not hypertrophy. It’s due to hormones; all hormone-stimulated glands undergo hyperplasia, not hypertrophy.
Since you have a decreased caliber of the urethra (due to prostate hyperplasia), the bladder has to work more and its muscle hypertrophies.• The bladder wall thickens b/c of hypertrophy of smooth muscle cells related to an increase in afterload.
- Metaplasia (Barrett’s)
o
The replacement of one adult cell type by another.o
In the lower esophagus, Barrett’s esophagus can present with mucous secreting cells and goblet cells (this is not what should be present there; it should be squamous).o
Barrett’s esophagus is a precursor to adenocarcinoma ; in adenocarcinoma, the distal esophagus has surpassed squamous cell carcinoma of the mid-esophagus; it’s the most common esophageal cancer in the U.S.o GERD is the number one precursor for esophageal cancer (instead of squamous, it’s adenocarcinoma).
Inflammation 2
Metaplasia and Hyperplasia in the lungs
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The main stem bronchus is lined by ciliated columnar-pseudostratified columnar. If you were smoking, you would undergo squamous metaplasia.-
If you had increased goblet cells in the mainstem bronchus (seen in all smokers).o
This is an example of hyperplasia b/c you normally have goblet cells in the mainstem bronchus.-
Smokers also have goblet cells in the terminal bronchioles; this is an example of metaplasia.Metaplasia in the stomach
-
Goblet cells in the stomach would be abnormal; they should be present in the intestine, not in the stomach (called glandular metaplasia).o
It is a precursor for adenocarcinoma of the stomach.o
The most common cause of adenocarcinoma of the stomach is H. pylori . Because H. pylori produces damage to the pylorus and antral mucosa, it produces a chronic atrophic gastritis with intestinal glandular metaplasia and it’s the precursor lesion for adenocarcinoma. Metaplasia can predispose cancer.
- Lungs
o
In the lungs, ciliated columnar epithelium becomes squamous metaplasia. You then get squamous dysplasia. From dysplasia, you can get into squamous carcinoma.- Esophagus
o
In the distal esophagus it went from squamous to a glandular epithelium (b/c squamous epithelium can’t handle acid; it needs mucous secreting epithelium as a defense against the acid injury).o
The glandular metaplasia can go on into an atypical metaplasia and go on to adenocarcinoma of the distal esophagus.- Parasites
o In parasitology, there’s only two parasites that produce cancer.
o
Clonorchis sinensis (Asian liver fluke) and it produces cholangial carcinoma.o
Schistosoma haematobium causes the transitional epithelium to undergo squamous metaplasia. From squamous metaplasia, squamous dysplasia, and from squamous dysplasia, squamous cancer.Hyperplasia predisposing Cancer
-
Hyperplasia left unchecked could potentially produce cancer; for example endometrial hyperplasia is the most common precursor lesion for endometrial adenocarcinoma (it’s usually due to unopposed estrogen).Dysplasia
-
Is an atypical hyperplasia. Dysplasia is a precursor for cancer; either glandular or squamous dysplasia. - The precursor for squamous carcinoma of the skin is Actinic keratosis.o Scenario: Actinic keratosis
A farmer had a lesion on the back of his neck (A SUN EXPOSED AREA). He scraped it off and then three months later it grew back. What is it?
Actinic keratosis (aka Solar keratosis). It’s a precursor for squamous cell carcinoma. It’s due to UVB damaged skin.- Basal cells carcinomas are more common than squamous cell carcinoma. Inflammation
- Acute Inflammation o Redness (Rubor)
Histamine is the most important vasodilator in acute inflammation. It vasodilates arterioles. It’s responsible for the redness of acute inflammation.o Hot (Calor)
Due to histamine. When you vasodilate, it gives off heat; this is why when you go in shock (endotoxic shock or septic shock), you get warm skin opposed to cold skin (due to vasodilating the arterioles).o Tumor
It becomes a raised structure. It’s due to increased vasopermeability by histamine of the venules. Venules are thin and are endothelial cell basement membrane. Histamine contracts the endothelial cells and leaves the basement membrane bare; you get increased vessel permeability producing an exudate and swelling of tissue.o Dolor (pain)
This is due to bradykinin (part of the kininogen system; between Hageman’s factor XII and XI). • When you activate the intrinsic pathway, you automatically activate the kinonogensystem.
• When you activate factor XII (Hageman’s factor) it activates factor XI and the kininogen system (the end product being bradykinin).
• Bradykinin is degraded by angiotensin converting enzyme.
o You get angioedema as a complication of an angiotensin converting enzyme inhibitor.
o
By using an angiotensin converting enzyme inhibitor, you also inhibit the metabolism of bradykinin which increases vessel permeability producing the angioedema (swelling of tissue).• Bradykinin can also produce cough.
Bradykinin and PGE2are the two things producing pain. o Pathogenesis of acute inflammation Pavementing (or Margination)
•
Neutrophils in the small vessels will begin getting sticky b/c of adhesion molecules synthesis.• The endothelial cells will also begin synthesizing adhesion molecules. Eventually the neutrophils will stick to the endothelial cells (called pavementing or margination). Passing through the Basement Membrane
• The neutrophils will then go and look for bare basement membrane on the venules.
•
The neutrophils have type IV collagenase (b/c collagen type IV is what makes up thebasement membrane). o Sidenote: Cancer cells
To stick to endothelial cells, they have adhesion molecules (usually against laminin in the basement membrane).
Cancer cells also have type IV collagenase; this is how they get through and metastasize.
Chemotaxis
• When the neutrophils get out of the small vessels (usually the venules) they emigrate.
•
They have directed chemotaxis. Some of the chemotactic molecules are C5a and LTB4(they’re also involved in making adhesion molecules in neutrophils). Opsonization
• If we have an infection (i.e Staph. aureus), we know that the bacteria are being prepared before they get destroyed (opsonization).
•
Two opsonizers are IgG and C3b. • Sidenote: Bruton’s agammaglobulinemiao It’s a sex-linked recessive disease where you are missing all the immunoglobulins including IgG.
o The most common cause of death is infection; you can’t opsonize.
o The mechanism of the infection is they have no IgG to opsonize bacteria; therefore, you can’t phagocytose it.
- Chronic Inflammation
o
For chronic inflammation instead of neutrophils, you have either macrophages or monocyte (monocytes become macrophages). TPhagocytosis and killing bacteria
- The macrophages, monocytes, and the neutrophils would obviously have to have receptors for the opsonins (IgG and C3b).
- When you phagocytose the bacteria, the lysosomes will go down the microtubules and empty their enzymes into the bacteria.
-
Sidenote: I-cell Diseaseo
It’s characterized by an inability to phosphorylate the mannose residues of the lysosomal enzymes in the Golgi apparatus.o The lysosomes therefore lack lysosomal enzymes and are unable to degrade complex substrates, which accumulate in the lysosomes as inclusion bodies.
o The acid hydrolases lacking the recognition marker cannot be targeted to the lysosomes but are secreted extracellularly.
o Patients have psychomotor retardation and an early death. Oxygen-dependent Myeloperoxidase system
- NADPH oxidase oxidizes NADPH and in the process, reduces oxygen to superoxide anion.
o
NADPH oxidase isin the cell membrane of neutrophils and monocytes, butnot macrophages (they lose the system).o
NADPH, the cofactor, is mainly synthesized in the pentose phosphate shunt; the enzyme responsible for that particular part of the reaction is glucose-6-phosphate dehydrogenase (glucose-6-phosphate is converted to 6-phosphogluconate). You get NADPH and a neutralizing factor for free radicals (glutathione).o NADPH oxidase responds to activating stimuli by producing reactive oxygen intermediates (such as
superoxide) within the lysosome where the ingested substances are segregated, and the cell’s own organelles are protected.
o Superoxide
Superoxide has an unpaired electron in its outer orbit that gives off energy (called a respiratory burst) whichcan be measured by radiation detectors or nitroblue tetrazolium (NBT dye test). Nitroblue Tetrazolium (NBT dye test)• They get a test tube and they add in a colorless dye (NBT).
•
If neutrophils and monocytes are working okay, they will phagocytose it, they’ll have a respiratory burst and the free radical oxygen (superoxide) will cause a color change to occur and make it colored (bluish).• The neutrophils (or monocytes) are removed and smeared on a slide and looked at for color in the dye.
•
If there’s color, you know that the respiratory burst is working; if there isn’t any color in the dye, it means they don’t have a respiratory burst system. This is used to find out if you have chronic granulomatous disease from childhood.
The free radical oxygen (superoxide) is neutralized by superoxide dismutaseinto peroxide. - Peroxide itself could kill bugs, but myeloperoxidase is even better.o
The red granules (eosinophilic granules) you see in monocytes and neutrophils are in lysosomes.Myeloperoxidase is one of many enzymes in these granules and it catalyzes the reaction joining peroxide together with chloride to form bleach (which kills bugs); this is why myeloperoxidase is the most potent bactericidal mechanism.
- The myeloperoxidase system is oxygen dependent and found in neutrophils and monocytes; not macrophages. - Sidenote: Macrophages as a reservoir for AIDS
o
The macrophage in the central nervous system is a microglial cell; it serves as the reservoir cell for CNS AIDS. Outside the CNS, the reservoir is the dendritic cell (a macrophage) located in the lymph nodes. - Glucose-6-phosphate dehydrogenase deficiencyo
If you have glucose-6-phosphate dehydrogenase deficiency, infection is the most common thing that precipitates hemolysis.o
This is because you don’t have NADPH, which means you have no functioning oxygen-dependent myeloperoxidase system. You would be susceptible to infection which would set off the hemolysis of the RBC.Chronic granulomatous disease of childhood & Myeloperoxidase Deficiency - Chronic Granulomatous Disease of Childhood
o
It’s sex-linked recessive. The mother (an asymptomatic carrier) is the one who gives it to the boy. All of the females of a male with the disease are asymptomatic carriers; they transmit the disease to 50% of their sons.o
They’re missing an enzyme – NADPH oxidase.o
The NBT dye test is abnormal; it doesn’t show the color of the dye.o
They’re missing the respiratory burst. They don’t have superoxide, peroxide, but they do have myeloperoxidase and chloride. We have myeloperoxidase and chloride, but these kids are missing peroxide (have no NADPH oxidase).
If a bacteria was phagocytosed in a neutrophil or monocyte and it could make peroxide and add it inside the phagolysosome, this would be enough to kill the bacteria.
All living organisms make peroxide; this includes bacteria. However, not all bacteria contain catalase (an enzyme that breaks down peroxide).
o
These kids can’t kill Staph., but they can kill Strep .
The reason is Staphylococcus is not only coagulase positive, butcatalase positive (have the ability to breakdown peroxide). Staph. aureus can make its peroxide and release catalase and neutralize it. The myeloperoxidase system is rendered useless in the child because it too depends on peroxide (to combine with chloride to make bleach).
If it was a Streptococcus (catalase negative), when it makes its peroxide (like any normal bacteria) it doesn’t have catalase, so it’s adding what the child was missing to make bleach. The kid can then kill Strep.
- Myeloperoxidase Deficiency
o
In someone with myeloperoxidase deficiency, they still have a respiratory burst (b/c they have NADPH oxidase).o They have peroxide, superoxide free radicals, and chloride.
o
They have a normal NBT dye test (it depends on the presence of superoxide), but they can’t kill the bacteria b/c they can’t make bleach.o
This type of defect would be called a microbiocidal defect.o
Myeloperoxidase deficiency is not sex-linked recessive; it’s autosomal recessive.- Chronic granulomatous disease of childhood and myeloperoxidase deficiency are both microbiocidal defects (can’t kill bacteria).
Adhesion Molecule Defect - Scenario
o A child has to have his umbilical chord removed surgically. Histologically it doesn’t show neutrophils w/in the tissue or lining the small vessels.
o This is an adhesion molecule defect; could be a beta2 integrin defect (integrins are adhesion molecules). The umbilical chord needs to have an inflammatory reaction involving neutrophils; they have to stick in order to get out.
Serotonin
-
It’s made from the tryptophan amino acid. - It’s a neurotransmitter.Anaphylatoxins - C3a and C5a.
-
They stimulate mast cells to release histamine (which causes vasodilatation and increase in vessel permeability).-
They also play a role in shock (if you activate the complement system, they will also be activated).Nitric oxide
- It’s made in endothelial cells. - It’s a potent vasodilator.
-
It’s used in treating pulmonary hypertension. - It plays a big role in septic shock.Il-1
- It’s a pyrogen; it stimulates the hypothalamus to make prostaglandins; the prostaglandins stimulate your thermoregulatory center to produce fever.
Corticosteroids
-
Inhibits phospholipase A2 ; you don’t release arachidonic acid from phospholipids (you don’t make prostaglandins or leukotrienes).-
Linoleic acid (omega 6 fatty acid) can make arachidonic acid. It’s found in walnuts and fish oils. They act like aspirin.-
Linolenic acid (omega 3 fatty acid) blocks platelet aggregation. Zileuton- It’s used as to block 5-lipoxygenase. Other drugs block the receptors. LTC4, LTD4, LTE4
- They are potent bronchoconstrictors. These are important in causing asthma. LTB4
- It’s increases neutrophil adhesion and neutrophil chemotaxis. Aspirin
- Blocks cyclooxygenase; it blocks it irreversibly (it preferentially affects platelets more than endothelial cells). PGI2 (prostacyclin)
- It’s made in the endothelial cell and is why it’s called prostacyclin synthase. - It’s a vasodilator and it inhibits platelet aggregation.
Thromboxane A2 (TXA2)
- It’s produced in platelets. It causes vasoconstriction, bronchoconstriction, and platelet aggregation. Dipyramidole
-
It blocks thromboxane synthase.- It’s also used in doing stress testing for coronary artery disease. PGE2
-
It’s a vasodilator in the kidney.-
It maintains the patent ductus open.-
It makes your mucous barrier in the stomach. PGF2-
It causes dysmenorrhia (primary dysmenorrhia). - It increases uterine contractility.-
It’s made as an abortifactant. Corticosteroids-
It blocks phospholipase A2. - Effects on cellso Increases Neutrophil Count
It increases adhesion molecule synthesis along with other steroids (like epinephrine and norepinephrine).
If you decrease adhesion molecule synthesis, it would increase the neutrophil count in the CBC (in a white person, 50% of neutrophils are already stuck to the endothelium of small vessels and 50% circulate). The white blood cell count would be doubled.
o
Corticosteroids destroy both T and B cells; they’re lymphocytotoxic. They do it by apoptosis. Corticosteroids are the signal for caspases to kill the cells.
o
It decreases eosinophil counts as well (this is why they’re used in type I hypersensitivity reactions). o When you’re on corticosteroids, the only thing increased is neutrophils (this is b/c it decreases adhesionmolecule synthesis). Lymphocytes and eosinophils are decreased.
-
If you had Addison’s disease, you don’t have cortisol and you have the opposite effect mentioned above. - Sidenote:o
Person who has a myocardial infarction has a high CBC count (most of which are neutrophils)o
The mechanism is epinephrine. It decreases adhesion molecule synthesis and the neutrophil count goes up. Electron Microscopy of Inflammatory Cells
- To identify the alveolar macrophage, you see black dots all over the place (lysosomes).
-
Lamellar bodies are the structures within type II pneumocytes.o
Inside lamellar bodies, you can find lecithin and phosphatidylcholine.o
They are involved in the production of surfactant.Monocyte
- It has a grayish cytoplasm. It usually has a single nucleus and has a lot of garbage in the cytoplasm (it scavenges around).
-
It can form a foam cell in an atherosclerotic plaque b/c it can phagocytose and oxidize LDL. Oxidized LDL is a free radical. Vitamin E neutralizes oxidized LDL.Lymphocyte
- On the electron microscope, it looks like all nucleus with very little cytoplasm.
-
The odds are T cells (60% of the peripheral blood lymphocytes are T). Since helper T-cells (CD4) outnumber suppressor (CD8) 2:1, the odds are that a lymphocyte would be a helper T cell.Rough Endoplasmic Reticulum
- It has ribosomes on it that makes protein (like immunoglobulins).
-
If it has a rough endoplasmic reticulum with many ribosomes, odds are it’s a plasma cell. o The nucleus is eccentrically located. The cytoplasm is always sky blue.o The plasma cell derived from a B cell.
They would be located in the germinal follicle. Eosinophil
- It has granules that are the red.
- It’s the only inflammatory cell that has crystals in the granules.
o
In an asthmatic, the crystals are Charcot-Leyden crystals; they’re degenerated eosinophil in the sputum of an asthmatic.-
Killing invasive helminths involves type II hypersensitivity.o
Eosinophils have IgE receptors; they hook into the IgE antibodies (that bind to helminths) and release their chemicals (the major one is major basic protein) that destroys the helminth.o It’s type II hypersensitivity b/c it’s a cell hooking into an antibody on a target cell. - Sidenote: type I hypersensitivity
o
In type I hypersensitivity, eosinophils aren’t the effector cells; mast cells are. o Mast cells release histamine and eosinophil chemoctactic factor.o Eosinophils’ purpose in a type I hypersensitivity reaction is neutralize leukotrienes (they have histaminase and aryl sulfatase).
Basophil
- It has purplish granules. Cluster Designations - CD4 – helper T-cell - CD8 – cytotoxic T-cell
-
CD3 – the recognition site for all T-cells-
CD1 – the antigenic marker for histiocytes (include Langerhan’s cells)-
CD10 – The marker for themost common leukemia in children; it’s also called CALLA (common ALL antigen; positive B cell leukemias).-
CD15 and CD30 – are the Reed-Sternberg-
CD21 – is only on B cellso
Epstein-Barr virus hooks onto this receptor .
The atypical lymphocytes, however, aren’t the B cells, but the T cells (reacting against the infected B cells).o Burkitt’s lymphoma is a B cell lymphoma.
-
CD45 – it’s on all leukocytesFever
-
Most of the time, Il-1 is responsible for fever. It stimulates the hypothalamus to makePGE2; that stimulates the thermoregulatory center.-
Fever is good b/c it right-shifts the oxygen-saturation curve.o
We want lots of oxygen in our tissue when we have inflammation b/c of oxygen-dependent myeloperoxidase system.o When we give antipyretics, we are diminishing the myeloperoxidase system. o Also, hot temperatures aren’t good for reproduction of bacteria and viruses. Types of inflammation
- Suppurative Inflammation
o Pus in the lacteriferous duct Scenario
• Post-partum woman has pus coming out of her lactiferous duct. What is the organism? • Staph. aureus. This is an example of suppurative inflammation.
o Osteomyelitis Scenario
• A child with sepsis shows in the metaphysis of bone a yellowish area which turns out to be an abscess. What is it?
•
Osteomyelitis due to Staph. aureus If the kid had sickle cell, it would be Salmonella.
It’s the metaphysis of bone b/c that’s where all the blood supply to the bone goes. The mechanism of osteomyelitis is hematogenous (it comes from another source).o Cellulitis on the face
Odds are it’s Strep. pyogenes. o Diptheria and a pseudomembrane. Scenario
• The type of necrosis in a person with diphtheria and a pseudomembrane would be analogous to what other type of necrosis?
• Clostridium difficile.
o Corynebacterium diphtheriae is a gram positive rod; it makes an exotoxin which ADP-ribosylates elongation factor 2 (EF-2). The toxin damages the mucosa and
