Cellular Reaction to injury

I.  Hypoxia = inadequate oxygenation of tissue (same definition of as shock). Need O₂ for oxidation phosphorylation pathway – where you get ATP from inner Mitochondrial membrane (electron transport system, called oxidative phosphorylation). The last rxn is O₂ to receive the electrons. Protons are being kicked off, go back into the membrane, and form ATP, and ATP in formed in the mitochondria

A.  Terms:

1.  Oxygen content = Hb x O₂ satn + partial pressure of arterial oxygen

(these are the 3 main things that carry O₂ in our blood)

In Hb, the O₂ attaches to heme group (O₂ sat’n)

Partial pressure of arterial O₂ is O₂ dissolved in plasma

In RBC, four heme groups (Fe must be +2; if Fe+ is +3, it cannot carry O₂)

Therefore, when all four heme groups have an O₂ on it, the O₂ sat’n is 100%.

2.  O₂ sat’n is the O₂ IN the RBC is attached TO the heme group = (measured by a pulse oximeter)

3.  Partial pressure of O₂ is O₂ dissolved in PLASMA

O₂ flow: from alveoli through the interphase, then dissolves in plasma, and increases the partial pressure of O₂, diffuses through the RBC membrane and attaches to the heme groups on the RBC on the Hb, which is the O₂ sat’n

Therefore – if partial pressure of O₂ is decreased, O₂ sat’n HAS to be decreased (B/c O₂ came from amount that was dissolved in plasma)

B.    Causes of tissue hypoxia:

1. Ischemia (decrease in ARTERIAL blood flow ……NOT venous)

MCC Ischemia is thrombus in muscular artery (b/c this is the mcc death in USA = MI, therefore MI is good example of ischemia b/c thrombus is blocking arterial blood flow, producing tissue hypoxia)

Other causes of tissue ischemia: decrease in Cardiac Output (leads to hypovolemia and cardiogenic shock) b/c there is a decrease in arterial blood flow.

2.  2^nd MCC of tissue hypoxia = hypoxemia

Hypoxia = ‘big’ term

Hypoxemia = cause of hypoxia (they are not the same); deals with the partial pressure of arterial O₂ (O₂ dissolved in arterial plasma, therefore, when the particle pressure of O₂ is decreased, this is called hypoxemia).

Here are 4 causes of hypoxemia:

a. Resp acidosis (in terms of hypoxemia) – in terms of Dalton’s law, the sum of the partial pressure of gas must = 760 at atmospheric pressure (have O₂, CO₂, and nitrogen; nitrogen remains constant – therefore, when you retain CO₂, this is resp acidosis; when CO₂ goes up, pO₂ HAS to go down b/c must have to equal 760;

Therefore, every time you have resp acidosis, from ANY cause, you have hypoxemia b/c low arterial pO₂; increase CO₂= decrease pO₂, and vice versa in resp alkalosis).

b. Ventilation defects – best example is resp distress syndrome (aka hyaline membrane dz in children).  In adults, this is called Adult RDS, and has a ventilation defect.  Lost ventilation to the alveoli, but still have perfusion; therefore have created an intrapulmonary shunt.  Exam question: pt with hypoxemia, given 100% of O₂ for 20 minutes, and pO₂ did not increase, therefore indicates a SHUNT, massive ventilation defect.

c. Perfusion defects – knock off blood flow

MCC perfusion defect = pulmonary embolus, especially in prolonged flights, with sitting down and not getting up.  Stasis in veins of the deep veins, leads to propagation of a clot and 3-5 days later an embolus develops and embolizes.  In this case, you have ventilation, but no perfusion; therefore there is an increase in dead space.  If you give 100% O₂ for a perfusion defect, pO₂ will go UP (way to distinguish vent from perfusion defect), b/c not every single vessel in the lung is not perfused.

Therefore, perfusion defects because an increase in dead space, while ventilation defects cause intrapulmonary shunts.  To tell the difference, give 100% O₂ and see whether the pO₂ stays the same, ie does not go up (shunt) or increases (increase in dead space).

d. Diffusion defect – something in the interphase that O₂ cannot get through…ie fibrosis.  Best example–Sarcoidosis (a restrictive lung disease); O₂ already have trouble getting through the membrane; with fibrosis it is worse.  Another example–Pulmonary edema; O₂ cannot cross; therefore there is a diffusion defect.  Another example is plain old fluid from heart failure leads to dyspnea, b/c activated the J reflex is initiated (innervated by CN10); activation of CN10, leads to dyspnea (can’t take a full breath) b/c fluid in interstium of the lung, and the J receptor is irritated. 

These are the four things that cause hypoxemia (resp acidosis, ventilation defects, perfusion defects, and diffusion defects).

3.  Hemoglobin related hypoxia

In the case of anemia, the classic misconception is a hypoxemia (decrease in pO₂).  There is NO hypoxemia in anemia, there is normal gas exchange (normal respiration), therefore normal pO₂ and O₂ saturation, but there is a decrease in Hb.  That is what anemia is: decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O₂ that gets to tissue, therefore get tissue hypoxia and the patient has exertional dyspnea with anemia, exercise intolerance.

a. Carbon monoxide (CO): classic – heater in winter; in a closed space with a heater (heater have many combustable materials; automobile exhaust and house fire.  In the house fire scenario, two things cause tissue hypoxia: 1) CO poisoning and 2) Cyanide poisoning b/c upholstery is made of polyurethrane products. When theres heat, cyanide gas is given off; therefore pts from house fires commonly have CO and cyanide poisoning.

CO is very diffusible and has a high affinity for Hb, therefore the O₂ SAT’N will be decreased b/c its sitting on the heme group, instead of O₂ (remember that CO has a 200X affinity for Hb).

(Hb is normal – its NOT anemia, pO₂ (O₂ dissolved in plasma) is normal, too); when O₂ diffuses into the RBC, CO already sitting there, and CO has a higher affinity for heme.  To treat, give 100% O₂.  Decrease of O₂ sat’n = clinical evidence is cyanosis

Not seen in CO poisoning b/c cherry red pigment MASKS it, therefore makes the diagnosis hard to make.  MC symptom of CO poisoning = headache

b. Methemoglobin:

Methemoglobin is Fe3+ on heme group, therefore O₂ CANNOT bind.  Therefore, in methemoglobin poisoning, the only thing screwed up is O₂ saturation (b/c the iron is +3, instead of +2).  Example: pt that has drawn blood, which is chocolate colored b/c there is no O₂ on heme groups (normal pO₂, Hb concentration is normal, but the O₂ saturation is not normal); “seat is empty, but cannot sit in it, b/c it’s +3”.  RBC’s have a methemoglobin reductase system in glycolytic cycle (reduction can reduce +3 to +2).

Example:  Pt from rocky mountains was cyanotic; they gave him 100% O₂, and he was still cyanotic (was drinking water in mtns – water has nitrites and nitrates, which are oxidizing agents that oxidize Hb so the iron become +3 instead of +2). Clue was that O₂ did not correct the cyanosis.  Rx: IV methaline blue (DOC); ancillary Rx = vitamin C (a reducing agent).  Most recent drug, Dapsone (used to Rx leprosy) is a sulfa and nitryl drug. Therefore does two things: 1) produce methemoglobin and 2) have potential in producing hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies.  Therefore, hemolysis in G6PD def is referring to oxidizing agents, causing an increase in peroxide, which destroys the RBC; the same drugs that produce hemolysis in G6PD def are sulfa and nitryl drugs.  These drugs also produce methemoglobin.  Therefore, exposure to dapsone, primaquine, and TMP-SMX, or nitryl drugs (nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia, G6PD def, and methemoglobinemia b/c they are oxidizing agents. Common to see methemoglobinemia in HIV b/c pt is on TMP-SMX for Rx of PCP.  Therefore, potential complication of that therapy is methemoglobinemia.

c. Curves: left and right shifts

Want a right shifted curve – want Hb with a decreased affinity for O₂, so it can release O₂ to tissues.  Causes: 2,3 bisphosphoglycerate (BPG), fever, low pH (acidosis), high altitude (have a resp alkalosis, therefore have to hyperventilate b/c you will decrease the CO₂, leading to an increase in pO₂, leading to a right shift b/c there is an increase in synthesis of 2,3 BPG).

Left shift – CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis

Therefore, with CO, there is a decrease in O₂ sat’n (hypoxia) and left shift.

4.  Problems related to problems related to oxidative pathway

a. Most imp: cytochrome oxidase (last enzyme before it transfers the electrons to O_2. Remember the 3 C’s – cytochrome oxidase, cyanide, CO all inhibit cytochrome oxidase.  Therefore 3 things for CO – (1) decrease in O₂ sat (hypoxia), (2) left shifts (so, what little you carry, you can’t release), and (3) if you were able to release it, it blocks cytochrome oxidase, so the entire system shuts down

b. Uncoupling – ability for inner mito membrane to synthesize ATP.  Inner mito membrane is permeable to protons.  You only want protons to go through a certain pore, where ATP synthase is the base, leading to production of ATP; you don’t want random influx of protons – and that is what uncoupling agents do.  Examples: dinitrylphenol (chemical for preserving wood), alcohol, salicylates.  Uncoupling agents causes protons to go right through the membrane; therefore you are draining all the protons, and very little ATP being made.  B/c our body is in total equilibrium with each other, rxns that produce protons increase (rxns that make NADH and FADH, these were the protons that were delivered to the electron transport system).  Therefore any rxn that makes NADH and FADH that leads to proton production will rev up rxns making NADH and FADH to make more protons. With increased rate of rxns, leads to an increase in temperature; therefore, will also see HYPERTHERMIA.  Complication of salicylate toxic = hyperthermia (b/c it is an uncoupling agent).  Another example: alcoholic on hot day will lead to heat stroke b/c already have uncoupling of oxidative phosphorylation (b/c mito are already messed up).

These are all the causes of tissue hypoxia (ischemia, Hb related, cyto oxidase block, uncoupling agents).  Absolute key things!

5.  What happens when there is:

a. resp acidosis – Hb stays same, O₂ sat’n decreased, partial pressure of O₂ decreased (O₂ sat decreased b/c pO₂ is decreased)

b. anemia – only Hb is affected (normal O₂ sat’n and pO₂)

c. CO/methemoglobin – Hb normal, O₂ sat’n decreased, pO₂ normal

Rx CO – 100% O₂; methemo – IV methaline blue (DOC) or vit C (ascorbic acid)

C.  Decreased of ATP (as a result of tissue hypoxia)

1.  Most imp: have to go into anaerobic glycolysis; end product is lactic acid (pyruvate is converted to lactate b/c of increased NADH); need to make NAD, so that the NAD can feedback into the glycolytic cycle to make 2 more ATP.  Why do we have to use anaerobic glycolysis with tissue hypoxia? Mitochondria are the one that makes ATP; however, with anaerobic glycolysis, you make 2 ATP without going into the mitochondria.  Every cell (including RBC’s) in the body is capable of performing anaerobic glycolysis, therefore surviving on 2 ATP per glucose if you have tissue hypoxia.  Mitochondrial system is totally shut down (no O₂ at the end of the electron transport system – can only get 2 ATP with anaerobic glycolysis). 

Good news – get 2 ATP

Bad news – build up of lactic acid in the cell and outside the cell (increased anion-gap metabolic acidosis with tissue hypoxia) due to lactic acidosis from anaerobic glycolysis. 

However, causes havoc inside the cell b/c increase of acid within a cell will denature proteins (with structural proteins messed up, the configuration will be altered); enzymes will be denatured, too.  As a result, cells cannot autodigest anymore b/c enzymes are destroyed b/c buildup of acid.  Tissue hypoxia will therefore lead to COAGULATION necrosis (aka infarction).  Therefore, buildup of lactic acid within the cell will lead to Coagulation necrosis.

2.  2^nd problem of lacking ATP: all ATP pumps are screwed up b/c they run on ATP.  ATP is the power, used by muscles, the pump, anything that needs energy needs ATP.  Na/K pump – blocked by digitalis to allow Na to go into cardiac muscle, so Ca channels open to increase force of contraction (therefore, sometimes you want the pump blocked), and sometimes you want to enhance it.

With no ATP, Na into the cell and it brings H20, which leads to cellular swelling (which is reversible).  Therefore, with tissue hypoxia there will be swelling of the cell due to decreased ATP (therefore will get O₂ back, and will pump it out – therefore it is REVERSABLE).

In true RBC, anaerobic glycolysis is the main energy source b/c they do not have mitochondria; not normal in other tissues (want to utilize FA’s, TCA, etc).

3. Cell without O₂ leads to irreversible changes.

Ca changes with irreversible damage – Ca/ATPase pump.  With decrease in ATP, Ca has easy access into the cell.  Within the cell, it activates many enzymes (ie phospholipases in the cell membranes, enzymes in the nucleus, leading to nuclear pyknosis (so the chromatin disappears), into goes into the mito and destroys it).

Ca activates enzymes; hypercalcemia leads to acute pancreatitis b/c enzymes in the pancreas have been activated. Therefore, with irreversible changes, Ca has a major role. Of the two that get damaged (mito and cell membrane), cell membrane is damaged a lot worse, resulting in bad things from the outside to get into the cell.  However, to add insult to injury, knock off mitochondria (energy producing factory), it is a very bad situation (cell dies)…CK-MB for MI, transaminases for hepatitis (SGOT and AST/ALT), amylase in pancreatitis.

II. Free Radicals

Liver with brownish pigment – lipofuscin (seen on gross pic; can also be hemosiderin, bilirubin, etc; therefore need to have a case with the gross pic); end products of free radical damage are lipofuscin b/c certain things are not digestible (include lipids).

A.  Definition of free radical – compound with unpaired electron that is out of orbit, therefore it’s very unstable and it will damage things.

B.  Types of Free Radicals:

1.  Oxygen:  We are breathing O₂, and O₂ can give free radicals.  If give a person 50% O₂ for a period of time, will get superoxide free radicals, which lead to reperfusion injury, esp after giving tPA when trying to rid a damaged thrombus.  Oxygentated blood goes back into the damaged cardiac muscle=reperfusion injury.  Kids with resp distress syndrome can get free radical injury and go blind b/c they destroy the retina – called retinopathy prematurity; also leads to bronchopulmonary dysplasia, which leads to damage in the lungs and a crippling lung disease. 

2.  Water in tissues converted to hydroxyl free radicals, leading to mutations in tissues.  Complication of radiation therapy is CANCER (MC cancer from radiation is leukemia, due to hydroxyl free radicals).  Fe2+ produces hydroxyl free radicals b/c of the fenton rxn. This is what makes Fe overload diseases so dangerous, b/c wherever Fe is overloaded, leads to hydroxyl free radicals which will damage that tissue (therefore, in liver leads to cirrhosis, in heart leads to restrictive cardiomyopathy, in pancreas leads to failure, and malabsorption, along with diabetes). 

3.  Tylenol (aka acetaminophen):

MCC drug induced fulminant hepatitis b/c free radicals (esp targets the liver, but also targets the kidneys).  Cytochrome P450 in liver metabolizes drugs, and can change drugs into free radicals.  Drugs are often changed in the liver to the active metabolite – ie phenytoin.  Where in the liver does acetaminophen toxicity manifest itself? – right around central vein.  Treatment: n-acetylcysteine; how? Well, the free radicals can be neutralized. Superoxide free radicals can be neutralized with supraoxide dismutase (SOD).  Glutathione is the end product of the hexose/pentose phosphate shunt and this shunt also generates NADPH.  Main function is to neutralize free radicals (esp drug free radicals, and free radicals derived from peroxide).  Glutathione gets used up in neutralizing the acetaminophen free radicals.  Therefore, when give n-acetylcysteine (aka mucamist); you are replenishing glutathione, therefore giving substrate to make more glutathione, so you can keep up with neutralizing acetaminophen free radicals.  (like methotrexate, and leukoverin rescue – using up too much folate, leukoverin supplies the substrate to make DNA, folate reductase).

4.  Carbon tetrachloride: CCl4 can be converted to a free radical in the liver (CCl3) in the liver, and a free radical can be formed out of that (seen in dry cleaning industry).

5.  Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen).  Free radicals from acetaminophen are destroying the renal medulla *only receives 10% of the blood supply-relatively hypoxic) and renal tubules.  Aspirin is knocking off the vasodilator PGE2, which is made in the afferent arteriole.  Therefore AG II (a vasoconstrictor) is left in charge of renal blood flow at the efferent arteriole.  Either sloughing of medulla or destroyed ability to concentrate/dilute your urine, which is called analgesic nephropathy (due mainly to acetaminophen).

III. Apoptosis

Programmed cell death.  Apoptotic genes – “programmed to die” (theory).  Normal functions: (1) embryo – small bowel got lumens from apoptosis. (2) King of the body – Y c’some (for men);  MIF very imp b/c all mullarian structures (uterus, cervix, upper 1/3 of vagina) are gone, therefore, no mullarian structures.  MIF is a signal working with apoptosis, via caspasases.  They destroy everything, then wrap everything in apoptotic bodies to be destroyed, and lipofuscin is left over.  (3)For woman – X c’some; only have one functioning one b/c the other is a barr body.  Absence of y c’some caused germinal ridge to go the ovarian route, therefore apoptosis knocked off the wolfian structures (epidydymis, seminal vesicles, and vas deferens).  (4) Thymus in anterior mediastinum – large in kids; if absent, it is DiGeorge syndrome (absent thymic shadow), and would also have tetany; cause of thymus to involute is apoptosis. (5) Apoptosis is the major cancer killing mechanism.  (6) Process of atrophy and reduced cell or tissue mass is due to apoptosis.  Ex. Hepatitis – councilman body (looks like eosinophilic cell without apoptosis) of apoptosis (individual cell death with inflammation around it).  Just needs a signal (hormone or chemical) which activate the caspases, and no inflammation is around it. Apoptosis of neurons – loss brain mass and brain atrophy, and leads to ischemia. Red cytoplasm, and pynotic nucleas.  Atherosclerotic plaque.  Therefore, apoptosis is involved in embryo, pathology, and knocking off cancer cells.

IV. Types of necrosis – manifestations of tissue damage.

A. Coagulation Necrosis: Results often from a sudden cutoff of blood supply to an organ i.e. Ischemia (definition of ischemia = decrease in arterial blood flow).  In ischemia, there is no oxygen therefore lactic acid builds up, and leads to coagulation necrosis.  Gross manifestation of coagulation necrosis is infarction.  Under microscope, looks like cardiac muscle but there are no striations, no nuclei, bright red, no inflammatory infiltrate, all due to lactic acid that has denatured and destroyed all the enzymes (cannot be broken down – neutrophils need to come in from the outside to breakdown).  Therefore, vague outlines = coagulation necrosis (see color change in heart). 

1.  Pale vs hemorrhagic infarctions: look at consistency of tissue. 

(a) Good consistency = grossly look pale: infarct: heart, kidney, spleen, liver (rarest of the organ to infarct b/c dual blood supply); ie coagulation necrosis.  Example of a pale infarction of the spleen, most likely due to emboli from left side of heart; causes of emboli: vegetations (rarely embolize in acute rheumatic endocarditis); infective endocarditis; mitral stenosis (heart is repeatedly attacked by group A beta hemolytic streptococcus); and clots/thrombi.  The worst arrhythmia associated with embolization in the systemic circulation is atrial fib b/c there is stasis in the atria, clot formation, then it vibrates (lil pieces of clot embolize). 

Gangrenous Necrosis: dry and wet gangrene: Picture of a dry gangrene – not wet gangrene b/c there’s no pus.  Occurs in diabetic’s with atherosclerosis of popliteal artery and possible thrombosis; (dry gangrene related to coagulation necrosis related with ischemia (definition of ischemia = decrease in arterial blood flow), which is due to atherosclerosis of the popliteal artery.  Pathogenesis of MI: coronary thrombosis overlying the atheromatous plaque, leading to ischemia, and lumen is blocked due to thrombosis.  MCC nontraumatic amputation = diabetes b/c enhanced atherosclerosis (popliteal artery = dangerous artery).  Coronary is also dangerous b/c small lumen.  In wet gangrene, it’s complicated by infective heterolysis and consequent liquefactive necrosis.

(b) Loose consistency of tissue= hemorrhagic infarct: bowel, testes (torsion of the testes), especially the lungs b/c is has a loose consistency and when the blood vessels rupture, the RBC’s will trickle out, leading to a hemorrhagic appearance.

Example:  hemorrhagic infarction of small bowel due to indirect hernia.  2^nd MCC of bowel infarction is getting a piece of small bowel trapped in indirect hernial sac.  MCC of bowel infarction is adhesions from previous surgery.

Example:  In the Lung – hemorrhagic infarction, wedge shaped, went to pleural surface, therefore have effusion and exudates; neutrophils in it; have pleuritic chest pain (knife-like pain on inspiration).  Pulmonary embolus leads to hemorrhagic infarction. 

B.  Liquefactive Necrosis:

Exception to rule of Coagulation necrosis seen with infarctions: brain.

MC site of infarction from carotid artery – why we listen for a bruit (hearing for a noise that is going thru a vessel that has a narrow lumen – place with thrombus develops over atherosclerotic plaque and leads to stroke); leads to transient ischemic attacks is little atherosclerotic plaques going to little vessels of the brain, producing motor and sensory abnormalities, that go away in 24 hrs.  Brain with ‘meshwork’ – in brain, astrocytes is analogous to the fibroblasts b/c of protoplasmic processes.  Therefore, acting like fibroblast (can’t make collagen), but its protoplasmic processes gives some structure to the brain.  Therefore, infarction of the brain basically liquefies it (has no struct), and you see a cyst space – liquefactive necrosis.  Therefore, exception to the rule of infarctions not being coagulative necrosis is the brain and it undergoes liquefactive necrosis (no struc, therefore leaves a hole).  Cerebral abscess and old atherosclerotic stroke -both are liquefactive necrosis.

Liquefactive – liquefies; think neutrophil, b/c their job is to phagocytosis with their enzymes (to ‘liquefy’); liquefactive necrosis relates to an infection with neutrophils involved (usually acute infection – producing an abscess or an inflammatory condition, which liquefies tissue).  Therefore, liquefactive necrosis usually applies to acute inflammation, related to neutrophils damaging the tissue.  Exception to the rule: liquefactive necrosis related to infarct (not an inflammatory condition, it just liquefies) (slide shows liquefactive necrosis due to infection in the brain).  So, if you infarct the brain, or have an infection, or have an abscess it is the same process – liquefactive necrosis.

Example:  Abscess – gram “+” cocci in clusters.  Why are they in clusters? Coagulase, which leads to abscesses with staph aur.  Coagulase converts fibrinogen into fibrin, so it localizes the infection, fibrin strands get out, resulting in an abscess.  Strep: releases hyaluronidase, which breaks down GAG’s in tissue, and infection spreads through the tissue (cellulitis).  From point of view of necrosis, neutrophils are involved, therefore it is liquefactive necrosis.

Example:  ABSCESS: Lung – yellowish areas, high fever and productive cough; gram stain showed gram “+” diplococcus, which is strep pneumoniae. (MCC of bronchopneumonia.).  Not hemorrhagic b/c its pale, and wedged shaped necrosis at the periphery, which leads to pleuritic chest pain.

Example: pt with fever, night sweats, wt loss – M tb, which has granulomatous (caseous) necrosis.  Pathogenesis of granuloma (involves IL-12 and subset of helper T cells and “+” PPD). 

C.  Caseous (cheesy consistency) Necrosis: – either have mycobacterial infection (any infections, including atypicals, or systemic fungal infection); these are the ONLY things that will produce caseation in a granuloma.  It is the lipid in the cell wall of the organism’s leads to cheesy appearance.

Sarcoidosis – get granulomas, but they are not caseous b/c they are not mybacterium or systemic fungi (hence ‘noncaseating’ granulomas)

Crohn’s dz – get granulomas, but not caseous b/c not related to mycobacterium or systemic fungi.

D. Fat Necrosis:

1.  Enzymatic Fat Necrosis: unique to pancreas

Example: pt with epigastric distress with pain radiating to the back – pancreatitis (cannot be Peptic Ulcer Dz b/c pancreas is retroperitoneal), therefore just have epigastric pain radiating to the back. A type of enzymatic FAT necrosis (therefore necrosis related to enzymes).  Enzymatic fat necrosis is unique to the pancreas b/c enzymes are breaking down fats into FA’s, which combine with Ca salts, forming chalky white areas of enzymatic fat necrosis (chalky white areas due to calcium bound to FA’s – saponification (soap/like salt formation)); these can be seen on xrays b/c have calcium in them.  Example: A pt with pain constently penetrating into the back, show x-ray of RUQ.  Dx is pancreatitis and esp seen in alcoholics.  Histo slide on enzymatic fat necrosis – bluish discoloration, which is calcification (a type of dystrophic calcification-calcification of damaged tissue).  What enzyme would be elevated? Amylase and lipase (lipase is more specific b/c amylase is also in the parotid gland, small bowel, and fallopian tubes).  What type of necrosis? Another example: Enzymatic fat necrosis.  Underlying cause? Alcohol produces a thick secretion that will lead to activation of enzymes; which leads to pancreatitis.  Therefore, whenever you see blue discoloration and atherosclerotic plaque in a pancreas, it will be calcium.

2.  Traumatic Fat Necrosis:  Example: woman with damage to breasts is TRAUMATIC FAT necrosis (not enzymatic); it can calcify, can look like cancer on mammogram.  Diff btwn that and calcification in breast cancer is that it is painFUL. (cancer = painless).  Traumatic fat tissue usually occurs in breast tissue or other adipose tissue

E.  Fibrinoid necrosis: (the -oid means: looks like, but isn’t)

Therefore, looks like fibrin, but is not fibrin….it is the necrosis of immunologic dz:

Examples of immunologic dz:

Palpable purpura = small vessel vasculitis (immune complex type III).

Fibrinoid necrosis has immune complex deposition of small vessel.

Pathogenesis of immune complex: damage of type III HPY (an immune complex is an Ag-Ab circulating in the circulation; it deposits wherever circulation takes it – ie glomerulus, small vessel, wherever).  It activates the complement system (the alt system), which produces C5a, which is chemotactic to neutrophils.  Therefore, damage done as a result of type III HPY is done by neutrophils.  And they are there b/c the immune complex activated the alternative complement system.  The complex has little to do with the damage, it’s the neutrophils do eventual damage)

Henoch-Scholein purpura – feel person’s legs, and see palpable purpura (due to type III HPY).  Rhematic fever (vegetations off the mitral valve) – have fibrin like (fibrinoid necrosis) materials (necrosis of immunologic dz).  Morning stiffness = rheumatoid arthritis, see fibrnoid necrosis b/c immunologic damage.  Therefore, fibrinoid necrosis is necrosis of immunologic damage (in vessel it’s a vasculitis, in kidney it’s a glomerulonephritis, and in lupus glomerulonephritis involving immune complexes).

F.  Liver:  Triad area: portal vein, hepatic artery, bile duct. Liver is unique b/c it has dual blood supply and so hepatic artery and and portal vein will dump blood into sinusoids.  Other examples of sinusoid organs are BM and spleen.  Characteristic of sinusoids: gaps between endothelial cells, with nothing there so things can fit through (things like RBC’s and inflammatory cells).  GBM is fenestrated, have little tiny pores within the cells, for filtration.  Sinusoids have gaps so large cells can get through them (not true with GBM b/c it is intact, and lil pores allow filtration).  Portal vein blood and hepatic artery blood go through sinusoids, and eventually taken up by central vein, which becomes the hepatic vein.  The hepatic vein dumps into the inf vena cava, which goes to the right side of the heart.  Therefore, there is a communication between right heart and liver.  Right HF (blood fills behind failed heart), therefore the liver becomes congested with blood, leading to nutmeg liver (aka congestive hepatomegaly).  If you block the portal vein, nothing happens to the liver, b/c it is BEFORE the liver.  Blockage of hepatic vein leads to budd chiari and liver becomes congested. Which part of liver is most susceptible to injury normally? Around central vein, b/c it gets first dibbies on O₂ coming out of the sinusoids (zone 1).  Zone 2 is where yellow fever will hit (midzone necrosis) due to ides egypti.  Zone 3, around portal vein, which will have least O₂ (analogous to renal medulla, which only receives 10% of the blood supply, and the cortex receives 90%).  Fatty change is around zone 3 (part around central vein).  Therefore, when asking about acetaminophen toxicity, which part is most susceptible? Around the central vein b/c it gets the least amount O₂, and therefore cannot combat free radical injury.

1.  Alcohol related liver damage: 

(a) MCC fatty change: alcohol.

(b) Metabolism of alcohol: NADH and acetyl CoA (acetate is a FA, and acetyl CoA can be converted to FA’s in the cytosol).  NADH is part of the metabolism of alcohol, therefore, for biochemical rxns: What causes pyruvate to form lactate in anaerobic glycolysis? NADH drove it in that direction, therefore always see lactic acidosis (a form of metabolic acidosis) in alcoholic’s b/c increased NADH drives it in that direction.  Also, in fasting state, alcoholic will have trouble making glucose by gluconeogenesis b/c need pyruvate to start it off.  However, you have lactate (and not pyruvate) therefore alcoholics will have fasting hypoglycemia.  Acetyl CoA can also make ketone bodies (acetoacetyl CoA, HMG CoA, and beta hydroxybutyric acid).  See beta hydroxybutyric ketone bodies in alcoholic’s b/c it’s a NADH driven reaction. Therefore, two types of metabolic acidosis seen in alcoholics are lactic acidosis (b/c driving pyruvate into lactate) and increased synthesis of ketone bodies b/c excess acetyl CoA; main ketoacid = beta hydroxybutyric acid.  Why does it produce fatty change? In glycolysis, around rxn 4, get intermediates dihydroxyacetone phoshphate (NADH rxn) and is forced to become glycerol 3-phosphate.  Big time board question! With glycerol 3 phosphate shuttle, get ATP.  Also imp to carbohydrate backbone for making tryglycerides (add 3 FA’s to glycerol 3 – phosphate, and you get TG’s).  In liver, the lipid fraction if VLDL (endogenous TG is synthesized in the liver from glycerol 3 phosphate derived from glycolysis).  Restricting fat will NOT decrease the synthesis of VLDL.  Restricting carbs WILL decrease the VLDL synthesis b/c it is glucose intermediate it is made from.  Glycerol 3 phosphate is a product of glycolysis which is why fatty liver is MC’ly due to alcoholism (this rxn)!

2.  Kwashiorker – kid with fatty change.  The mechanism: when you make VLDL, and to be able to get it out of the liver, the VLDL must be surrounded by apoproteins.  In kwashiorkor, there is decreased protein intake; they have adequate number of calories, but its all carbs.  Therefore, they cannot get VLDL that they made in the liver out b/c there are no apolipoproteins to cover it and put it out in the bloodstream and solubilize it in water. Lipid and water do not mix; therefore it is necessary to put proteins around the lipid to dissolve it in water. Therefore, the protuberant abdomen in these pts is there for two reasons: 1) decreased protein intake which decreases oncotic pressure, leading to ascites.  2) The biggest reason is that they have huge livers related to fatty change.  The mechanism for fatty change is different from alcohol b/c in alcohol; the mech is due to increased synthesis of VLDL.  In this case, there is a lack of protein to put around the VLDL and export it out of the liver.

3.  Hemosiderin and Ferrtin: brief discussion:  Ferritin = soluble form of circulating Fe, and is a good marker for Fe in BM.  It is the test of choice in dx’ing any Fe related problem – Fe def anemia, or Anemia of Chronic Dz or Fe overload dz’s such as hemochromatosis and hemosiderosis (would be elevated).  Ferritin is a soluble form of Fe, while hemosiderin is an insoluble form of Fe storage, and is stored in macrophages and BM.  Stain it with Prussian blue.

V. Types of calcification: dystrophic and metastatic

A.  Dystrophic calcification: means abnormal calcification.  The damaged tissue gets calcified. 

1.  Example: Seen in enzymatic fat necrosis (chalky white areas on x-ray are a result of dystrophic calcification). 

2. Example: football player with hematoma in foot, that becomes calcified dsystrophically (Ca binds and co-produces dystrophic Ca deposits).  Serum Ca is normal, but damaged tissue becomes calcified. Occurs in atheromatous plaques (causes serious tissue damage), therefore they are difficult to dissolve (need to be on the ornish diet – a vegan diet). 

3. MCC aortic stenosis (MCC: congenital bicuspid aortic valve) = dystrophic calcification (also leads to a hemolytic anemia).  Slide: the aorta has only 2 valves doing the job of three, and gets damaged, leading to dystrophic calcification which narrows orifice of valve, leading to aortic stenosis.

B.  Metastatic calcification: In cases of Hypercalcemia or hyperphosphatemia, Calcium is actually made to deposit in normal tissues, non-damaged tissues. 

MCC hypercalcemia (outside of hospital) = primary hyperparathyroidism

MCC hypercalcemia (inside the hospital) = malignancy induced hypercalcemia.

With hypercalcemia, can put Ca in NORMAL tissues; this is called metastatic calcification.  In dystrophic calcification there is damaged tissue with normal serum Ca levels.  Metastatic calcification is when there is high Ca or phosphorus serum levels (actually when Ca is deposited into bone, it is the phosphorus part of solubility product that drives Ca into bone). High phosphate levels (very dangerous) will take Ca and drive it into normal tissue. This is why have to put a pt with renal failure on dialysis (have high phosphorus serum levels) therefore need to dialyze the phosphate b/c the phosphate will drive Ca into normal tissue – ie heart, conduction system, renal tubules, basement membrane (nephrocalcinosis) – all lead to damage.

VI. Cell Membrane Defects

A.  RBC membrane defect:  Spherocytosis is a defect in spectrin within RBC cell membrane; if you can’t see a central area of pallor (if you don’t see a donut) then it’s a spherocyte.  Absence of spectrin with in the RBC does not allow the RBC to form a biconcave disk; it is defective, and therefore forms a sphere. 

B.  Ubiquitin – stress protein.  High ubiquitin levels are associated with high levels of stress.  Some of the intermediate filaments (keratin, desmin, vimentin) are part of the superstructure of our cells (“frame of the cell”, upon which things are built). When these intermediate filaments get damaged, the ubiquitin marks then for destruction.  The intermediate filaments have been tagged (ubiquinated) and marked for destruction.  Some of these products have names, for example: there are open spaces within the liver tisse, these spaces are fat and they are probably due to alcohol.  The ubiquinited products of the liver are called Mallory bodies.  These are the result of ubiquinated filaments called keratin and these are seen in alcoholic hepatitis.  Another example: Silver stain of neurofibilary tangles – Jacob crutzfelt and alzheimers dz.  Tau protein is associated with neurofib tangles; this is an example of a ubiquinated neurofilament.  Example: Substantia nigra in Parkinson’s Dz – include inclusions called Lewy bodies, neurotransmitter deficiency is dopamine.  Lewy bodies are ubiquinated neurofilaments. Therefore, Mallory bodies, Lewy bodies, and neurofib tangles are all examples of ubiquintation.

VII. Cell Cycle- very very important: big big big time

A.  Different types of cells:

1. Labile cells – cell where the division is via a stem cell.  Three tissues that has stem cells: bone marrow, basement membrane of skin, and the base of crypts in the intestine.  These cells have the tendency of being in the cell cycle a lot.  In pharm: there are cell cycle specific and cell cycle nonspecific drugs.  The cells that are most affected by these drugs are the labile cells b/c they are in the cell cycle.  Complications of these drugs are BM suppression, diarrhea, mucocidis, and rashes on the skin (there are stem cells in all these tissues!).

2. Stable cells – in resting phase, G_o phase.  Most of perenchymal organs (liver, spleen, and kidney) and smooth muscle are stable cells.  Stable cells can ungo division, but most of the time they are resting, and something must stimulate them to get into the cell cycle and divide – ie a hormone or a growth factor.  For example: estrogen in woman will help in the proliferative phase of the menstrual cycle.  The endometrial cells are initially in the G_o phase and then the estrogen stimulated the cells to go into the the cell cycle. Therefore, they can divide, but they have to be invited by a hormone or a growth factor.

3. Permanent cells – can no longer get into the cell cycle, and have been permanently differentiated.  The other types of muscle cells: striated, cardiac and neuronal cells.  Only muscle that is NOT a permanent tissue = smooth muscle; hyperplasia = increase in #, while hypertrophy = increase in size. Would a permanent cell be able to under hyperplasia? NO, b/c that means more copies of it.  Can it go under hypertrophy? Yes.  A smooth muscle cell can undergo hyperplasia AND hypertrophy. 

B.  Different phases of cell cycle:

1.  G₁ phase: The most variable phase of cell cycle is the G₁ phase.  Compare with menstrual cycle: The most variable phase is the proliferative phase (not the secretory phase).  The prolifertive phase varies with stress; however, once ovulation has occurred, it is 14 days.  Therefore, proliferative phase is analogous to G₁ phase of the cell cycle b/c it can be shorter or lengthened; none of the other phases (S, G₂, and M phase) changes, they stay the same.  Therefore, in cancer cells, ones with a longer cell cycle will have a longer G₁ phase, and cancer cells with a shorter cell cycle will have a shorter G₁ phase. 

G₁ phase is the mastermind of everything.  Cyclin dependent kinase (kinase = phosphorylation = activation).  Phosphorylation usually involves sending a message to activate something.  Glucagon is a phosphorylator, while insulin is a dephosphorylator.  Glucagon will phosphorylate protein kinase and activate it, while Insulin would dephosphorylate protein kinase and inactivate it. 

G1 to S phase:  Inactive Cyclin d dependent kinase:  Cyclin d activates it, and G₁ phase makes cyclin D.  Once cyclin D is made in the G₁ phase, it then activates the enzyme: cyclin dep. kinase (therefore it is now active).  Key area to control in cell cycle: transition from G₁ to S phase.  Because if you have a mutation and it goes into S phase, it then becomes duplicated, then you have the potential for cancer.  Two suppressor genes that control the transition:  (1) Rb suppressor gene: located on chromosome 13, which makes the Rb protein, which prevents the cell from going from the G₁ to the S phase.  In general, to go from G₁ to S, the active cyclin dep kinase phosphorylates the Rb protein; when it is phosphorylated=activation, it can go from the G₁ phase to the S phase.  A problem occurs if there is a mutation.  Therefore the enzyme is checked by (2) p53 suppressor gene: located on chromosome 17, which makes a protein product that inhibits the cyclin d dep kinase.  Therefore, it cannot go into the S phase; p53 is the number 1, most imp gene that regulates human cancer.

Example:  HPV – inactivates Rb suppressor gene and p53 suppressor gene.  HPV makes two genes products – E6 (which knocks off the p53) and E7 (which knocks of the Rb suppressor gene). 

If you have a point mutation the Rb suppressor gene, the Rb suppressor gene is knocked off, there will be no Rb protein, and the cell will progress to the S phase b/c it is uncontrolled.  This mutation in the Rb suppressor gene predisposing to many cancers, such as retinoblastoma, osteogenic sarcoma (ie kid with pain around knees, Codman’s triangle – sunburst appearance on x-rays), and breast cancer (Rb suppressor can be involved).  Depending on the age bracket, it hits in different areas. If you knock of p53 suppressor gene: the kinase will be always active, it will always phosphorylate the Rb protein, and that means that it will always go into the S phase, and this is bad.  If you knock off any of those genes, the cell will go into the S phase.  The p53 suppressor gene is the guardian of the genome, b/c it gives the cell time to detect if there are any defects/abnormalities in the DNA (splicing defects, codon thing, whatever, etc).  DNA repair enzymes can splice out the abnormality, correct it, and the cell is ready to go to the S phase.  If the cell has too much damaged DNA, then it is removed by apoptosis. Therefore this gene is imp b/c it gives the cell an opportunity to clean its DNA before going into the S phase. 

2.  S phase = synthesis phase, where everything is doubled, includes DNA and chromosomes (from 2N to 4N). For example: if it’s in muscle, it will have double the number of contractile elements.

3.  G₂ phase = where tubulin is made (imp to microtubule of the mitotic spindle); it is blocked by etoposide and bleomycin.

4.  M phase = mitosis; where the cell divides into two 2N cells.  The cell can either go into the G_o resting phase, or can continue dividing in the cycle, or can be permanently differentiated.  p53 gene makes a protein to inhibit the kinase, therefore prevents the Rb protein from being phosphorylated, therefore stays in the G₁ phase. Therefore, when you knock it off, no one is inactivating the kinase, and the cell is constantly phosphorylated and that keeps the cell dividing, and then has the potential to lead to cancer.

C. Drugs that act on the cell cycle:

1.  Drugs acting on S phase:

a) Ergot alkaloids work on the mitotic spindle in S phase

b) Methotrexate works in S phase:  Example: pt with rheumatoid arthiritis has macrocytic anemia. Drug responsible for this is in what phase of the cell cycle? S phase b/c it is methotrexate blocking dihydrofolate reductase

2.  Drugs acting on G₂ phase:

a) Etoposide

b) Bleomycin

3.  Drugs acting on M phase:                                                                                                            

a) Gresiofulvin in M phase

b) Paclitaxel specifically works in the M phase: Clinical scenario: this drug is a chemotherapy agent made from a yew tree? Paclitaxel (m phase)

c) Vincristine and Vinblastine

d) This drug used to be used for the treatment of acute gouty arthritis but b/c of all the side effects is no longer used.  What drug and where does it act? Colchicine (m phase)

4.  Clinical scenario that does not work on the cell cycle:  HIV “+” person with dyspnea and white out of the lung, on a drug; ends up with cyanosis; which drug? Dapsone

VII. Adaptations to environmental stress: Growth alterations

A. Atrophy: Diagnosis: the decrease in tissue mass and the cell decreases in size.  The cell has just enough organelles to survive, ie less mitochondria then normal cells, therefore, just trying to ‘eek’ it out until whatever it needs to stimulate can come back. 

1.  Example:   hydronephrosis, the compression atrophy is causing thinning of cortex and medulla, MCC hydronephrosis is stone in the ureter (the pelvis is dilated).  Question can be asked what kind of growth alteration can occur here.  Answer is atrophy b/c of the increased pressure on the cortex and the medulla and produces to ischemia, blood flow decreases and can produce atrophy of renal tubules.

2.  Example:  Atrophied brain due to atherosclerosis (MC) or degeneration of neurons (alzheimers, related to beta amyloid protein, which is toxic to neurons). 

3.  Example:  In muscle, many causes of atrophy – ie Lou Gehrig’s Dz (amylateral sclerosis) knock off neurons to the muscle, so it is not stimulated, leading to atrophy.

4.  Example:  Endocrine related:

a) Hypopituitarism will lead to atrophy of adrenal cortex: the zona fasiculata and retiucularis layers of the adrenal cortex; NOT the glomerulosa b/c ACTH has nothing to with stimulating aldosterone release.  The fasiculata is where glucocorticoids (cortisol) are made, while reticularis is where sex hormones are made (17 ketosteroids and testosterone).  ACTH is responsible for stimulating these, therefore zona fasiculata and zona reticularis are atrophied.

b) Taking thyroid hormone will lead to atrophy of thyroid gland.  This is due to a decrease of TSH and therefore nothing is stimulating the thyroid gland which leads to atrophy.

5.  Example:  Slide showing a biopsy of a pancreas in a patient with cystic fibrosis.  What is growth alteration? Atrophy, b/c the CFTR regulator on c’some 7 is defective and has problems with secretions.  The secretions become thicker and as a result, it blocks the ducts and so that means that the glands that were making the fluids (the exocrine part of the gland) cannot make fluids b/c of the back pressure blocking the lumen of the duct, which leads to atrophy of the glands, which then leads to malabsorption in all children with cystic fibrosis.

6.  Example:  Slide of an aorta, with atherosclerotic plaque, which leads to atrophy of the kidney and secondary HTN (renovasuclar HP, leading to high renin level coming out of the kidney).  In the other kidney, it is overworked, therefore there is hypertrophy (renin level coming out of this vein is decreased and suppressed).

B.  Hypertrophy increase of the SIZE of cell, not number

Scenario:  A cell biology question:  what is the N of this?

Hypertrophy of a cardiac muscle (permanent muscle), suppose there is a block just before the G2 phase.  What is the number of chromosomes? Answer: # of c’somes is 4N, b/c it already underwent synthesis: already doubled.

1 N = sperm (23 c’somes)

2 N = normal (diploid cell)

3 N = trisomy

4 N = double the number

C.  Hyperplasia – increase in the # of cells

In normal proliferative gland, there are thousands of mitoses, therefore see more glands with hyperplasia. 

1.  Example leading to cancer:  With unopposed estrogen, you may end up with cancer, b/c if you didn’t have progesterone (undoes what estrogen did-counteracts the estrogen), you will get cancer.  The cells will go from hyperplasia, to atypical hyperplasia to endometrial cancer.  Therefore hyperplasia left unchecked there is an increased risk of cancer.  One exception: benign prostatic hyperplasia; hyperplasia of the prostate does NOT lead to cancer; just urinary incontinence.

2.  Example:  gravid uterus (woman’s uterus after delivery).  This is an example of 50:50: 50% hypertrophy of the smooth muscle cells in the wall of the uterus, and 50% related to hyperplasia. 

3. Example:  Bone marrow: normally should have 3X as many WBC’s as RBC’s.   Slide shows few WBC’s, and increased RBC’s.  Therefore, have RBC hyperplasia.  This is not expected to be seen in Iron def anemia nor in thalassemias b/c in those, there a defect in Hb production.  It is expected to be seen in chronic obstructive pulmonary dz (COPD) b/c the hypoxemia causes the release of hormone EPO (erythropoietin); which is made in the endothelial cells of the peritubular capillaries.  So in the slide this is an example of EPO stimulated marrow.

 4.  Example:  psoriasis on elbow –an example of hyperplasia (unregulated proliferation of squamous cells in the skin), leading to red skin, and raised red plaque, b/c excessive stratum corneum.  This is why methotrexate works here, b/c it’s a cell cycle specific for the S phase, and prevents the basal cells from proliferating. 

5.  Example:  prostate gland and bladder – hyperplasia of prostate glands, it a hormone related hyperplasia; all hormone stimulated glands undergo hyperplasia, not hypertrophy.  The wall of the bladder is too thick; b/c urine has to go out thru a narrow opening in the urethra, therefore the muscle has to work harder which leads to hypertrophy of smooth muscle cells of the bladder wall (more urine must go out against a greater force b/c of an increase in after load).

D.  Metaplasia – replacement of one adult cell type by another

1.  Example: Slide of an esophagus, part of if is all ulcerated away. On a section surrounding the ulcer (right at the edge of the muscosa) there are mucous secreting cells and goblet cells (these are grandular cells).  These cells are not supposed to be present in lower esophagus; squamous cells should be there (not glandular cells).  Metastatic grandular: Barrets esophagus is a precursor for adenocarcinoma.   Adenocarcinoma has surpassed squamous cell carcinoma of mid-esophagus as the MC cancer of the esophagus.  Therefore, GERD is the number one precursor to esophageal cancer (adenocarcinoma).

2. Example: Lining of mainstem bronchus – ciliated columnar, pseudostatified columnar.  In smokers, this would be an example of metaplasia would be squamous.

3. Example: There are increased goblet cells within mainstem bronchus of an old smoker, also see goblet cells in the terminal bronchial.  Normally there are goblet cells in the mainstem bronchus but there are no goblet cells in the terminal bronchus, therefore this is an example of hyperplasia. 

4. Example: Goblet cells in the stomach are abnormal (should be in the intestines, only).  This is a glandular metaplasia, which is a precursor for adenocarcinoma of the stomach.  H. pylori are a precursor for adenocarcinoma in the stomach.  B/c H. pylori causes damage to pylorus and antral mucosa b/c it is a chronic gastritis which intestinal glandular metaplasia, which is a precursor for adenocarcinoma.  MCC adenocarcinoma of the stomach = H. pylori. 

5. Example: Cases where metaplasia causes an increased risk to caner:

a) Remember that if hyperplasia is left unchecked, could potentially lead to cancer.  For example: in endometrial hyperplasia the MC precursor lesion to endometrial carcinoma due to unopposed estrogen.  The exception is prostatic hyperplasia, which doesn’t become cancer. 

b) Metaplasia can also go through a process leading to cancer:

(1) In lung, ciliated columnar epithelium BECOMES squamous, therefore, this is called SQUAMOUS metaplasia; this will lead to squamous dysplasia, which then proceeds to cancer (squamous carcinoma);

(2) In distal esophagus, went from squamous to glandular epithelium b/c squamous epithelium cannot handle the acid, therefore it needs mucous secreting epithelium as a defense against cellular injury.  However, the glandular metaplasia can go on to an atypical metaplasia, predisposing to adenocarcinoma of the distal esophagus. 

(3) Parasites: 2 parasites produce cancer: clonesis sinesis leads to cholangiocarcinoma (Chinese liver fluke); and shistosoma hematoabia.  The schistosomias hematobia causes bladder cancer by causing the transitional epithelium to undergo squamous metaplasia.  This leads to squamous dysplasia, and then on to squamous cancer.  Transitional epithelium leads to squamous epithelium (called metaplasia), then dysplasia, then on to cancer.

E.  Dysplasia is really an atypical hyperplasia. 

1.  Example: Slide of a squamous epithelium is disorganized, with nuclei that are larger near the surface and the basal cell layer is responsible for the dividing; cells at top are bigger than the ones that are dividing, it has lack orientation.  If it was found during a cervical biopsy in pt with HPV infection, or if it was found in the mainstem bronchus biopsy, you should be able to tell that it is dysplastic.  Therefore dysplasia, whether glandular or squamous, is a precursor for cancer.

2.  Example: There was a farmer with lesion on the back of his neck (can grow on any part of the body, due to sun exposure), which could be scraped off and grew back – actinic keratosis (aka solar keratosis) – is a precursor for sq. cell carcinoma of the skin.  UV-b light damages the skin. Actinic keratosis does not predispose to basal cell carcinoma, even though basal cell carcinoma is the most common skin cancer.