Pathology: Cell Injury, apoptosis and necrosis

What is a vasopressor

Any medication that raises blood pressure (treats hypotension) = i.e. "presses your vasculature to raise BP"

Difference between apoptosis and necrosis

Apoptosis = ATP required; no significant inflammation Necrosis = always followed by inflammation + extravasation; always pathologic in nature (never physiologic)

Apoptotic ratio of Bax to Bcl-2 in apoptosis

Bax increases (pro-apoptotic) Bcl-2 decreases (anti-apoptotic) "Bax is Bad"

Why is subendocardium in LV most susceptible to ischemic damage?

Because the LV is the thickest layer of the heart and the subendocardium is the furthest layer away from coronary blood supply

Organs where fibrinoid necrosis occurs

Blood vessels

Organs affected by liquefactive necrosis

Brain Bacterial abscesses Pleural effusion Pancreatitis

Why are watershed areas of the brain susceptible to ischemia (decreased flow)?

Brain watershed regions: ACA/MCA/PCA boundaries = these areas have dual supply that comes from the DISTAL branches of arteries as protection for single-artery blockage - but because these branches are distal, more likely to suffer ischemia!

Another name for Fas-Ligand receptor

CD95

serum markers of skeletal muscle infarct (irreversible damage)

CPK Aldolase

Name the type of shock: Caused by PE

Cardiogenic shock

Name the type of shock: caused by tension pneumothorax

Cardiogenic shock

Name the type of shock: caused cardiac contusion

Cardiogenic shock

Name the type of shock: BP 130/85, low CO

Cardiogenic/hypovolemic shock

CO and TPR in hypovolemic/cardiogenic vs. septic shock

Cardiogenic/hypovolemic shock: CO decreased either because not enough blood or heart dysfunction; TPR increased in response to low CO; HR increased to compensate for low CO Septic shock: Dilated arterioles (due to endotoxin) = increased venous return to heart = increased CO

End-mediators of apoptosis

Caspases activated proteases/endonucleases: 1. Proteases = break down protein in cell 2. Endonucleases = break down DNA

What is the end result of irreversible injury?

Cell death - all the types of necrosis we talked about followed by inflammation!

Histological sign of apoptosis

Cell shrinkage Basophila Membrane blebbing Pyknosis and Karyorrhexis Apoptotic bodies "B-CAMP"

Hallmark sign of reversible injury

Cellular swelling (#1 sign) RER swelling + dissociation of ribosomes

Name the necrosis type: necrotic tissue remains firm, cell shape and organ structure are preserved by coagulation of proteins but nuclei are all gone

Coagulative necrosis

Name the type of necrosis: Infarction of any organ except the brain

Coagulative necrosis

Name the type of necrosis: Occurs in heart, liver and kidneys

Coagulative necrosis

Appearance of patient in cardiogenic/hypovolemic shock

Cold, clammy and cyanotic (from vasoconstriction)

Difference between dry vs. wet gangrenous necrosis

Dry = coagulative necrosis that resembles mummified tissue Wet = bacterial infection that causes liquefactive necrosis to occur over coagulative necrosis

Dystrophic calcification vs. metastatic calcification

Dystrophic = fat necrosis with normal serum calcium/phosphate Metastatic = fat necrosis with elevated serum calcium/phosphate - often due to hyperparathyroidism or nephrocalcinosis

Define necrosis

Enzymatic degradation of protein denaturation of a cell resulting from exogenous injury = extravasation and inflammation

Another name for CD95

Fas-Ligand receptor

Name the type of necrosis that can occur in pancreas

Fat necrosis (saponification of lipase) Liquefactive necrosis (proteolytic enzymes)

Type of necrosis that occurs in blood vessels

Fibrinoid necrosis

Name the type of necrosis: results from malignant hypertension or vasculitis

Fibrinoid necrosis of vessels

Name the necrosis: coagulative necrosis that resembles mummified tissue

Gangrenous necrosis

Name the type of necrosis: Lower limbs and GI tract

Gangrenous necrosis

Organs that can have coagulative necrosis

Heart Liver Kidney

Appearance of patient in septic shock

Hot patient (vasodilated) and flushed

Four causes of hypoxemia

Hypoxemia = low pO2 in blood (PaO2 < 60 mmHg and SaO2 < 90%) 1. High altitude 2. Hypoventilation 3. Diffusion defect 4. V/Q mismatch

Hallmark cause of reversible/irreversible injury

Hypoxia (decrease delivery of O2 to tissues) - caused by hypoxemia, ischemia and Hb defect/loss Everything relates back to hypoxia!

Three processes that occur during reversible injury (caused mainly by hypoxia)

Hypoxia = No O2 decrease ATP generation 1. Na/K+ pump fails = water accumulates in cells 2. Ca2+ pump fails = Ca2+ builds up in cell (starts to activate proteolytic enzymes) 3. Lactate accumulation = switch from aerobic to anaerobic glycolysis) - cell pH decreases (denatures proteins/DNA precipitation)

Hypoxia vs. Ischemia

Hypoxia = decrease O2 delivery to tissue Ischemia = decrease blood through THROUGH an organ - a form of hypoxia

Hypoxia vs. hypoxemia

Hypoxia = low O2 delivery to tissue Hypoxemia = low PO2 in the blood (PaO2 < 60 mmHg, SaO2 < 90%) - a form of hypoxia

Name a common cause of coagulative necrosis

Infarction of any organ except the brain

Three processes that occur during irreversible cell injury

Irreversible injury always comes back to membrane damage: 1. PM damage = cytosolic enzymes leak into serum, calcium enters cell 2. Mitochondrial membrane damage = Loss of ETC; cytochrome c leaks into cells 3. Lysosomal membrane damage = hydrolytic enzymes leak into cytosol (activated by high Ca2+ from irreversible injury)

Three causes of hypoxia

Ischemia = decreased flow THROUGH an organ Hypoxemia = decreased pO2 in the blood Decrease O2 carrying capacity = Hb loss or dysfunction

Organs where gangrenous necrosis occurs

Limbs (especially in diabetics via popliteal occlusion) GI tract

Histologic sign of atrophy

Lipofuscin granules (result from proteolysis - i.e. decreased metabolic activity will decrease protein synthesis in a cell leading to ubiquitination of unused proteins = lysis)

Type of necrosis: Occurs in pancreas, brain, pleural effusions

Liquefactive necrosis

The guiding principal behind reversible cell injury

Low O2 = low ATP = cell transporters stop working

Define hypoxia

Low O2 delivery to tissue = cause of cellular injury

Hallmark of irreversible injury

Membrane damage

Causes of cardiogenic shock

PE = overloads RV (increased afterload) and decreases preload to left ventricle

Cells that mediate liquefactive necrosis in abscesses

PMNs secrete proteolytic enzymes

Organs where fatty necrosis occurs

Pancreas (saponification of lipase) Breast (fat necrosis)

The guiding principal behind irreversible cell injury

Permanent membrane damage: Cell PM (calcium influx, proteolytic enzymes leak out), mitochondrial PM (no ETC, cyt c leaks), lysosomal membrane damage

Cells that mediate liquefactive necrosis in pancreatitis

Protelytic enzymes from pancreatic cells liquefy parenchyma

What brain cells are most affected in brain ischemia?

Pyramidal cells of hippocampus Purkinje cells

Define red infarction

Region of coagulative necrosis (often an infarct) that is then re-perfused with blood (i.e. pulmonary or testicular infusion)

Cellular swelling is a sign of what type of injury

Reversible injury

RER swelling and ribosome dissociation is associated with what type of injury

Reversible injury

Name the type of shock: BP 80/60, high CO

Septic shock

"B-CAMP goes to die"

Signs of apoptosis (die): B = basophilia C = cellular shrinkage A = apoptotic bodies M = membrane blebbing P = pyknosis and karyorrhexis

Define caseous necrosis

Soft and friable "cottage-cheese like appearance"

What tissues are pale infarcts most likely to occur in?

Solid tissues with single blood supply 1. Kidney 2. Heart 3. Spleen

Regions of the colon most susceptible to ischemia

Splenic flexure Rectum *Watershed regions like the brain = receive dual supply but from distal-most portions of arteries

What area of the kidney is most vulnerable to ischemia

Straight segment of the proximal tubule (medulla) Thin ascending limb (medulla)

Area of the heart most vulnerable to ischemia

Subendocardium (LV) = why? Because LV is the thickest layer of the heart and the subendocardium is the furthest layer away from coronary blood supply!

Enzyme that converts O2- (hydroxyl) to H2O2

Superoxide dismutase

Examples of caseous necrosis

TB Systemic fungal infections *Most things that cause granulomatous inflammation

What processes is the intrinsic apoptotic pathway involved in?

Tissue remodeling Embryogenesis

What tissues are most vulnerable to red-infarcts

Tissues with collaterals or loose tissues: 1. Lungs 2. Liver 3. Intestine 4. Testicles

Immediate treatment for cardiogenic shock for trauma/blood loss or severe burns

Treat hypovolemia with IV fluids or blood transfusion

serum markers of cardiac myocyte infarct (irreversible damage)

Troponin I CPK CK-MB

What area of the liver is most susceptible to ischemia

Zone III (area around the central vein)

Name the type of necrosis: TB or systemic infections

caseous necrosis

Name the type of necrosis: occurs in pancreas and breast

fat necrosis

Name the type of necrosis: Caused by vasculitis

fibrinoid necrosis

Cells that mediate liquefactive necrosis in the brain

microglial cells secrete proteolytic enzymes

Immediate treatment for cardiogenic shock

"LMNOP" 1. Loops (furosemide) 2. Morphine = relax and decrease sympathetcis 3. Nitrates (venodilation to pull blood out of pulmonary circulation) = reduce volume load on the heart 4. Oxygen 5. Positioning/pressors = ionotropic drugs

Immediate treatment for septic shock

1. Antibiotics (i.e. broad-spectrum like meropenem 2. IV fluid 3. Vasopressor (NE)

Examples of apoptosis mediated processes

1. Endometrial shedding during menstrual fcycle 2. CD8 mediated killing of virally infected cells 3. Removal of cells during embryogenesis

Extrinsic apoptosis via Fas/Fas-Ligand mechanism

1. Fas ligand binds CD95 (Fas-Receptor) on cell targeted for death 2. Fas-receptor activates caspases downstream

What are the two methods of extrinsic apoptosis

1. Fas/Fas-ligand mediated apoptosis 2. CD8 lymphocyte killing via perforin and granzyme B

Intrinsic apoptotic pathway mechanism

1. Growth factor withdrawn from proliferating cell population (i.e. decrease IL-2 after completed immune reaction); or injury occurs (i.e. radiation, toxins, hypoxia) 2. Changes in proportions of prop-apoptotic factors (Bax increase, Bcl-2 decrease) 3. Bax increase and Bcl-2 decrease = increased mitochondrial permeability 4. Cytochrome C leaks out = activates caspases

How does PE cause cardiogenic shock?

A massive pulmonary embolism may also produce cardiogenic shock by impeding blood flow in the pulmonary vessels, leading to volume overload of the right ventricle and a drastic reduction in left ventricular filling volume

serum markers of hepatocyte irreversible damage

AST ALT ALP GGT

"Bax is Bad"

Mnemonic to remember that: Bax = pro-apoptotic (increases in apoptosis) Bcl-2 = anti-apoptotic (decreases in apoptosis)

"LMNOP"

Mnemonic to remember treatment for cardiogenic shock 1. Loops = furosemide (Lasix) 2. Morphine = release and decrease sympathetics 3. Nitrates = for venodilation (reduce volume load on heart) 4. Oxygen 5. Position/pressors = ionotropic drugs

Define fat necrosis

Necrotic adipose tissue with chalky-white appearance due to deposition of calcium on dead tissue (in setting of NORMAL serum calcium and phosphate)

Define coagulative necrosis

Necrotic tissue (nuclei are all gone) held together by coagulation of proteins = 1. Tissue remains firm 2. Cell shape retained 3. Organ structure retained Architecture preserved because everything is coagulated (just no nuclei!)

Define liquefactive necrosis

Necrotic tissue becomes LIQUEFIED due to enzymatic lysis of cells and protein

Name the type of shock: Decreased TPR (BP) and CO

Neurogenic shock

Nuclear changes of apoptosis

Nuclear shrinkage (pyknosis) Nuclear fragmentation (karyorrhexis