Tissue Injury Lecture Oct 1

Question 1

WHat is etiology?

Pathogenesis?

Clinical manifestations?

Answer 1

etiology is the causation

pathogenesis is the mechanism of disease development

Clinical manifestations are the end result of the changes resulting in functional abnormalities

Question 2

What are the four main adaptations in response to cell injury?

Answer 2

hypertrophy

hyperplasia

autrotrophy

metaplasia

Question 3

What is hypertrophy?

give an exmaple.

Answer 3

Hypertrophy is the increase in cell size, resulting in an increase in the organ size.

This results from increased production of cellualr proteins in response to increased demand or stimulation (can be physiologic or pathologic)

Selective hypertrophy can occur at the level of the subcellular organelle even (SER)

Examples include myocardial hypertrophy - thickening of ventricle wall - caused by an increased blood flow requiring greater mechanical effort by myocardial cells

Another example is the physiologic hypertrophy of the uterus during pregnancy

Question 4

What is hyperplasia?

Give an example.

Answer 4

Hyperplasia is the increase in the number of cells, resulting in an increase in the size of the organ.

This will only occur if the cells of the organ are capable of dividing - the brain cant for example

This can be physiologica (hormonal or compensatory) or pathologic (excess hormones or growth factors)

An example is nodular prostatic hyperplasia - older men tend to have an increased sensitivity to testosterone, resulting in cell proliferation around the prostate gland

Question 5

What is atrophy?

GIve an example

Answer 5

Decrease in cell size and number resulting in reduced size of the tissue or organ

this can be physiologic or pathologic

uptimately results from a decreased protein synthesis and increased protein degradation within the cells (increased autophagy may be involved)

Question 6

WHat is metaplasia

GIve an example.

Answer 6

Reversible chain in which one differentiated type of cell is replaced by antoher cell type.

This results from the reprogramming of stem cells present in normal tissue or reprogramming of undifferentiated mesenchymal cells

External stimuli promote expression of genes that lead to a specific differentiation pathway

Barrett esophagus converts squamous to columnar in response to the high acid.

Connective tissue metaplasia - formation of bone instead

columnar to squamous (in the lungs)

Question 7

What are the possible causes of cell injury?

Answer 7

osygen deprivation (hypoxia through ischemia, inadequat blood oxygenation, or decreased O2 carrying capacity – anemia, CO2, blood loss, etc)

Physical agents (trauma, temps, pressure, radiation, shock)

Chemicals and drugs

infectious agents

genetic derangements

nutritional imablance

Question 8

What happens in necrosis?

Answer 8

If the injury is not reversible, the ER and mitochondria will beging to swell and myelin figures will develop.

the plasma membrane breaks down

organelles and nucleus break down

contents leak out of the cell

Extracellular cell contents trigger immune response

the hydrolytic enzymes that were withint the cell start to digest the cell parts and nearby tissue

NECROSIS

Question 9

What are some morphological signatures of reversible cell injury?

in liver…

Answer 9

Cellular swelling (due to failure of ion pumps)

fatty change (buildup of cytoplasmic lipid vacuoles)

plasma membrane alterations

mitochondrial changes (swelling, condensation)

dilation of ER

Nuclear alterations

Question 10

What is the morphology of necrosis (irreverislbe cell damage)?

Answer 10

increased cytoplasmic eosinophilia in tissue stains (DNA/RNA break down so it’s less blue and more pink)

myelin figures (dead cell replaced by mass of damaged cell membranes)

nuclear changes of karyolysis (nucleus faces away), pyknosis (srhunken nucleus) and karyorrhexis (fragmentation of the nucleus)

Question 11

What are the 6 forms of necrosis?

Answer 11

coagulative

liquifactive

gangrenous

caseous

fat

fibrinoid

Question 12

what happens in coagulative necrosis?

Answer 12

the architecture of the dead tissue is preserved (as is the case in an infarct)

Question 13

WHat happens in liquefactive necrosis?

Answer 13

Digestion of the dead tissue results in liquid viscous mass

this is typically seen in focal bacterial or fungal infections because the microbes stimulate the accumulation of neutrophils which die and liberate enzymes that will break down the area into a liquid mass

Question 14

What is gangrenous necrosis?

Answer 14

it’s a clinical term applied to necrosis of a limb undergoing coagulative ischemic necrosis (dry gengrene) or liquifactive necrosis (wet gangrene)

Question 15

Describe caseous necrosis

Answer 15

cheeselike necrosis associated with necrotizing granulomas seen with TB and fungal infections

Question 16

Describe fat necrosis

Answer 16

this refers to focal areas of fat destruction that result from the release of pancreatic enzymes into the nearby fat layers during pancreatitis

on the picture…the areas of white chalky deposits represent foci of fat necrosis with salcium soap formation (saponification) at sites of lipid breakdown in the mesentary

This can sometimes be associated with fibrosis and dystrophic calcification

Question 17

What is fibrinoid necrosis?

Answer 17

a pattern of necrosis seen in immune reactions involving vessels

Question 18

What are the 6 mechanisms of cell injury?

Answer 18

depletion of ATP

mitochondrial damage

influx of calcium/loss of Ca homeostais

accumulation of ROS

defects in membrane permeability

damage to DNA and proteins

Question 19

How does depletion of ATP result in cell injury?

what are some causes of ATP depletion?

Answer 19

ATP is required for virtually every process in the cell

ATP depletion can be caused by reduces supply of oxygen and nutrients, mitochondrial damage or exposure to certain toxins

Effects of ATP depletion:

failure of Na pump (alteration in ion concentrations - swelling)

altered energy metabolism - use anaerobic glycolysis (so increase in lactic acid)

calcium pump failure

disruption of ribosomes with rreduced protein synthesis (and misfolded proteins)

eventually irreversible damage and cell death

Question 20

How does mitochondrial damage occur?

What is the impact of mitochondrial damage on the cell?

Answer 20

Mitochondria can be damaged by osygen deprivation, ROS, or increased cytosolic calcium

Mitochondria supply ATP to the cell through oxidative phosphorylation, so it can alo cause a depletion of ATP

mitochondrial membrane proteins will also excape out of the mitochondria which can activate apoptosis: cytochrome C

Question 21

How does influx of calcium/loss of calcium homeostasis result in cell injury?

Answer 21

Cytosolic free calcium is normally very low, but if a cell is injuryed the calcium is released from intracellular stores and the cell membrane becomes more permeable to extracellular calcium

This results in mitochondrial membrane defect and failture of ATP generation

activation of lytic enzymes

this can activated casoases leading to apopotisis

Question 22

How does ROS accumulation occur?

What is the effect of ROS on the cell?

Answer 22

ROS are types of osygen derived free radicals that are produced normally in the cell during mitochondrial respiration and energy production. THere are cellular defense mechanisms to remove ROS. However, if these e=mechanisms don’t work or if there is a sudden increase in ROS production, the cell runs into issues.

disruption of plasma membrane and organelles

loss of enzymatic activity and abnormal folding

DNA oxidation resulting in mutations and breaks

Question 23

What are three “scavenger” mechanisms to remove ROS from the cell?

Answer 23

superoxide dismutates converts it to peroxide

glutathione peroxidase and catalase will convert the peroxide to water

antioxidants will also take care of ROS - like vitamin E, A, and C

Question 24

WHat can cause membrane damage?

What will membrane damage cause in the cell?

Answer 24

Membrane damage can occur as a result of ROS species, decreased phospholipid synthesis, increased phospholipid breakdown, and cytoskeletal abnormalities (stretching)

Membrane damage will result in:

mitochondrial membrane damage - decreased ATP and necrosis

loss of osmotic balance and loss of cellular components

injury to lysosomal membranes with release of lytic enzymes with enzymatic digestion of proteins, RNA, DNA, glycogen, etc.

Question 25

THe "point of no return" in cell injury is not fully understood, but what is irreverisbility typically characterized by?

Answer 25

inability to reverse mitochondrial dysfunction profound distrubances in membrane function

Question 26

WHat does ischemia refer to? What does hypoxia refer to? Which tends to be worse for the cell?

Answer 26

Hypoxia is reduced oxygen availability ischemia refers to reduced blood flow, so oxygen AND nutrients are decreased Ischemia tends to be works because anaerobic glycolysis can continue in hypoxia but not in ischemia

Question 27

What is an ischemia-reperfusion injury?

Answer 27

Often times, restoration of blood flow can promote recovery of reverisbly damaged cells However, in some instances injury can be exacerbated by reperfusion THis is because reperfusion can increase ROS production, it can cause an influx of neutrophils, and can activate the complement system

Question 28

Briefly describe chemical (toxic) injury. Which organ is the primary target of this and why?

Answer 28

Injury will occur ether by the direct effect of the toxin or throuhg a toxic metabolite they can damage membranes, create ROS, or disrupt enzymes The liver is often the target because it metabolizes many drugs and toxins through first pass metabolism

Question 29

Why does apoptosis limit collateral damage?

Answer 29

The membrane never lyses, so cell contents don't enter the ECM and an immune response isn't initiated

Question 30

What are three examles of physiologic apopotisis?

Answer 30

cell loss in embryogenesis loss of uterine epithelial cells in menstrual cycle cell loss in normal proliferating cell populations (lymphocytes)

Question 31

What are 4 causes of apoptosis initiation?

Answer 31

DNA damage (radiation, cytotosic drugs, ypoxia) accumulation of misfolded proteins cell death in infections (particularly viral) pathologic atrophy of organs associated with duct obstruction

Question 32

What are hte morphological features of apoptotic cells?

Answer 32

cell shrinkage condensation of nuclear chromatin formation of blebs and fragments (apoptotic bodies) Phagocytosis (usually by macrophages)

Question 33

WHy will DNA damage lead to apoptosis?

Answer 33

Damaged DNA activates the p53 tumor suppressor gene which can induce apoptosis by expression of Bax and inhibition of Bcl2 in the intrinsic pathway

Question 34

How can protein misfolding trigger apoptosis?

Answer 34

Unfolded or misfolded proteins can accumulate in the ER This accumulation will induce an unfolded protein response which results in apoptosis

Question 35

THe TNF receptor family including Fas and FasL are important for the regulation of lymphocyte apoptosis. What happens if this is mutated?

Answer 35

You don't get appropriate apopotsis of the lymphocytes, resulting in lymphomas

Question 36

How do cytotoxic T cells mediate apoptosis?

Answer 36

They will recognize antigens present on the surface of infected cells they will bind infected cells and secrete perforin which pokes holes in the cell's membrane it then secretes granzymes through the holes which will activate caspases inside the cell and induce apoptosis

Question 37

What is autophagy? How does it occur? When does it occur?

Answer 37

a process of cell death in which the cell eats its own contents under times of stress the cell forms an autophagic vacuole which then fuses with a lysosome to form an autophagolysosomes cellular components are brought into these autophagolysosomes and digested by the lysosomal enzymes this may play a role in degenerative diseases of the nervous system and muscle

Question 38

What are the four main types of intracellular accumulations?

Answer 38

1. abnormal metabolism (as in lipid accumulation in the liver) 2. Defect in protein folding and transport resulting in the accumulation of abnormal proteins 3. Lack of an enzyme so you don't break down a complex substrate to a soluble product and lysosomal storage diasease results: accumulation of the complex substrate 4. Ingestion of indigestable materials , resulting in the accumulation of exogenous products

Question 39

What are some of the ways proteins can accumulate?

Answer 39

1. reabsorption droplets in proximal renal tubues in renal diseases 2. excessive protein production (Russell bodies in plasma cells) 3, Defective secretion of proteins (alpha-1-antitrypsin def.) 4. Addumulation of cytoskeletal proteins (Mallory bodies in liver) 5. Aggregation of abrnomal proteins - amyloidosis 6. Hyaline change

Question 40

What are some endogenous pigments that can accumulate in cells?

Answer 40

lipofuschin - it's a brown lipid that results from free radical injury and membrane breakdwon - it's seen in liver and heart as normal aging, also in malnutrition and cancer melanin hemosiderin granules - these are aggregates of ferritin - a protein iron complex. THe common bruise is an example of localized hemosiderosis. can also be systematic if there is an overload of iron

Question 41

Lipofuschin and hemosiderin addumulation will look similar on an H&E stain, so what do you need to use to distinguish the two?

Answer 41

a prussian blue stain which is specific for iron and will stain blue in hemosiderin

Question 42

What does pathological calcification refer to?

Answer 42

the abrnomal tissue accumulation of calcium

Question 43

Under what two situations does calcification occur?

Answer 43

1. dystrophic calcification - occurs in areas of necrosis with deposition of crystalline calcium phosphate, which can result in heterotopic bone formation (often seen with atherosclerosis, valve disease, fat necrosis, or TB) 2. Metastatic calcification - due to hypercalcemia secondary to disordered calcium metabolism - elevated serum Ca. THis will result in serum calcium phosphate being depositied in normal tissues (lungs, kidneys, gastric, arteris, pulmonary beigns, heterotopic bone formation

Question 44

What are the 4 principal causes of hypercalcemia in the serum?

Answer 44

1. increased parathyroid hormone production 2. destruction of bone tissue 3. renal fialure 4. Vitamin D related disorders

Question 45

Which cellular changes contribute to cellular aging?

Answer 45

Decreased cellular replication (after a fixed # of divisions all somatic cells become arrested in senescence). telomere shortening likely involved. Accumulation of metabolic and genetic damage over time

Question 46

WHat do laboratory tests for cellular injury rely on

Answer 46

THey rely on cellular constituents that will be in the blood after a cell is lysed through necrosis

Question 47

What tests will establish the presence of hepatocellular damage?

Answer 47

AST and ALT will be eleveted NOTE: AST is not specific for liver because its also found in heart, skeletal muscle, brain and kidneys ALT is only located in the liver, so ALT is a more specific indicator of hepatocyte injury

Question 48

Which tests will etablish the presence of bile duct damage?

Answer 48

Alkaline phosphatase (ALP) will increase usually due to bone or liver disease A second test, gamma-glutamyl transferase (GGT) will only be elevated in biliary damage, so it will assist in determining if an ALP is elevated due to bone or liver disease

Question 49

What elevated enzyme suggests damage to cardiac muscle?

Answer 49

troponin 1