1/6 Murphy Cell Injury: Damage

Front 1

Warm it up: 7 causes of cell injury

Back 1

hypoxia/ischemia
physical agents
drugs/chemicals
infectious agents
immunologic reactions
nutritional imbalances
genetic

Front 2

most common cause of hypoxia

Back 2

ischemia

Front 3

Examples of physical agents causing cell injury

Back 3

trauma
burns
deep cold

Front 4

A genetic example of a cell injury cause

Back 4

sickle cell anemia

Front 5

What are the three responses a cell can have to an injurious agent?

Back 5

Adaptation
Injured reversibly
Injured irreversibly and dies (via either necrosis or apoptosis)

Front 6

What factors determine if a cell injury is reversible/irreversible?

Back 6

Duration of exposure
Dosage
Type of cell and its ability to adapt (neurons are weaksauce compared to cardiomyocyte during hypoxia)

Front 7

What are the four grand biochemical themes in cell injury/death?

Back 7

Role of oxygen
Intracellular Ca/loss of Ca homeostasis
ATP depletion
Defects in membrane permeability

Front 8

How is O2 like money a parent gives a kid?

Back 8

In ischemia it ain't flowing to kid; in hypoxia, the parent just doesn't have any. Kid doesn't get any and runs out of (A)TP.

Or kid gets spoiled with lots of O2, bad morals, drugs, and too much tanning (radiation, inflammation, straight up oxygen toxicity, reperfusion, chemicals) -> ROS

Best case is balanced

Front 9

What are those ROS's again?

And what are they destroying?

Back 9

Oxygen-derived free radicals: superoxide O2-, hydrogen peroxide H2O2, hydroxyl radical OH'

Cellular proteins, phospholipids, nucleic acids

Front 10

Why/how is Ca loosed in damaged cells? Explain by contrasting to healthy cell.

Back 10

Healthy/normal cell: Ca is sequestered in organelles (mitochondria, smooth ER) and little is free in cytoplasm. Ca ATP-ases pump Ca across membranes to maintain this environment.

Agents can affect the ATP-ases (hypoxia -> lack of ATP or directly targeted)

Front 11

What 5 things can happen once Ca homeostasis is lost?

Back 11

Phopholipases activated -> destroy membrane
proteases activated -> destroy cytoskeleton -> destroy membrane
endonucleases activated -> destroy DNA/chromatin fragmentation
ATPases activated -> ATP depletion

Mitochondrial permeability transition pores formed -> no ATP production

Front 12

What is the relationship between the cytoskeleton and membrane?

Back 12

They are physically attached to each other, so if the cytoskeleton is disrupted, the membrane will be destroyed.

Front 13

What are sources of mitochondrial injury or dysfunction?

Back 13

Increased cytosolic Ca
ROS
lipid peroxidation

Front 14

What effects does mitochondrial damage cause? What do these lead to?

Back 14

With mitochondrial permeability transition -> membrane potential (proton gradient) is lost -> cannot make ATP -> necrosis

Cytochrome c and other pro-apoptotic proteins escape -> apoptosis

Front 15

ATP depletion is a common theme in cell injury- what is causing this?

Why is this bad exactly?

Back 15

Either activation of ATPases and/or decreased ATP synthesis.

Need ATP to support the membrane (synthesizing materials and maintaining pumps)- without enough ATP, membrane will fail.

Front 16

Defects in membrane permeability: causes

Back 16

direct damage by toxin
indirectly through Ca dependent enzymes

Front 17

What are the key features in reversible injury caused by ischemia?

Back 17

mitochondria cannot make ATP (no O2 to accept electrons) ->
1 increased anaerobic glycolysis -> lactic acid -> lowers pH -> impairs intracellular enzymes
2 Na/K pumps fail -> influx of Na and H2O

These are all early stage- if oxygen restored, all fixed.

Front 18

What are the key features in irreversible injury caused by ischemia?

Back 18

After a certain point, mitochondria are beyond repair:

phospholipids lost (Ca-> phospholipases and no ATP for new ones; breakdown products act like detergent -> more damage)
cytoskeletal abnormalities (Ca -> proteases)
reperfusion injuries (O2 reestablished -> oxygen-derived free radicals pillage what's left and local healthy cells -> lipid peroxidation)
amino acids lost (normally protect membrane from hypoxic damage)

Front 19

What amino acid in particular did he list as protector of membranes?

Back 19

Gly

Front 20

What was the name of the pink stain used in the examples to look at healthy and dead cells?

Back 20

hematoxylin and eosin
H & E