0514 Ischemia

Question 1

Name the 7 sources of hypoxia and give an example

Answer 1

• physical – trauma, temperature, radiation, shock
  - chemical – drugs, toxins
  - infectious – all infectious agents
  - immunologic - autoimmune
  - genetic - metabolic abnormalities
  - nutrition – too much or too little

Question 2

What does severity of outcome of hypoxia/ischemia depend on?

Answer 2

• site of injury
  - liver vs CNS, how organs tolerate injury
• severity of injury – magnitude of insulting agent?
  - how much or how little O2 was available? O2 sickness
• timecourse
  - fast? Slow? Long? Short?
  - formation of embolus vs. acute occlusion
• environment
  - under what condition was the injury sustained? Other problems?
• mechanism of agent
  - intravenous K+ injection vs KOH oral intake

Question 3

What are the cardinal signs of cell injury?

Answer 3

• ATP depletion (both ischemia and hypoxia)
  - from decreased mitochondrial activity
  - increased ROS production
  - integrity of membrane compromised
  - intracellular calcium increase
  - could lead to cell death
  - mitochondrial change (membrane and activity)

Question 4

What are some causes of hypoxia? (name 3)

Answer 4

• low oxygen partial pressure
  1. altitude - environment
  - can cause cerebral edema
  2. body – anemia (decreased PO2 in blood)
  3. constriction of vessels
  - embolus, plaques
  - causes tissue atrophy, pain, colour change
  4. poor delivery (pulmonary or cardiovascular)
  - poor gas transfer, heart failure

Question 5

What is the general course of ischemic or hypoxic injury?

Answer 5

• decreased oxygen availability due to either ischemia or hypoxia
• decreased ATP production by mitochondria (less oxygen)
  - mitochondrial swelling
  - decreased Na/K ATPase function due to less ATP
  - cell swelling due to lack of ion balance maintenance by ATPase
• Calcium influx into cells, activation of many pathways
  - phospholipases that degrade plasma and organelle membranes
• anerobic metabolism by glycolysis
  - process lowers pH in the cell (lactic acid)
  - pH can affect a host of things in the cell
• decreased protein synthesis (ribosomes detached from ER)
• loss of cytoskeleton
• membrane bleb formation
• deposition of lipids

Question 6

What is reperfusion injury? Describe how the damage is mediated?

Answer 6

• rapid reintroduction of oxygen into tissue may cause secondary damage
  - increased production of ROS (free radicals)
  - from mitochondria and leukocytes
  - release of transition metals from mitochondria
  - cytokine production worsens inflammation

Question 7

When is ischemic/hypoxic injury irreversible?

Answer 7

Cell damage is considered irreversible once:

• more calcium influx, pH changes, loss of membrane integrity
• under electron microscope: mitochondrial swelling, nuclear chromatin clumping

Question 8

What is are the differences between apoptosis and necrosis?

Answer 8

Necrosis: unregulated process of cell death

• 3 observable nuclear changes:
• Karyolysis: the chromatin of the nucleus fades due to the loss of the DNA by degradation.
• Pyknosis: the nucleus shrinks and the chromatin condenses.
• Karyorrhexis: the shrunken nucleus fragments to complete dispersal.
• produces inflammation

Apoptosis: programmed cell death

• important process for development, remodeling, immune response, response to injury
• does not produce inflammation
• clear chromatin condensation and nuclear fragmentation