Eicosanoid Signaling

Question 1

What are autocoids?

Answer 1

Substances that are produced locally, act locally, and are rapidly metabolized locally

AKA paracrine

Question 2

Eicosanoids mediate what types of processes?

Answer 2

A variety of physiological and pathophysiologcal processes:
- Asthma
- Allergy
- Inflammation
- Clotting
- Immunity
- Pain
- Fever

Question 3

Where are precursors to eicosanoids stored?

Answer 3

In the inner layer of the plasma membrane - C20 fatty acids stored at C-2 of membrane phospholipids

Arachidonic acid most prevalent, but other fatty acids are present

Question 4

How is arachidonic acid freed from the plasma membrane?

Answer 4

• Phospholipase A2 acts on phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol to release arachidonic acid
• Phospholipase A2 cleaves arachidonic acid, whic is then used as a substrate for the cyclooxygenase, lipoxygenase, and epoxygenase pathways

Question 5

What is produced by the cyclooxygenase pathways?

Answer 5

Prostaglandins, prostacyclin, and thromboxane

Question 6

What is produced by the lipoxygenase pathways?

Answer 6

Leukotrienes and lipoxins

Question 7

What doe NSAIDs target?

Answer 7

COX-1 and COX-2

Question 8

Describe the properties of the COX-1 enzyme.

Answer 8

Expression: constitutive
Tissue location: ubiquitous expression
Role: protection and maintenance functions
Induction: no induction

Question 9

Describe the properties of the COX-2 enzyme.

Answer 9

Expression: inducible; not normally present in tissues; constitutive in parts of nervous system
Tissue location: Inflamed and activated tissues
Role: proinflammatory and mitogenic functions
Induction: induced by LPS, TNF-alpha, IL-1, IL-2, EGF, IFN-gamma

mRNA rises 20- to 80- fold upon induction

Question 10

What determines where various PGH2-derived products are biosynthesized?

Answer 10

Tissue-specific enzyme expression:
- Prostacyclin synthase in endothelium
- Thomboxane synthase in platelets
- PGE2 isomerase in macrophages, mast cells
- PGF2alpha reductase in uterus, lungs
- PGD2 isomerase in brain, mast cells

Question 11

How can prostaglandins impact pain perception?

Answer 11

• COX-2 induction by inflammatory mediators increases synthesis of PGE2
• PGE2 sensitizes sensory neurons in the periphery by reducing threshold for firing
• PGE2 can also sensitize central neurons involved in pain perception

Question 12

Why were selective COX-2 inhibitors developed as “safer” alternatives to conventional NSAIDs, and why were they withdrawn from the market?

Answer 12

• The rationale was that they could block inflammation induced-prostanoid synthesis but maintain constitutive synthesis
• Most were withdrawn due to risk of heart attack and stroke

Question 13

What are the CV effects of thromboxane?

Answer 13

• Platelets produce thromboxane in response to blood vessel injury
• Thromboxane promotes aggregation of platelets
• Thromboxane is also a vasoconstrictor

Question 14

What are the CV effects of prostacyclin?

Answer 14

• Endothelial cells synthesize PGI2
• PGI2 opposes the effects of thromboxane
• The balance of thromboxane and PGI2 controls the extent of vasoconstriction

Question 15

A diet rich in omega-6 fatty acids would tilt towards the effects of which prostaglandin?

Answer 15

Towards thromboxane - platelet aggregation/vasoconstriction

Question 16

A diet rich in omega-3 fatty acids would tilt towards the effects of which prostaglandins?

Answer 16

Towards PGI3 - reduced platelet aggregation/vasodilation

Question 17

How can prostaglandins induce fever?

Answer 17

Pyrogenic agents increase the synthesis of COX-2 and release of PGE2 in the hypothalamus, which results in the activation of a sympathetic response that increases body temperature

Question 18

Unlike other ARA derived eicosanoids, lipoxins are what?

Answer 18

Anti-inflammatory agents