34 - Lipid Mediators Flashcards
Arachidonic acid
Precursor for many bioactive lipids
Also called C20:4 (20 carbons, 4 double bonds), eicosatetraenoid acid.
How does the body get arachidonic acid?
From dietary poly-unsaturated fatty acids
Indirectly as linoleic acid, which is converted to arachidonic acid.
Directly as arachidonic acid
Type of fat that arachidonic acid is
Omega-6-polyunsaturated acid
How is arachidonic acid stored?
Stored esterified in membrane phospholipids (plasma, nuclear membranes)
How is arachidonic acid released from cell membranes?
Phospholipase A2 releases arachidonic acid.
Phospholipase A2 is activated by increased intracellular Ca2+ or ERK (extracellular receptor kinase)
Part of arachidonic acid pathway that is tightly regulated
Phospholipase A2 activation. If not controlled, can have excessive bradykinins and leukotrienes produced.
Component of many snake venoms
Phospholipase A2
Name for biologically-active metabolites of arachidonic acid
Eicosanoids
What determines eicosanoid type?
Which type of enzyme metabolises arachidonic acid
Enzymes that can metabolise arachidonic acid
1)
2)
3)
1) Cyclo-oxygenase I (COXI) - constitutively expressed
2) COXII - Inducible by inflammatory stimuli (EG: IFN)
3) Lipoxygenase (expressed in inflammatory cells, eosinophils, mast cells)
Effect of arachidonic acid metabolism by COXI
Physiological prostaglandin production
Effect of arachidonic acid metabolism by COXII
Patho-physiological prostaglandin production
Intermediate stage between arachidonic acid and stable prostaglandins?
Cyclic endoperoxidases (very unstable). These are quickly converted to stable prostaglandins by peroxidases.
Nomenclature of stable prostaglandins
Letter describes ring structure.
Number describes number of double bonds
PGE2 1) 2) 3) 4)
1) Relaxes vascular smooth muscle
2) Hyperalgesic
3) Pyrogenic
4) Angiogenic (wound healing, tumour growth)
Prostaglandins that are bronchoconstrictors
PGD, PGF2alpha
Site of action of prostaglandins
Very local.
Degraded by endothelial cells of pulmonary capillaries.
Unstable, don’t last more than a few minutes.
Main indications of NSAIDS
1)
2)
3)
1) Analgesic
2) Antipyretic
3) Anti-inflammatory
Effect of PGE2 on blood flow
Increases blood flow
Local mediators that increase vascular permeability
Histamine, bradykinin
Difference in hyperalgesia induced by bradykinins and prostaglandins
Bradykinins are directly painful.
Prostaglandins enhance sensitivity to pain, but aren’t painful in and of themselves
Long-term interaction between IL-1b and arachidonic acid pathways
1)
2)
1) IL-1b induces increase in bradykinin receptors,
2) Increased COXII, phospholipase A2 levels
Factor responsible for core temperature rise in fever
PGE2
PGE2 effects on the gut 1) 2) 3) 4)
1) Promotes blood flow (vasodilation)
2) Promotes angiogenesis
3) Increases mucus secretion
4) Reduces gastric acid secretion
How can chronic NSAID use lead to gastric ulcers?
PGE2 protects the gut by promoting blood flow (increased healing), increasing mucus secretion and reducing gastric acid secretion in the gut). NSAIDS inhibit PGE2 formation, so there is no more gastric protection by it
Characteristic chemical structure in prostaglandins
Cyclopentane ring
Prostacyclin effects
1)
2)
1) Vasodilator
2) Reduces platelet activation
Prostacyclin half life
Very short.
T1/2 is about 3 minutes
Thromboxane A2 effects
1)
2)
1) Increases platelet activation
2) Vasoconstrictor
Thromboxane A2 half life
Very short.
About 30 seconds
Two opposing factors controlling platelet aggregation
Thromboxane A2 and prostacyclin
Cells that produce prostacyclin
Endothelial cells
Cells that produce thromboxane A2
Platelets
Thromboxane A2 function in clotting
Platelets release thromboxane in a positive feedback loop.
The more platelets near each other, the more thrmoboxane is released, and the more vasoconstriction and platelet activation occur
Factor that promotes coronary artery disease
Thromboxane A2
Factor that protects against coronary artery disease
Prostacyclin
Another name for prostacyclin
PGI2
How does aspirin protect against heart disease?
1)
2)
3)
1) Aspirin covalently binds COX, inactivates it.
2) Endothelial cells can replenish COX as they are nucleated. Therefore they can continue releasing prostacyclin (takes a few hours to re-synthesise COX).
3) Platelets can’t replenish COX, as they don’t have a nucleus. Therefore can make more thromboxane for the rest of their lifespan (~8 days)
Effect of aspirin on lipoxygenase
Increases activity of lipoxygenase.
Therefore when aspirin is administered, there is an increase in anti-inflammatory arachidonic acid derivatives (‘aspirin-triggered lipoxins’)
Aspirin-triggered lipoxins
Analogues of normally-triggered lipoxins.
Generated from aspirin-mediated enhancement of lipoxygenase activity
Why are omega-three fatty acids considered beneficial to health?
Replace arachidonic acid derivatives with those from omega3 fatty acids.
These derivatives are converted to prostacyclin at the same level, but much less thromboxane A2 is produced.
How are leukotrienes formed?
1)
2)
3)
1) Arachidonic acid is metabolised by 5-lipoxygenase instead of COX.
2) 5-lipoxygenase converts arachidonic acid to 5-HPETE.
3) 5-HPETE converted to leukotrienes
5-lipoxygenase cell distribution
Only known to be made by inflammatory cells
5-lipoxygenase function
Only known function is inflammation
LTA4 1) 2) 3) 4)
1) Bronchoconstrictor
2) Vasoactive - leads to tissue oedema.
3) Implicated in asthma
4) Derived from 5-PETE.
Leukotriene B4
No direct action on smooth muscle
Promotes inflammation by attracting leukocytes
How do glucocorticoids work?
Induces annexin-1, which inhibits phospholipase A2
Leukotriene receptor antagonist
Montelukast
