Eicosanoids Flashcards
what are eicosanoids?
Eicosanoids are lipid derivatives
They are members of a class of compounds called autacoids
They have the following characteristics:
They are lipid mediators
locally synthesised and locally acting
They have varied functions, especially important in inflammation
They are not stored but made as required
Except those in semen, which causes contraction of uterine muscle
what are the 3 categories of eicosanoids?
There 3 categories of Eicosanoids:
Prostaglandins (PG)
Thromboxanes (TX)
top 2 are prostanoids ^^
Leukotrienes (LT)
what is step 1 in the biosynthesis of eicosanoids?
All eicosanoids are synthesised from arachidonic acid (4 double bonds)
NB: eicosapentaenoic acid is the source of eicosanoids in fish (5 double bonds)
Arachidonic acid is esterified to the phospholipid bilayer of the cell membrane
Step 1:
Arachidonic acid is first freed from the lipid bilayer of cells by phospholipase A2 (and PLC)
The stimuli for this step (which cause phosphorylation of these enzymes) is either:
Cytokines: Released in inflammation. They activate GPCRs which then goes on the activate the enzymes.
Mechanical stimulation: causes Ca2+ influx that activates enzymes
This is the mechanism for endothelial cells
what is step 2 in the biosynthesis of eicosanoids?
explain 1st pathway
The next step has 2 alternative pathways:
Cyclooxygenase (COX) pathway:
Prostanoids (PG + TX) are synthesised with this pathway
Enzymes involved:
COX1:
Constitutively active
Found in most cells (therefore most cells can produce Prostanoids)
COX2:
Inducible (expressed when needed e.g. during inflammation)
Found in inflammatory cells.
This enzyme that is particularly important for producing Prostanoids during inflammatory processes.
These Cyclooxygenase enzymes convert arachidonic acid to cyclic endoperoxides.
This intermediate product of this pathway is found in most cells
Then depending on the enzymes present within the cell one of two end products are produced (both have two double bonds)
Presence of Prostacyclin synthase (found in endothelial cells)
PGI2
Presence of Thromboxane synthase: (found in platelets)
TXA2
Immune cells have mix of enzymes to produce mix of Prostanoids.
how do drugs modulate the COX pathway – to achieve anti-inflammatory effect?
The following drugs are anti-inflammatories:
Non selective NSAIDs 🡪 inhibit both COX1 and COX2, so they therefore inhibit the production of Prostanoids.
Example: Aspirin (irreversible inhibition) and Ibuprofen (reversible inhibition)
Selective NSAIDs 🡪 inhibit just COX2
Example: Celecoxib (Side effect: risk of heart attack)
Eliminates side effects that result in inhibition of COX 1
Glucocorticoids
Inhibit the expression of COX2
Induce expression of annexin-1. This protein inhibits PLA2 (enzyme responsible for freeing arachidonic acid from the membrane). This therefore ↓ free arachidonic acid
NB: this reduces both Prostanoids and leukotrienes.
what is step 2 in the biosynthesis of eicosanoids?
explain 2nd pathway
Lipoxygenase pathway:
This pathway synthesises leukotrienes (LT)
The main enzyme is 5-lipoxygenase
It acts on the arachidonic acid to produce HPETE.
This is then converted (via enzymes) into:
LTB4 (four double bonds)
Cysteinyl leukotrienes: LTD4 , LTC4 (four double bonds) (main class)
These are produced in eosinophils, mast cells, macrophages (immune cells participating in inflammation)
how do drugs modulate the Lipoxygenase pathway?
Anti-inflammatories:
Zileuton 🡪 inhibitor of 5-Lipoxygenase (used to treat asthma)
Glucocorticoids:
Induce expression of annexin-1 (same effect above)
what is the Action of Prostanoids?
Prostaglandins (PGI2):
Contribute to inflammatory response
Cause Vasodilation
Raise body temperature set point (action at hypothalamus)
Enhance activity of peripheral sensory nerves
Particularly sensitise nociceptors to substances that cause pain e.g. bradykinin
Other effects
Act on muscles causing contraction/relaxation
E.g. myometrium, GIT, Bronchi.
Stimulate Gastric mucous secretions (protective to stomach lining)
Inhibit Platelet aggregation
This is conjunction with vasodilation means it has anticlotting effects
Thromboxane (TXA2)
Actions (opposite to PGI2):
Vasoconstriction
Bronchoconstriction
Stimulate platelet aggregation
Vasoconstriction with stimulation of platelet aggregation means it is a compound that promotes clotting
what is the action of leukotrienes?
They have an important role in inflammation:
Chemotaxis: attracting immune cells (neutrophils and macrophages) to site of Leukotrienes production
Stimulate the proliferation of immune cells
Stimulate the release of cytokines
They have important role in inflammatory diseases (Rheumatoid arthritis; Ulcerative Colitis; Psoriasis)
Other effects:
Cause Bronchoconstriction mucus secretion (important)
Vasodilation/vasoconstriction
what is the actions of Eicosanoids mediated by receptors?
Eicosanoids are locally produced and are locally acting 🡪 they act on adjacent cells
They bind to GPCR on the membrane of the cells.
There are 5 types of Prostanoid receptors:
IP receptor (ligand: PGI2) 🡪 activates cAMP/Protein kinase A pathway
TP receptor (ligand: TXA2) 🡪 activates PLC/Protein Kinase C
There are three types of LT receptors 🡪 act via PLC/PKC pathways
what drugs modulate eicosanoids receptors?
Receptor antagonists:
Montelukast is an antagonist for CystLTs receptors 🡪 used in asthma (inhibit bronchoconstriction)
Receptor agonists:
Epoprostenol is an IP receptor agonist 🡪 used to manage pulmonary HT; (given by infusion)
Misoprostol is an EP receptor agonist 🡪 used to treat gastric ulcer (as it supresses HCl production and increases the production of mucus)
It can also cause contraction of uterine smooth muscle so causes induction of labour
how do prostanoids cause thrombosis??
Prostanoid
Platelets contain COX-1 🡪 Produce TXA2
TXA2 is an Aggregatory Agent (aggregates platelets) and is also a vasoconstrictor.
Therefore it promotes formation of clots.
Endothelium contains COX-1 (COX-2 in some people*) 🡪 Both produce PGI2
PGI2 is an Anti-aggregatory agent and vasodilator
It therefore prevents clot formation
* Reason why specific COX-2 inhibitors can cause heart attacks
Therefore, if you are taking a COX-2 inhibitor (Selective NSAIDs) you are inhibiting production of PGI2 but not effecting production of TXA2
So, you are leading to destabilisation of balance of those two compounds
You have more TXA2 relative to PGI2 🡪 increases risk of clot formation 🡪 increases risk of heart attack.
Therefore, balance is important 🡪 PGI2 dominant 🡪 prevent clot formation
In atherosclerosis TXA2 becomes dominant
how to prevent thrombosis using fish oil?
Fish oil (contains eicosapentaenoic acid)
If you eat a lot of fish (or fish oil supplements) then you have reduced incident of heart attack and strokes.
This is because EPA is used to make Prostanoids instead of arachidonic acid
Therefore because of extra double bond in EPA you get:
TXA3 (not TXA2) 🡪 weaker aggregator (less likely to form clots)
PGI3 (not PGI2) 🡪 more potent inhibitor of aggregation of platelets (less likely to form clots)
Fish has been shown to improve survival following myocardial infarction due to reduced blood clots.
No evidence beneficial impact on people who have not had heart attack.
how to prevent thrombosis using aspirin?
low dose! (prevents clots)
The action of Aspirin preventing clots depends on its irreversible block of COX1 enzyme
Platelets:
COX-1 enzyme blocked permanently (as they have no nucleus)
This is until new platelets are synthesised
Therefore, this inhibits TXA2 synthesis
Endothelial cells:
COX-1 resynthesised in endothelial cells (as they have a nucleus).
For a short while after the low dose of aspirin the COX-1 enzyme in endothelial cells is inactivated.
But then as this low dose wears off the the endothelial cells can make new enzymes and make PGI2 (between doses)
The low dose give endothelial cells opportunity to recover to produce PGI2.
Now you now have more PGI2 than TXA2 (this has antithrombotic impact)
what are the roles of Eicosanoids in Respiratory System?
Prostanoids 🡪 bronchoconstriction/bronchodilation (little clinical relevance)
LTs:
bronchoconstriction (clinically relevant)
Mucous production
Chemotaxis
LTC4/D4 – 1000x more potent than histamine in causing bronchoconstriction
how is LT relevant to Allergic Asthma?
Antigen (pollen, dust) binds to IgE antibodies which are found on mast cells
Intermediate phase: binding results in degranulation of mast cells and release of LT++, Histamine, Interleukins.
Late phase: Recruitment/activation of eosinophils and Th2 lymphocytes 🡪 major basic & cationic proteins are released 🡪 cell damage
