Flashcards in L10. Lipid Mediators Deck (30):
What is arachadonic acid?
Is a 20 carbon molecule (omega 6) that is relatively inactive polyunsaturated fatty acid.
It requires conversion into other active lipids (precursor).
What is meant by Omega 6?
Means that the first double bond of the polymer is at Carbon 6
What is the major polyunsaturated fatty acid acquired in the diet?
Arachadonic acid is ingested from the diet but the major PUFA is linoleic acid C8:2 which is converted into arachadonic acid in the body.
How are polyunsaturated fatty acids from the diet transported in the body?
They are carried in the circulation by travelling albumin: important to ensure it doesn't just sit anywhere
Describe the storage of polyunsaturated fatty acids (arachadonic acid)
Arachadonic acid is esterified at the C2 position into the phospholipids of cellular and nucleic plasma membranes
Why is it important to keep arachadonic intracellular levels low and under tight regulation?
To ensure that the cellular mechanisms don't inadvertantly convert arachadonic acid into its highly reactive products
How are the arachadonic acids liberated from the plasma membrane when needed?
The enzyme phospholipase A cleaves the arachadonic acid at the C2 position freeing arachadonic acid
How are the levels of phospholipase A2 controlled? (3 mechanisms) and the timing of these
Acute: Increases in intracellular calcium increase the activiy of Phospholipase A (small amounts)
Within seconds to minutes
Also an extracellular kinase (Brk) can also regulate it
Chronically: the abundance of the enzyme itself (build up over time) leads capacity to release arachadonic acid to change.
What are the biologically active metabolites of arachadonic acids called?
There are many different types of eicosanoids (bioactive products of arachadonic acid) - What determines which one is formed?
The CELL TYPE
Which regulates the expression of different enzymes which mediate the pathways that happen to create the different eicosanoids and the different proportions of them.
List the steps of arachadonic acid metabolism into its products
1. COX conversion into cyclic endoperoxides
2. Isomerase action on the cyclic endoperoxides for form prostaglandins
What is the difference between COX 1 and COX 2
Constitutively expressed in most cells (house keeping) enzyme that ensures prostacyclin is made constantly by vascular endothelial cells to keep blood flowing through.
Different promotor region sensitive to factors: growth or inflammation (Eg. IL-1) with response elements that responds to NFkB and Protein 1 complexes (inflammogens)
- COX 2 expression increases the capacity to make bioactive products and occurs within hours of the stimulus and can persist for several days
What is an alternative (lipoxygenase) pathway following from arachadonic release?
Arachadonic acid can acted upon by the enzyme 5-lipoxygenase into 5HPETE which then becomes LTA4.
LTA4 leads to the the cysteinyl leukotrienes while the LTB4 (also from LTA4) is an inflammatory mediator that recruits inflammatory cells.
This is important in asthma and allergy
What determines whether the pathway diverts to lipoxygenase or cycloxygenase?
Lipoxygenase has a limited expression/distribution. Only highly expressed in inflammatory cells (mast cells, eosinophils and neutrophils) and so are SELECTIVELY ACTIVATED during inflammation (not active physiologically).
What are the 'stable' prostaglandins and what determines which ones are present? How long do they last?
PGE2, FGF2 and PGD2
Determined by the relative abundance of different isomerases
Lsat 2-5 minutes (work locally and thus actions are controlled)
What is the main action of the stable prostaglandins?
PGE2 - relaxes VSMCs (vasodilation), hyperalgesic (sensitises to pain), pyrogenic (fever) and angiogenic (wound healing/tumor growth)
FGF and PGD2 are bronchoconstrictors
What are the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Anti-inflammatory drugs (both acute and chronic) that act on COX (ie. inhibit prostaglandin formation)
- reduce redness and oedema
What is meant by the synergy of autocoids? (PG and bradykinin)
PGE2 and Histamine and Bradykinin are all able to increase blood flow and vascular leakage and pain. So when they are all released locally: there is a major synergistic inflammatory reaction.
How is the synergy of autocoids affected in chronic states?
It is elevated much further.
Chronic inflammation can lead to the overproduction of IL-1B which leads to the expression of more BK1 receptors.
This increases the PGE2 productions 100-1000x
What are the housekeeping roles of PGE2?
Promotes blood flow
Secretion of mucous
Reduction of gastric acid secretion
What is the disadvantage of chronic NSAID use?
Lose the housekeeping roles of PGE2: especially leading to a loss of gastro-protection and stomach ulceration
What is the relationship between prostacyclines and thromboxane?
They are a yin and yang balance opposing each other and the relative abundance of the two determines the actions
How are prostacyclines and thromboxane formed?
From arachadonic acid the cyclic endoperoxides are converted into these depending on the isomerase concentrations and the CELL TYPE
What is prostacyclin (PGI2) and where is it made?
Expressed by ENDOTHELIAL CELLS
Is chemically unstable (3 minute half life)
Acts to reduce platelet activation and promote vasodilation which promotes blood flow and protects against coronary artery disease
What is thromboxane (TXA2) and where is it made?
Expressed by PLATELETS (and macrophages)
Highly unstable (30 seconds)
Increase platelet activation and promote vasoconstriction thus favours clot formation
What is aspirin?
A widely used NSAID (cheap and effective)
Covalently binds to an active site of COX and inhibits it
What is meant by the "cardioprotective" effect of aspirin?
At low dosages, the aspirin only act on the gastric and portal platelets and not on the endothelial COX pathways. This means that circulating platelets (8-10days) are unable to produce thromboxane A2 and hence don't clot = Cardioprotective effects
What is the pharmacodynamics of aspirin?
Oral dose is absorbed from the stomach and reaches a high concentration in the gastric circulation
It is subject to 1st pass metabolism by the liver
But in the portal system it acts on platelets (and in gastric system) and since platelets have no nucleus they cannot remake COX
Thus the COX inhibited platelets circulate to the rest of the body and cannot cause coagulation - because it is a relatively localised effect the endothelial cells that produce PGI2 from COX are protected
What are aspirin-triggered lipoxins?
During inflammation there is a unique mix of lipoxygenases that adds a hydroxyl group onto arachadonic acid making molecules that are anti-inflammatory (inflammatory resolving).
Aspirin produces analogues of these lipoxins to aid in inflammation resolution.