Lipid Mediators Flashcards
What is the structure of arachidonic acid?
- aka eicosatetraenoic acid
- 20 carbons, 4 double bonds
- omega-6 FA (1st double bond is on position 6 from methyl end)
- **not biologically active, needs to be transformed to be bioactive**
From where is arachidonic acid mainly derived?
- dietary lineolic acid C18:2 (PUFA)
How is arachidonic acid stored?
- esterified in membrane phospholipids (plasma, nuclear)
- because it can be convereted into bioactive metabolites that are not controlled by homeostasis
- esterified to various phospholipid types
- choline
- phosphatidylethanololine
- usually at SN2 carbon of the glycerol backbone
- activated by phospholipase A2
How is esterified arachidonic acid liberated from glycerol?
phospholipase A2 activity
What triggers activity of phospholipase A2 (and therefore increases arachidonic acid concentration)?
- increases in intracellular calcium
- other versions of phospholipases are released in a pro-inflammatory manner e.g. rheumatoid arthritis
- snake venom contains ++PPLA2
What are eicosanoids?
biologically active metabolites of arachidonic acid
Metabolism of arachidonic acid occurs by
- cyclo-oxygenases:
- COX-1 = AA –> physiological prostaglandins (PGs) and prostacyclin
- COX-2 = induced in any cell by inflammatory (LPS, TNF, IL-1) or growth stimuli, ++capacity to produce PGs, can lead to pathophysiological overproduction
- [5-] lipoxygenase:
- expressed in inflammatory cells (eos, macros, neu, baso, mast)
- make leukotrienes
- expressed in inflammatory cells (eos, macros, neu, baso, mast)
Cyxlo-oxygenase metabolism of arachidonic acid yields
- highly unstable cyclic-endoperoxides
- converted rapidly into stable PGs by isomerases
- prostaglandin E2, H2, F2
What makes prostaglandins local mediators?
- rapidly metabolised by endothelium in the pulmonary circulation (single pass)
- tf never make it to systemic circulation, tend to work locally
What is the function of PGE2?
- vascular smooth muscle relaxation
- vasodilation (decreased BP), natiuration
- hyperalgesic - increased sensitivites to painful stimuli
- pyrogenic (fever-inducing)
- angiogenic (blood vessel formation in wound healing, tumour growth)
What is the function of PGF2a and PGD2?
bronchoconstriction
Why are NSAIDs related to gastric ulceration?
- NSAIDs inhibit PGE2 production to decrease pain (algesia)
- PGE2 functions in angiogenesis of wound healing, and tf healing of ulcers
NSAIDs are
cyclo-oxygenase inhibitors (anti-inflammatory drugs)
What are the indications for NSAIDs?
- anti-inflammatory: acute and chronic conditions e.g. rheumatoid arthritis, gout (not aspirin)
- analgesia: headache, menstrual pain, MSK pain
- antipyretic: fever (usually Paracetamol, aspirin contraindicated by adverse effects)
What are the major adverse effects of NSAIDs?
gastric irritation/ulceration
In inflammation, prostaglandins are involved in
vascular component: vasodilation
produces the heat of inflammation, predisposes to oedema by other mediators (histamine, bradykinin)
What causes the sensation of pain, and how is it exacerbated?
- bradykinin produces pain, some vasodilation
- PGE2 increases sensitivity to pain, plus local reddening through vasodilation
How is pain blocked?
- analgesics to block bradykinin receptors
- removal of PGE2 to remove the increased sensitivty of pain (NSAIDs)
What happens to PGE2 in chronic pain?
- chronic inflammation induces IL-1beta:
- +BK1 (bradykinin) receptors
- +COX-2 and PLA2
- tf much more PGE2 is produced
- tf getting increased pain receptors and increased sensitivity to pain
How does PGE2 cause fever?
- inflammation induces maco activation
- get cytokine production (IL-1)
- IL-1 travels via circulation to the hypothalamus (outside BBB)
- IL-1 induces COX to overproduce PGE2
- PGE2 acts via cAMP to increase the temperature set point, causing fever
What are the gastro-protective roles of PGE2?
- promotes blood flow by vasodilation, maintains oxygenation
- promotes angiogenesis (wound healing)
- increases mucous secretion
- reduces gastric acid secretion
Cyclic endoperoxides are converted to
- products of AA + COX
- isomerases convert CEs into:
- prostaglandins: PGE2, PGD2, PGFa
- prostacylcin: PGI2
- thromboxane A2
How is prostacyclin produced?
- phospholipase A2 liberates arachidonic acid from esterified stores in membrane phospholipids
- COX converts AA to cyclic endoperoxides
- isomerase converts CE to prostacyclin
How is thromboxane A2 produced?
- phospholipase A2 liberates arachidonic acid from esterified stores in membrane phospholipids
- COX converts AA to cyclic endoperoxides
- isomerase converts CE to thromboxane A2
Prostacyclin is produced by
endothelial cells
What is the function of prostacyclin?
- reduces platelet activation
- vasodilator via cAMP at IP (prostacyclin receptors) in the vascular smooth muscle
- prevents coronary artery disease by preventing atherosclerotic deposition
Thromboxane A2 is produced by?
platelets
What is the function of thromboxane A2?
- opposes prostacyclin
- increases platelet activation via TP receptors
- causes vasoconstriction
- promotes coronary artery disease (plaque deposition)
What is unique about the mechanism of aspirin to other NSAIDs?
it binds irreversibly to the active site of cyclo-oxygenase, inhibitin its activity
What is the mechanism of low-dose aspirin treatment in coronary artery disease?
- platelets in the GIT circulation are exposed to high [aspirin] that inhibits their COX function
- aspirin binds irreversibly to COX, inhibiting the enzyme
- platelet has no nucleus tf cannot regenerate COX
- [aspirin] is lower systemically and the endothelium can regenerate COX within hours
- tf PGI2/TXA2 ratio is increased in favour of PGI2; thromboxane and tf clotting is impaired
What is the exception to COX inhibition by aspirin?
- COX-1 is inhibited by COX-2 retains ability to act on arachidonic acid, but at the 15th position, generating 15-epi-lipoxin-A4 and 15-epi-lipoxin-B4, epimers of endogenous lipoxins A4 and B4
- epi-lipoxins function similar to endogenous lipoxins, that promote resolution of inflammation by directing macrophages to phagocytose dead cells and halting neutrophil infiltration
- they may explain some of the added benefits of aspirin in inflammation over other NSAIDs
What are lipoxins?
- icsonoids, derived from arachidonic acid
- produced in inflammation by lipoxygenases, epithelial cells, and leukocytes
- anti-inflammatory/pro-resolution function
- signal macrophages to dead cells for phagocytosis
- switch off neutrophil invasion
- receptor is formyl-peptide receptor 2 (FPR2)
What are the dietary PUFAs?
poly-unsaturated fatty acids:
- omega 6:
- linoleic acid (C18:2) –> AA (20:4)
- omega 3:
- eicosapentaenoic acid/benefishoil (20:5)
- docosahexanoic acid (C22:6)
What is different in the metabolism of omega-3 fatty acids from metabolism of omega-6 arachidonic acid?
- 3-series of prostaglandins and prostacyclins (instead of 2) - extra double bond
- PGH3 is not a good substrate for thromboxane synthesis
- PGI3 retains biological activity
- tf metabolism of omega-3s favours prostacyclin and therefore reduces incidence of cornary artery disease
How do omega-3 fatty acids favour decreased incidence of coronary artery disease?
- their metabolism leads to production of 3-series prostaglandins and prostacyclins
- PGH3 however is a less functional substrate for thromboxane synthesis than PGH2
- PGI3 retains same bioactivity as PGI2
- tf metabolism of omega-3 favours prostacyclin, reducing clotting factors and therefore decreasing incidence of coronary artery disease
What is the function of 5-lipoxygenase?
- inflammation
- acticated by increased intracellular calcium by stimuli produced in infection, allergic response, or other inflimation e.g. trauma
What are the products of arachidonic acid metabolism by 5-lipoxygenase?
- 5-HPETE, the precursor to leukotriene A4 (LTA4)
- LTA4 is converted to LTB4 or LTC4
- LTC4 is precursor to D4, E4
What is the significance of leukotriene E4?
- causes bronchospasm in airways in asthma
- causes leaky vessels
- blockage of cysteinyl-leukotrienes like E4 is a target for asthma medication
Leukotriene B4
- promotes inflammation by attracting lymphocytes
- currently no therapeutic targets
