Eicosanoids & Lipid Mediators: Prostaglandins, Thromboxane, Leukotrienes Flashcards
COX
cyclooxygenase enzyme (COX-1 and COX-2), contains iron, needs O2 co-factor, converts AA –> PGH2
NSAID
non-steroidal anti-inflammatory drug
PUFA
polyunsaturated fatty acid
Eicosanoids
Lipid mediators derived from 20 carbon PUFA, includes prostaglandins, thromboxane, leukotrienes
Eicosanoids are autacoid mediators
Omega 6 PUFA
arachidonic acid –> 2-series prostaglandins & thromboxane
Omega 3 PUFA
EPA (eicosapentanoic acid) –> 3-series prostaglandins & thromboxane
ARACHIDONIC ACID
REMEMBER ARACHIDONIC ACID – is the substrate for COX
Eicosanoid Biosynthesis
- Arachidonic acid is liberated from the PM following a stimulus
- COX enzymes transform AA into PGs or Tx
- PGs exit cells and bind to receptors to transmit signals to cells
Arachidonic Acid Cascade
- Phospholipase A2 releases AA
- COX converts AA to PGH2
- Tissue Isomerases convert PGH2 to PGD, PGE, PGF, PGI and TxA2
- PG dehydrogenase or hydrolysis
COX
Cyclooxygenase enzyme contains iron and requires O2 co-factor to convert AA to PGH2
Eicosanoids are made, not stored
Is not a form of paracrine signaling (hormones, steroids)
PG, Tx synthesis acts only after a stimuli activates phospholipase A2
Phospholipase A2 induces AA to come out of PM
Limiting reagents of PG/Tx synthesis
O2 and AA, auto-inactivation of COX enzyme, metabolic degradation of PGs and spontaneous hydrolysis of Tx and PGI2
Can find COX in all cells except
RBC
Eicosanoids mediate autocrine and paracrine signaling nearby the cells that make them.
Unlike hormones, autacoids are short-lived. PGDH limits their accumulation and circulation via the blood stream.
Autocrine signaling
Cell can make PGs/Tx and respond to PGs/Tx binding to receptor
Paracrine signaling
Cell B lacks enzymes to make PGs or Tx, responds to PG/Tx made from cell A
Not every cell can make every prostaglandin
Not every cell has every membrane receptor
Prostaglandin and Thromboxane Receptors are G-proteins (7 layer)
Gs and Gq stimulatory G-proteins
Gs associated with AC (adenyl cyclase –> cAMP)
Gq associated with PLC (phospholipase C –> DAG/IP3 –> Ca2+)
PGE2 (EP) and PGI2( IP) associate with Gs and AC
PGF2 (FP) and TxA2 (TP) associate with Gq and PLC
Receptors: EP2, EP4 and IP
RELAX smooth muscles
Receptors: FP and TP
CONSTRICT smooth muscles
Phospholipase A2 (PLA2)
Liberate AA (arachidonic acid) from phospholipids
Phospholipase C (PLC)
Liberates IP3 & DAG from phospholipids (PIP2)
PGI2 name
Prostacyclin
Important to have balance in constricting and relaxing eicosanoids
Or else you can have effects like angina pectoris
COX-1 vs COX-2
COX-1 is constitutive (always expressed)
COX-2 is inducible
COX-1 functions
Responds to physiological stimuli to regulate physiological functions of PGs and Tx
Has role in gut, repro and development
NSAIDS cause a decrease in PG
Overuse of NSAID can cause gastric ulcer
PGE2 in gut
Too little = gastric ulcer
Too much = diarrhea
PGs in repro
Too little = delayed birth
Too much = pre-mature labor, birth
PGs in development
PG keeps ductus arteriosus patent in fetus, NSAIDs help close it
At birth, PGE2 is removed, ductus arteriosus closes
COX-2 exception
COX-2 is normally expressed and plays a prominent role in kidney physiology
COX-2 expression
Prominent role responding to pathological stimuli (inflammation, cancer)
COX-2 in kidney
Deficit of PGs in kidney leads to Na/H2O retention (edema) and hypertension
Cardinal signs of inflammation
- Vasodilation, decreased platelet aggregation
- Increased permeability
- Increased temperature
- Increased sensitivity to pain
Redness, swelling, pain
COX-1 and COX-2, PGs and inflammation
- Inflammation stimulates AA release
- COX-1 converts AA into PGE2 (increases)
- PGE2 causes redness, swelling, pain
Induced COX-2 follows same pathway and AMPLIFIES symptoms
Platelets
- No nucleus
- Generate TxA2 (thromboxane)
- Constrict blood vessels and amplify platelet aggregation
Endothelium
- Cells that line blood vessels
- Make PGI2 (prostacyclin)
- Relaxes blood vessels and inhibits platelet aggregation
How does body regulate ratios of PGs and Tx?
By varying the levels of isomerases/synthases among different tissues
Different cells can make different eicosanoids
Hemostasis
Maintaining blood flow
Collagen stimulates TxA2 formation by platelets
Clotting mechanism, reaction to severed blood vessels
Platelet aggregation pathway
PLA2 activation –> AA –> COX-1 –> PGH2 –> TxA2 –> TP receptors –> signal transduction
PGI2 and TxA2 work in concert with each other
Prevent systemic effect, when TxA2 is in action, PGI2 is working downstream of it
COX-2 can be induced by endothelial cells
COX-2 induction may amplify PGI2 synthesis
COX-2 cannot be induced by platelets
No nucleus, no de novo transcription of proteins (unlike endothelial cells)
Arachidonic Acid rich in beef, EPA rich in fish
EPA –> TxA3 which is a weak vasoconstrictor, weak platelet aggregation
Omega-3 PUFA reduce inflammatory processes, vasoconstriction, platelet aggregation
Leukotrienes made from same pathway, substitute COX for 5-LOX (lipoxygenase)
Leukotrienes named because they are made by leukocytes and have a conjugated triene in structure
Leukotriene A4 = LTA4
No receptor
Leukotriene B4 = LTB4
BLT1,2 receptor
Leukotriene C4 = LTC4
CysLT1, 2 receptor
Leukotriene D4 = LTD4
CysLT1 receptor
Leukotriene E4 = LTE4
CysLT receptor
TEST ADVICE
Leukotrienes are always an incorrect test question answer
