Eicosanoids Flashcards
COX1 vs COX2
COX1 is more sensitive than COX2
aspirin reacts irreversibly and other NSAIDs are reversible
PGI synthesis
MECHANICAL R on outside of endothelial cell senses blood flow
phospholipid (Phospholipase A2) –> arachidonic acid –> (COX1 or 2 + O2 + Glutathione-SH) –> PGH2 (PGI synthase) –> PGI (secreted)
prostacyclin
endothelial cells synthesize
inhibits clotting
TXA synthesis
arachidonic acid (COX1 or 2, O2, glutathione-SH) –> PGH2 –> (TXA synthase) –> thromoxane
stimulate clotting
synthesized by platelets
PGH2
from COX1/2 action on arachidonic acid
precursor to prostacyclin and thromboxane
phosphlipase A2
inactive when cytosolic
extracellular signal signals (blood flow) - signalling pways - Ca 2+ and phosphorylation - activate phospholipase A2 ad make it active in nuclear and ER membrane
cuts phospholipid into arachidonic acid in ER or nuclear membrane
normal conditions - no blood clotting
PGI>TXA
PGI is being made (mechanoreceptor –> phospholipase A2) - inhibit platelet aggregation
TXA is not made (no signals to platelet for clotting) so not positive signaling
no changes
PGI signaling
into platelet through IP receptor
Gs singling - increase cAMP
TXA signaling
out of cell and into same/close cell
Gq signaling - stimulate clot formation
PGI and TXA after a wound
mechanoreceptor not on - no phospholipas A2, no PGI, no inhibitory signaling to platelet
collagen and thrombin –> phospholipase A2 –> TXA2, secreted and back in –> Gq signaling - stimulate platelet aggregation
Vasodilation
PGI –> smooth muscle cell IP –> Gs signaling –> vasodilation (none after a wound)
vasoconstriction
TXA2 out of platelet, into smooth muscle cell TP R –> Gq signaling –> vasoconstriction (for clotting after a wound)
MLCK
myosin light chain kinase
inhibited by IP - camp (Gs)
activated by TP - PIP2 –> IP3 –> Ca 2+
low dose aspirin effects
irreversibly inhibits cox1, no effect on cox2
most cells have rapid turn over of cox, so aspirin has little effect on most cells
platelets don’t make proteins, no cox turnover - last 10 days, when block it in platelets
irreversibly inhibit COX1 and decrease plately aggregation and vasoconstriction, no long term effects on endothelial cells
PGE
promotes pain, fever, inflammation, COX-2 is strongly induced during injury, infection, inflammation
PGD
promotes inflammation
aggrevates asthma and allergy
cox2 strongly induced during injury, infection, inflammation
COX-1
housekeepng enzyme
in all cells
expression not highly regulated
required for homeostasis
NSAIDs hit COX1 harder than COX 2
high doses of aspirin to reduce pain and inflammation –> drastic reduction of COX1
COX2
emergency enzyme
in selected cell types
expression is highly inducible, stimulated by need in response to injurt
mediator of pain and inflammation
less sensitve to NSAID’s than COX1
low dose aspirin
anti-throbotic
primarily inhibits COX1 and reduces platelet TXA2 production
moderate aspirin
anagesic, antipyretic, mild antiinflammatory
significantly affects COX1 and 2 throughout the body
high dose aspirin
anagesic, antipyretic, antinflammatory
drastically affects cox 1 and 2 throughout the body
Aspirin and GI symptoms
mucus plug and bicarbonate separates tisses from acid,
PGE - helps repair holes in lining increases bicarbonate release, mucus production and decreases acid production in stomach, made in stomach cells
take synthetic PGE or proton pump inhibitor with aspirin
childbirth
PGE promotes uterine contractions
Gs Giand Gq - PG can hae different effects in different tissue
leukotrienes
mediators of inflammation
increase vascular permeability
increase chemotaxis of immune cells
increse immune cell activation and production
powerful bronciocontstrictors
smooth muscle contraction
leukotriene signaling
singal via Gq (incrase IP3 –> increase Ca2+)
Gi receptors (decrease cAMP)
lead to smooth muscle contraction
