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
leukotriene production
arachidonic acid (5-lipoxygenase) –> leukotrienes
Zyflo/Zileuton
inhibits 5-lopoxygenase - leukocytes can’t make leukotrienes, decrease asthma and allergy symptoms
on leukocytes and mast cells
FLAP
holds everything together in membrane - phospholipase A2 and 5 lipoxygenase - make leukotrienes
LTB receptors
leukotriene receptor
promote inflammation
on immune cells (neutrophils)
CysLT
leukotriene receptor that promotes inflammation and bronchioconstriction
immune cells (mast cells)
and smooth muscle
sinulair inhibits
Singulair
cysLT receptor antagonist on leukocytes
cysLT - promotes inflammation and bronchioconstriction
leukocytes
secrete histmine and leukotrienes
stimulated by other leukotrienes
Aspirin induced asthma
block COX branch so increase arachadonic acid making leukotrienes
arachidonic acid shunt
extra amount of leukotrienes prduced
Lipoxins
produced by epithelial cell-leukocyte interactions
require cell to cell interactions
resolve inflammation
block cysLT receptor (inhibits inflammatory leukotriene action)
activates lipoxin receptor - inactivates inflammatory cell and stim phagocytosis of dead cellls and would healing
arachidonic acid (15-lipoxygenase) - 15 hydroxyarachidonic acid in epithelial cell
goes to leukocyte
5-lipoxygenase makes lipoxins
resolvins and protectins
act like lipoxins
derived from omega 3 fatty acids
acetylated COX2
aspirin modified COX2 does not make prostanoids, make a lipoxin precursor - Anti Inflammatory!!!
Glucocorticoid
stimulates Annexin 1 - agonist of lipoxin receptor - decreases inflammatory response
annexin inhibits phospholipase a2 and glucocorticoids repress cox2 - no inflammatory response
