|Release of arachidonate||Increase in calcium in cell from inflammatory cytokines, IgE antigen, mechanical shear, etc. activates phospholipase A2 (PLA2), which releases arachidonate from glycerophospholipid.|
|COX reactions||COX1 or COX2 catalyze 2 reactions that bring arachidonate to PGH2, which is an unstable molecule that is further acted on by tissue-specific synthases to make prostaglandins.|
|COX1 vs. COX2 expression|| -COX1: constitutively expressed in most tissues. Has housekeeping functions.|
-COX2: inducible expression by inflammatory agents. In capillary endothelial cells and elsewhere.
|Prostacyclin vs. thromboxane effects|| -Prostacyclin (PGI2) decreases platelet aggregation, vasoconstriction. Produced by endothelial cells.|
-Thromboxane (TXA2) increases platelet aggregation and vasoconstriction; associated with vascular occlusion. Produced by platelets.
|Rationale for fish oil use|| -Fish oils are rich in omega 3 fatty acids, which are used by COX to make TXA3 and PGI3. PGI2 and PGI3 have the same potency, but TXA3 has less potency than TXA2.|
-Therefore taking in a lot of omega 3 fatty acids tips balance away from platelet aggregation.
|Glucocorticoid effect on arachidonate synthesis||Indirectly inhibit PLA2, inhibiting arachidonate formation.|
|Aspirin and low dose aspirin therapy||-COX1 and COX2 covalent inhibitor - inhibits both prostacyclin and thromboxane.|
-At low doses, can still increase prostayclin to thromboxane ratio because vascular endothelial cells continue to synthesize more COX and make prostacyclin, while platelets are anucleate and cannot synthesize more COX, inhibiting synthesis of thromboxane.
|Tylenol (acetaminophen)||Converted to cannabinoid CB1 receptor agonist in brain and spinal cord. Acts as analgesic.|
|Leukotriene general effects||Inflammatory mediators: Constrict airway smooth muscle, attract inflammatory cells, contribute to anaphylaxis, increase vascular permeability.|
|Leukotriene synthesis and activation|| -LTA4 synthesized from arachidonate by 5-lipoxygenase LTA4 then converted to other leukotrienes.|
-5-lipoxygenase expressed in monocytes, macrophages, neutrophils. Activated by immune complexes and injury.
|Peptidoleukotrienes||LTC4, LTD4, LTE4, made from further conversion of LTA4. Are slow reacting substances of anaphylaxis.|
|Lipoxins, resolvins, protectins general effects||Mediators of resolution phase of inflammation: remove leukocytes/debris from inflamed sites, decrease recruitment of immune cells to inflamed sites.|
|Problem with Vioxx||Vioxx is a selective COX2 inhibitor. COX2 is expressed in capillary endothelial cells, where it helps to make prostacyclin. By inhibiting COX2, the prostacyclin/thromboxane balance is tipped towards thromboxane - platelet aggregation, clot formation, etc.|
|Prostaglandin F2alpha||Causes uterine contractions.|
|Prostaglandin E2||Present in most cells, housekeeping functions.|