FORM & FUNCTION (Eicosanoid) Flashcards
Eicosanoid:
-modified 20 carbon polyunsaturated fatty acids
-3 major classes
-synthesized from dietary fats (Omega-3 and Omega-6)
-mediate several processes
3 major classes:
-prostaglandins (PGs)
-thromboxanes (Txs)
-Leukotrienes (LTs)
Eicosanoids mediate
several processes:-inflammatory response
-production of pain and fever
-regulation of blood pressure
-induction of blood clot
-induction of labor
-etc.
Eicosanoids AND. hormones:
-induce profound physiological effects at extremely low concentrations
-bind to GPCR to initiate a signal transduction cascade (cAMP)
Eicosanoids different from hormones:
-are not transported in the blood to their site of action
-produced by all mammalian organ cells except RBC
-very unstable and rapidly degraded
-promotes local and cell specific actions
Palmitic acid:
-generated from lipid biosynthesis
-further modified to form other lipids
Animals can’t make omega-3 and omega-6:
-missing desaturases that form the double bonds past the 9th carbon
Double bonds in omega-3 and omega-6:
-double bond is 3 C away from the terminal group: omega-6
-double bond is 6C away from the terminal group: omega-3
Dietary supplement:
-plant oil (flaxseed) or fish oil
-fish omega-3 comes from their dietary consumption of microalgae
How are omega-3 and omega-6 stored?
-as a phospholipids
*important for cell membranes
Omega-3 family breakdown:
- Alpha-linolenic acid
- Eicosapentaenoic acid (EPA)
- Docosahexaenoic acid (DHA)
Omega-6 family breakdown:
- Linoleic acid
- Arachidonic acid (AA)
Delta-6 desaturase:
-enzyme that converts:
>alpha-linolenic acid to EPA
>linoleic acid to AA
AA, EPA, DHA:
-precursors to:
>prostaglandins
>thromboxanes
>leukotrienes
Omega-3 and omega-6 generally produce eicosanoids:
-omega-6: associated with pro-inflammatory
-omega-3: with anti-inflammatory response
Healthy diet:
-low omega-6/omega-3 ratio is recommended
Cats and omega-3/6 processing:
-lack delta-6 desaturase activity
-must obtain EPA, DHA, or AA from other animal organs or via transport
Eicosanoid synthesis:
-omega-3/6 are stored in the cell membrane
-phospholipase A2 cleaves AA, EPA, DHA to get them in active form
-2 pathways
Phospholipase A2 activated by:
-greater [Ca2+]
-physical trauma
-immunoglobulins
-microbial products
Phospholipase A2 inhibited by:
-anti-inflammatory signals (glucocorticoids)
2 pathways: eicosanoid synthesis:
- Cyclooxygenase (COX-1 and COX-2)
- Lipooxygenase
*compete for the same substrates
*oxidation reaction
Cyclooxygenase (COX-1 and COX-2):
-prostanoids
>prostaglandins
>thromboxane
Lipooxygenase:
-leukotrienes
Prostanoids:
-COX-1 is constitutively expressed
-COX-2 is inducible by inflammation stimuli
-different prostaglandins are produced by specific cell types to regulate local responses
Different prostaglandins local responses:
-control muscle function (vessel constriction and dilation)
-regulate CNS activity (pain reception)
-mediate cytokine production for inflammation response
NSAIDS:
-nonsteroidal anti-inflammatory drug
*inhibit COX-1 and COX-2
>side effects
NSAIDS used to:
-reduce pain
-decrease fever
-decrease inflammation
-commonly used to treat prescribed (arthritis)
COX-1:
-constitutive enzyme that generates the signal ligand for homeostatic intracellular signaling
COX-2:
-inducible enzyme with increased activity accompanying acute and chronic inflammatory conditions
NSAIDS block PGE2 production:
-PGE2 normally inhibits gastric secretion
-inhibition consequences:
>increase HCl secretion (can’t control how much HCl is in mucous)
>decrease mucous secretion (barrier) in the stomach
>GI bleeding
NSAIDS: PGI2
-vasodilators that increase renal perfusion
-inhibition consequence:
>reduced afferent blood flow that can lead to acute kidney injuries
COX-2 specific inhibitor:
-developed to treat acute and chronic inflammations
-reduce side effects of GI bleeding and kidney necrosis
*not used in humans
-effective in reducing prostaglandins, but increase the ration of thromboxane that regulates clotting
COX-2 specific inhibitor examples:
-Firocoxib (Equioxx)
-Previcox (used to treat canine arthritis and tumors)
Don’t use COX-2 specific inhibitors in humans:
-can lead to 40% increase in risk for cardiovascular complications
Thromboxanes:
-synthesized primarily in platelets (thrombocytes)
-activated by damage to the arterial wall
Activated Thromboxanes:
-induce platelet aggregation and vascular muscle contraction
Normal conditions thromboxanes:
-PGI2 and nitric oxide cause vasodilation to inhibit thromboxanes
Increased Thromboxanes from COX-2 inhibtion:
-constricted vessel
-platelet aggregation
*increase risk of heart attacks
Leukotrienes:
-synthesized by the enzyme lipoxygenase (LO)
-primarily act as inflammatory mediators
-various biologic responses
>bind to receptors on individual cells
Lipoxygenase (LO):
-synthesizes leukotrienes
-primarily found in leukocytes
Leukotrienes biologic responses:
-pro-inflammatory action
-bronchoconstriction (10-100x more potent than histamine)
-mucus secretion
-edema in airways
Leukotrienes and asthma:
-elevated leukotrienes levels (chronic inflammation, allergies) lead to asthma in humans and similar in cats
Asthma:
-characterized by increased mucous production and bronchoconstriction
-laboured breathing and wheezing
Asthma treatment:
-with bronchodilator (beta-agonist) or corticosteroid (reduce inflammation)
Leukotriene receptor agonist:
-blocks leukotriene binding in target cells (montelukast & zafirlukast)
-promising anti-inflammatory agents
*need further validation in vet med
