Eicosanoids Flashcards
What are Eicosanoids?
Lipids derived from 20 carbon fatty acids, that act locally via paracrine and autocrine signaling that lead to inflammation, smooth muscle contraction, H2O/Na+ excretion, blood pressure, clotting, and bronchodilation/constriction. Examples of these are prostaglandins, thromboxanes, leukotrienes, and lipoxins.
What is precursor for eicosanoids?
Arachidonic acid which comes from fatty foods like salmon, eggs, chicken, and it is synthesized from linoleic acid via desaturation and elongation. This arachidonic acid is released via activation of Gq activates Phospholipases A/C to cleave phosphatidyl choline and phosphatidylinositol from membrane to make arachidonic acid.
How are prostaglandins and thromboxanes synthesized?
Arachidonic acid is cyclized by cyclooxygenase to form PGG2. Peroxidase adds a hydroxyl to the PGG2 to make PGH2. This isomerizes tissue specifically to give PG or TX. If cyclooxygenase is (COX1) it is constitutive, if it’s COX2 it’s inducible by cytokines or inflammation.
What structure of prostaglandin vs Thromboxane?
PG: 5 carbon ring, has double bonds and causes vasodilation/inhibition of platelets. TX: is six membered ring including oxygen, and causes vasoconstriction/platelet aggregation.
What are prostanoid (varying prostaglandins/thromboxanes) functions?
Involved in signaling, location, and tissue specific effects. Some pathways they’re involved in are Gs-cAMP (PGD, PGE, PGI), Gq-PLC (PGF and PGE), Gi-cAMP (PGE and PGD), and G12/13-Rho (TXA). Specifically PGE does vaso/bronchiodilation, inflammation. PGI does inhibits platelets, renal homeostasis, and TXA does vasoconstriction, platelet aggregation.
Which Prostanoids do COX1 and COX2 synthesize?
COX1: TXA, PGF, and PGE; affect GI mucosa by increasing secretions/ HCO3. COX2: makes PGI and some PGE. This is expressed in leukocytes and inflamed cells. Both COX 1 and 2 cause vasodilation and salt excretion in kidney and vasodilation/inhibition of platelets in cardio vasculature.
Compare and contrast PGI (prostacyclin) and TXA (thromboxane)
PGI made in the vascular endothelium by COX2. Targets IP receptor and does Gs signaling which causes vasodilation and decreases leukocyte aggregation. TXA comes from platelets and made by COX1. It targets TP receptor causing Gq-calcium signaling which leads to vasoconstriction and lymphocyte proliferation. (PGE and PGD similar to PGI)
What forms leukotrienes and lipoxins?
Leukotrienes made from LOX 5 enzyme and lipoxins made from LOX 15 enzymes. The LTs are trienes made by leukocytes and mast cells. They’re associated with inflammation and immunity such as asthma/anaphylactic shock. Examples, LTB = chemotaxis, LTC, LTD, LTE = in asthma causes bronchospasm and permeable venules. LXS are conjugated tetraenes made by leukocytes and platelets to resolve inflammation.
What are functions of LTB and LTE?
LTB produced by mast cells, does neutrophil chemotaxis, and vascular permeability via Gq and Gi signaling (so does LTE). LTE stimulates bronchoconstriction, asthma/anaphylaxis spasm, and mucus secretion in resp. tract.
What is function of cytochrome P450?
Synthesizes HETE (hydroxylase) to cause vasoconstriction in kidney, and EET (epoxygenase), to cause vasodilation, inhibition of NA+ transport and esterified into phospholipids of kidney.
What causes fever?
prostaglandin synthesis in the CNS due to bacteria such as pyrogenes cause fever.
What are treatments for eicosanoids?
- steroids which are anti-inflammatories that reduce transcription of COX2 and pro-inflamm cytokines. 2. COX inhibitors which are NSAIDS like ibuprofen (inhibit COX) and aspirin (inhibit COX or anti platelets via acetylation) that suppress prostanoids only. 3. LOX inhibitors treat asthma 4. and LT receptor antagonists treat asthma
Why is acetaminophen (Tylenol) not a NSAID?
weakly inhibits COX 1/2
Why have COX2 inhibitors been removed from the market?
Drugs like rofecoxib and valdecoxib have been removed because they caused increased thrombosis, stroke, and myocardial infarction due to high thrombitic state.
