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Set 16: Inflammation II - Ecosanoids
68
Pharmacology
Graduate
08/23/2012

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Term
def

eicosanoids
Definition
long chain fatty acids that act as autocrine or paracrine agents.

include:
prostaglandins, prostacyclin, thromboxanes, leukotrienes
Term
What is the usual precursor of eicosanoids?
Definition
arachidonic acid
Term
Where does arachidonic acid come from?
Definition
released from membrane phospholipids by phospholipase A2
Term
What is another possible substrate for eicosanoids (other than the usual arachidonic acid)?
Definition
fatty acids s.a eicosapentanoic acid (found in fatty fishes), but yield different eicosanoid products
Term
Effects

dietary fish oil
Definition
1) reduce cholesterol, triglycerides in recovery from acute coronary disease
2) increase tachycardia/fibrillation/cardiac death in chronic coronary disease
3) reduce Sx of inflammation in RA & psoriasis
Term
What do COX1 & COX2 catalyze?
Definition
2 step reaction (oxygenation & peroxidation) => prostaglandin PGH2 formation
Term
Where is COX1 found?
Definition
constitutive form in stomach, platelets, & other tissue
Term
Where is COX2 found?
Definition
1) inducible form in inflammatory tissues
2) constitutive form in kidney & vascular endothelium
Term
What eicosanoid product(s) predominate in the stomach?
Definition
PGE2 & PGI2
Term
What eicosanoid product(s) predominate in platelets?
Definition
TXA2
Term
What eicosanoid product(s) predominate in vascular endothelium?
Definition
PGI2
Term
How are COX products released?
Definition
facilitated transport
Term
How do COZ products act?
Definition
via specific GPCRs
Term
Duration

eicosanoids
Definition
minutes (very short half lives)
Term
What inactivates eicosanoids?
Definition
specific enzymes by fatty acid oxidation
Term
What eicosanoid products do not come from the precursor PGH2?
Definition
none
Term
What eicosanoid products are found in the kidney?
Definition
PGE2 & PGI2 TXA2 (very little)
Term
Function PGE2 & PGI2 in kidney
Definition
1) increase release of renin from juxtaglomerulat apparatus (JMA)
2) vasodilation => increase GFR
3) reduce effects of ADH in collecting duct
Term
Effect PGE2 & PGI2 in kidney
Definition
increase sodium & water clearance
Term
What synthesizes TXA2 during infiltration of inflammatory cells?
Definition
monocytes & macrophages
Term
Effect TXA2 on kindey
Definition
vasoconstriction & decline in renal function
Term
What is the only vasoconstrictor eicosanoid (in humans)?
Definition
TXA2
Term
What eicosanoids are produced by vascular endothelial cells?
Definition
PGI2 (main source) & PGE2 (in microcirculation)
Term
Effect PGI2 & PGE2 on blood vessels
Definition
vasodilation (=> hypotension & reflex tachycardia if IV injection of prostacyclin PGI2)
Term
Effect

prostaglandins & thromboxanes on GI smooth muscle
Definition
contraction
Term
What eicosanoids are produced by COX1 in the stomach?
Definition
PGE2 & PGI2
Term
Function PGE2 & PGI2 in stomach
Definition
cytoprotective by maintaining secretion of mucins & limiting pepsin & acid secretion
Term
What happens to GI if COX1 is inhibited?
Definition
considerable distress
Term
Function

COX2 in GI
Definition
healing existing ulcers
Term
What happens to GI if COX2 is inhibited?
Definition
delays healing
Term
What is the major COX1 eicosanoid product of platelets?
Definition
TXA2
Term
Function TXA2
Definition
1) vasoconstrictor
2) potent platelet aggregator
3) increase effects of thrombin & other aggregators
Term
What can counteract TXA2 effects?
Definition
1) prostacyclin (COX2 systnesis in vascular endothelium) 2) PGD2
Term
What eicosanoids relax bronchiolar & tracheal muscle?
Definition
prostacyclin (PGI2) & PGE2
Term
What eicosanoids constrict bronchiolar & tracheal muscle?
Definition
TXA2 & other prostaglandins
Term
What can induce PGE2 synthesis in the nervous system?
Definition
pyrogenes => IL-1 induced synthesis of PGE2
Term
Function PGE2 on CNS
Definition
1) fever
2) transmission of pain fibers in SC
Term
What 2 eicosanoids sensitize nerve endings of pain fibers in the periphery?
Definition
PGE2 & PGI2
Term
What eicosanoids can cause uterine contraction?
Definition
1) TXA2 2) PGF 3) low doses of PGE2
Term
What effect does COX1 & COX2 inhibition have on inflammation?
Definition
palliative relief from inflammation (inspite of the fact that prostaglandins & prostacyclin has anti-inflammatory effects)
Term
How is PGE2 anti-inflammatory?
Definition
1) inhibits differentiation of B-lymphocytes into plasma cells
2) inhibits mitogen induced proliferation & lymphokine release by T lymphocytes
Term
How is TXA2 pro-inflammatory?
Definition
1) promotes cloncal expansion of T lymphocytes
2) stimulates IL & IL receptor synthesis
Term
What is the most likely explanation for the anti-inflammatory effect of COX inhibitors?
Definition
diminished eicosanoid effects on vasodilation & sensitization of nociceptive nerves
Term
def

alprostadil
Definition
PGE1 used for: 1) vasodilating effect in Tx of impotence when injected directly into corpora cavernosa 2) maintain patent ductus arterosus prior to cardiac surgery
Term
def

misoprostol
Definition
PGE11 derivative used: 1) with mifepristone in terminating pregnancies 2) for protection against peptic ulcer
Term
What eicosanoids are used with oxytocin to induce labor?
Definition
PGE2 & PGF
Term
What eicosanoid is used to treat pulmonary & portopulmonary HTNs?
Definition
prostacyclin
Term
def

lipoxygenases
Definition
family of enzymes that can catalyze oxygenation of arachadonic acid to hyperoxides
Term
Where is 5-LOX isoform found?
Definition
PMNs, basophils, mast cells, eosinophils, & macrophages
Term
What physiological processes are associated with 5-LOX products?
Definition
asthma, anaphylactic shock, & CVD
Term
What leads to the release of arachidonate & association of 5-LOX with FLAP on the nuclear membrane?
Definition
activation of 5-LOX containing cells
Term
def

FLAP
Definition
5-LOX activating protein
Term
What is arachidonate oxygenated & dehydrated by 5-LOX to produce?
Definition
unstable leukotriene LTA4
Term
What happens to the unstable LTA4 produced by 5-LOX?
Definition
1) hydrated to LTB4 or 2) conjugated to LTC4 by a thiol bond to the tripeptide, glutathione
Term
What happens to LTC4?
Definition
sequentially degraded by extracellular enzymes to LTD4 & LTE4
Term
Where is 12-LOX isoform found?
Definition
platelets + all inflammatory cells containing 5-LOX
Term
Function

12-LOX
Definition
coverts arachidonic acid directly to stereoisomers 12S-HETE & 12R-HETE
Term
What happens to LTA4 when exposed to 12-LOX?
Definition
coverted to lipoxins A & B
Term
What shares the same receptor as LTB4?
Definition
12-HETEs (the conjugated leukotrienes bind to another class of receptors)
Term
What happens to LTB4 & LTC4?
Definition
actively transported out of the cell
Term
Duration

leukotrienes & HETEs
Definition
short haf lives
Term
What inactivates LTB4?
Definition
CYP4F P450 family in leukocytes
Term
Where are the conjugated leukotrienes degraded?
Definition
lung, liver & kidney
Term
Function LTB4
Definition
chemoattractant for PMNs, eosinophils, & monocytes
Term
Function LTC4 & LTD4
Definition
1) attract eosinophils
2) vasoconstrict (=> depression of cornonary & myocardium blood flow)
3) increase vascular permeability (=> mucus secretion & plama exudation in airways)
4) airway: Slow Reacting Substance of Anaphylaxis (SRS-A) secreted in anaphylaxis & asthma => bronchoconstriction
Term
Which leukotriene is screted by colonic epithelial cells & are therefore high in inflammatory bowel disease?
Definition
LTB4
Term
Function

12-HETEs
Definition
mediate angiotensin II's release of aldosterone (not ACTH's)
Term
SOA

5-LOX & LT receptor antagonists
Definition
asthma
(not generalized inflammation s.a. RA)
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