Eicosanoids Flashcards
What are eicosanoids?
polyunsaturated fatty acids
- potent mediators
- used in immune system and vasculature
What are the biologic functions of eicosanoids
participate in inflammatory response -fever -swelling -pain participate in smooth muscle contraction - increase water and sodium excretion in kidney regulate bp can constrict or relax blood vessels
What best describes paracrine signaling?
short range cell-to-cell communication
What best describes autocrine signaling?
self signaling
What is the source of eicosanoids?
arachidonic acid from fatty acids
- linoleate
- essential fatty acids from plant oils
What is the major source for arachidonate synthesis?
linoleate
How do we make eicosadoids?
arachidonic acid is esterified to the phospholipid
- phospholipase A2*** (& C)
- triggered by infection
What are the 3 types of eicosanoids pathway? products of each?
Cyclo-oxygenase - prostaglandins, thromboxanes
Lipoxygenase - leukotrienese, HETE, lipoxins
Cytochrome P450- diHete, HETE
Describe the structure of Prostaglandins.
20 carbon atoms with a 5-C ring
Naming (PG with letter and number)
Describe the structure of Thromboxanes.
20 carbon atoms with 6-C ring
Naming (TX with letter and number)
**What enzyme is used to synthesize prostaglandin and thromboxanes?
cyclooxygenase (COX)
What is the key intermediate in the process of synthesis for prostaglandin/thromboxanes?
PGG2»_space;»PGH2
Pair the synthase with the product that it makes.
TXA Synthase - platelets - Thromboxane
PGI Synthase - vascular endothelium - Prostocyclin
What is Prostacyclin a major modulator of?
modulator of vascular tone (can be constriction or dilation) cAMP platelet aggregation leukocyte aggregation IL-1 and IL-2 T-cell proliferation Lymphocyte migration
How are thromboxanes synthesized?
TXA synthase
What is the function of Thromboxanes?
modulator of vasoconstriction
- platelet aggregation
- lymphocyte proliferation
- bronchoconstriction
What two forms do cyclo-oxygenase come in?
Cox-1 - constitutively active
Cox 2 - induced form
Describe location of COX-1
widely expressed in most tissues
only form expressed in mature platelets
involved in production of PG and TX
Decribe COX-2
normally low levels
- upregulated in inflamed tissue
- protein is upregulated by a variety of cytokines n growth factors
What inhibits COX-1 and COX-2?
NSAIDs
aspirin
ibuprofen
(acetaminophen)
How do NSAIDs work?
aspirin transfers an acetyl group to the enzyme which inactivates it
**irreversible
Ibuprofen and acetaminophen are ***reversible
Low dose aspirin therapy is given to manage risk of thrombosis. Which actions of eicosanoids does aspirin interfere with to protect against thrombosis?
platelet aggregation
What drugs block just COX-2?
serve as anti-inflammatory w/o negative GI
Celecoxib (Celebrex)
Rofecoxib (Vioxx) - removed due to increased risk of cardiovascular events
What is glucocorticoids used for?
inhibit inflammation by blocking the action of phospholipase A (which make arachidonic acid)
Describe leukotrienes.
expressed in leukocytes
-characteristic triene structure (3 double bonds in a series)
Lipoxin (LX)
Tri-hydroxyl derivatives of arachidonic acid
-oh
made by leukocytes
What pathway makes leukotrienes, HETE, and lipoxins?
lipoxygenase pathway - add peroxides
What is the first step in conversion of arachidonic acid?
conversion of HPETE via lipooxygenase
What will the unstable hydroperoxy group convert to?
HETE
What are the activities of LTB4
vascular permeability
T-cell proliferation
leukocyte aggregation
INF-y, IL-1, IL-2
What are the activities of LTC4
Bronchoconstriction
Vascular permeability
INF-y
What makes lipoxins different?
OH group reductions
LX can induce chemotaxis and superoxide production in leukocytes.
Epoxides, certain HETE and diols of HETE are generated via what pathway?
cytochrome p450
What physiologic roles have been implicated with epoxides?
ocular
vascular
endocrine
renal
What is the mechanism of action of eicosanoids?
bind to cellular receptor which can trigger activation of :
adenylyl cyclase >cAMP > protein kinase A pathway
phosphorylates CREB and initiate transcription of gene
What are the stimulators for the pathway?
PGE, PGD, PGI
What is another mechanism of action of eicosanoids?
cytosolic
What type of actions can eicosanoids provoke?
pro and anti-inflammatory actions
What are the clinical uses of eicosanoids?
suppress gastric ulceration, inhibit secretion of hydrochloric acid in the mucosal cells of the stomach
- analogs of PGE1 for sexual impotence treatment
PGE2 PGF2a - stimulate uterine muscle contraction to induce labor
PGE1 - palliative therapy in neonates with congenital heart defects
Analog of PGI - treatment of primary pulmonary hypertension
