Eicosanoids Flashcards by Angela Mitchell

What are eicosanoids?

polyunsaturated fatty acids

potent mediators
used in immune system and vasculature

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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

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What best describes paracrine signaling?

short range cell-to-cell communication

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What best describes autocrine signaling?

self signaling

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What is the source of eicosanoids?

arachidonic acid from fatty acids

linoleate
essential fatty acids from plant oils

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What is the major source for arachidonate synthesis?

linoleate

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How do we make eicosadoids?

arachidonic acid is esterified to the phospholipid

phospholipase A2*** (& C)
triggered by infection

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What are the 3 types of eicosanoids pathway? products of each?

Cyclo-oxygenase - prostaglandins, thromboxanes
Lipoxygenase - leukotrienese, HETE, lipoxins
Cytochrome P450- diHete, HETE

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Describe the structure of Prostaglandins.

20 carbon atoms with a 5-C ring

Naming (PG with letter and number)

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Describe the structure of Thromboxanes.

20 carbon atoms with 6-C ring

Naming (TX with letter and number)

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**What enzyme is used to synthesize prostaglandin and thromboxanes?

cyclooxygenase (COX)

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What is the key intermediate in the process of synthesis for prostaglandin/thromboxanes?

PGG2&raquo_space;»PGH2

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Pair the synthase with the product that it makes.

TXA Synthase - platelets - Thromboxane

PGI Synthase - vascular endothelium - Prostocyclin

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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

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How are thromboxanes synthesized?

TXA synthase

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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