Eicosanoids

Prostaglandins and related compounds are

collectively known as eicosanoids. The term
eicosanoid is derived from eicosa meaning
twenty, referring to the 20 carbon atoms in
most of the molecules.

Most are produced from arachidonic acid.

The eicosanoids are considered local hormones

or paracrine hormones.

They have specific effects on target cells close

to their site of formation.

Arachidonic Acid
a 20-carbon
polyunsaturated
fatty acid with
four double
bonds by using
interrelated
pathway.

 Eicosanoids are rapidly metabolized

to inactive products, so
they are not stored and
they are not transported to distal sites
within the body.

Examples of eicosanoids:
Prostaglandins (PGE2, PGF2 etc.)
Prostacyclins (PGI2)
Thromboxanes (TXA2)
Leukotrienes
Epoxyeicosatrienoic acid (EETs)

 Prostacyclin and thromboxane are often

considered as the members of the
prostaglandin group since they are also
cyclized
derivatives
(known
as
prostanoids).
The leukotrienes retain the straight chain
configuration of arachidonic acid.

 Leukotriene A4 is
a leukotriene.
Leukotriene A4
hydrolase converts it
to leukotriene B4.
Leukotriene C4
synthase converts it
to leukotriene C4.

 Leukotrienes are a family

of eicosanoid inflammatory
mediators produced in leukocytes.
Produced by the oxidation of arachidonic
acid by the enzyme arachidonate 5lipoxygenase.
First discovered in leukocytes, but have
since been found in other immune cells.

 Leukotrienes use lipid signaling to convey

information to either the cell producing
them (autocrine signaling) or neighboring
cells (paracrine signaling) in order to
regulate immune responses.
Leukotriene production is usually
accompanied by the production
of histamine and prostaglandins, which
also act as inflammatory mediators.

 One of their roles (specifically, leukotriene

D4) is to trigger contractions in the smooth
muscles lining the bronchioles;
their overproduction is a major cause of
inflammation in asthma and allergic rhinitis.
Leukotriene antagonists are used to treat
these disorders by inhibiting the production
or activity of leukotrienes

Functions of eicosanoids:

Inflammation
Pain
Fever
Regulation of blood pressure
Blood clotting
Immune system modulation
Control of reproductive processes & tissue
growth
Regulation of sleep/wake cycle

Functions of eicosanoids (Contd.):

PGE2
Bronchodilation
Vasodilation
Uterine muscle contraction
Hyperalgesia
Inhibits gastric acid secretion
Increases gastric mucus secretion
Mediation of fever

PGD2
Bronchoconstriction
Inhibition of platelet aggregation

Functions of eicosanoids:
PGF2
Contraction of uterine muscles
Bronchoconstriction

PGI2
Inhibition of platelet aggregation
Vasodilation

TXA2
Platelet aggregation
Bronchoconstriction
Vasoconstriction

Prostaglandin receptors:
Prostaglandins & related compounds are transported
out of the cells that synthesize them.
Most affect other cells by interacting with plasma
membrane G-protein coupled receptors.
Depending on the cell type, the activated G-protein
may stimulate or inhibit formation of cAMP, or may
activate Ca++ release.

Eicosanoid synthesis:
AA is the primary precursor of eicosanoids.
AA is present as a component of the phospholipids
of cell membranes.
Free AA is released from tissue phospholipids by
hydrolysis catalyzed by phospholipase A2 of cell
membrane or cytoplasm in response to various
stimuli, eg, physical injury, immune reactions.
Synthesized also from essential dietary fatty acids,
esp. linoleic acid.

 There are two major pathways in the

synthesis of the eicosanoids from
arachidonic acid:
- Cyclooxygenase pathway
- Lipoxygenase pathway

Cell Membrane Phospholipids

Phospholipase A2

C
yc
lo

ox
y

ge
n

as
e

Arachidonic Acid

Prostaglandins
Thromboxanes
Prostacyclins

Li
po

xy

ge
na

se

Leukotrienes

Cyclooxygenase pathway:

COX-1 is found in many tissues;

the prostaglandins produced in these tissues

by COX-1 appear to be important for a variety of
normal physiologic processes-

protective prostaglandins in the kidney and

stomach, as well as the functional thromboxane
of platelets.

COX-1 is known as house keeping enzyme.

In contrast, Cyclooxygenase-2 (COX-2) is found

primarily in inflammatory cells (White blood
cells); the products of its actions play a major
role in tissue injury, eg, inflammation.

COX-2, not normally found in most tissues,

expressed under conditions of tissue damage
and plays an active role in the inflammatory
response.

Lipoxygenase pathway:

Several lipoxygenases (most common 5lipoxygenase) can act on arachidonic acid to

form leukotrienes or lipoxins, depending on the
tissue.

Leukotrienes assist in the pathophysiology of

asthma.