Download Function of prostaglandins

Membrane phospholipids
and Inflammatory
mediators
MSS Module- Lecture 14
All of us know the famous drug “ASPIRIN”
and why we use it
 But do you know how it works?
 It works by inhibiting an enzyme called
cyclooxgenease
(it
is
also
called
prostaglandin
endoperoxide
G/H
synthetase).

So, what is cyclooxygenase enzyme?
 It is an enzyme acting on a component of
membrane
phospholipids
(
namely
arachidonic acid) resulting in formation of
biologically active compounds known as
eicosanoids that include: prostaglandins
(mainly PGE and PGFά) , prostacyclin (PGI)
and thromboxanes (TX) .

Many factors control the synthesis and
secretion of different eicosanoids, for
example:
 in pregnancy they are produced under
the effect of oxytocin hormone,
 in the thermoregulatory center of the
hypothalamus they are secreted by the
effect of pyrogens.
 Corticotrophin
releasing
hormone
stimulates
their
synthesis
while
glucocorticoids inhibit their synthesis.

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


In the body, fatty acids, including arachidonic
acid; a C20 polyunsaturated f.a.;
are found
incorporated
in
membrane
phospholipids:
phosphatidylcholine, phosphatidyl-ethanol-amine,
phosphatidylinositol.
Arachidonic acid is released from phospholipids
in response to specific signals(compare to the
formation of second messengers)
One of the enzymes responsible of this release is
phospholipase A2 whose activity is inhibited by
lipocortin, annexins released under the influence
of the glucocorticoids ( e.g. cortisol)
Many stimuli (e.g. epinephrine, thrombin and
bradykinin) activate phospholipase A2
The
immediate
dietary
precursor
of
arachidonate is linoleic acid.

Linoleic acid (arachidonate precursor) and ά-
linolenic acid (eicosapentaenoate precursor) are
essential fatty acids, so they must be taken in the
diet otherwise the body can not synthesize the
eicosanoids.
Minor
eicosanoids
are
eicosopentaenoic acid, e.g.TXA3
derived
from

All cells with the exception of RBCs can produce
eicosanoids.

All eicosanoids are locally active compounds and
mediate their action through receptor-mediated Gprotein linked signaling pathways leading to an
increase ( or sometimes a decrease) in cAMP levels.
 They
differ from hormones in the following aspects:
1. They
are produced in small amounts in almost all
tissues rather than specialized glands.
2. They
act locally rather than after transport to target
tissues
3. They
are not stored, have extremely short half life,
and are metabolized rapidly to inactive products at
their site of synthesis.
4. Their
biological effects are mediated by plasma and
nuclear membrane receptors, which are different in
different organ systems.
Biosynthesis of Eicosanoids.
Two main pathways are involved in the
biosynthesis of eicosanoids.
 The prostaglandins, prostacyclin, and
thromboxanes are synthesized by the
cyclic pathway involving the
cyclooxygenases, while
 the leukotrienes are synthesized by the
linear pathway involving
lipoxygenases.
 Both types of enzymes are iron metalloenzymes.

Cyclooxygenases (COX)



Cyclooxygenases (COX) are called thus
because they lead to the formation of a
cyclopentanic cycle.They are also called
PGH synthases because they lead to
formation of prostaglandin H.
There are two major different forms
(isoenzymes)
of
cyclooxygenase;
cyclooxygenase
1
(COX1)
and
cyclooxygenase 2 (COX2).
The following table summarizes the
characters of both of them:
COX 1
COX 2
Continuously produced in
gastric mucosa, kidney,
platelets
and
vascular
endothelial cells
Inducible form (not present
normally in the cells) and
expressed
mainly
in
macrophages
and
monocytes.
Used for signaling pain and
inflammation,
and
produces prostaglandins in
inflammatory responses.
Its
production
is
stimulated by inflammatory
cytokines (IL-1) and growth
factors (e.g. PAF)
Important for formation of
prostaglandins required for
normal
physiological
functions.
It is important in many
tissues such as stomach
(production of mucous
secretion and regulation of
gastric acidity), and in the
kidney for water regulation.
Synthesis of prostaglandins prostacyclins and thromboxanes from
arachidonic acid. Many stimuli (e.g. epinephrine, thrombin and
bradykinin) activate phospholipase A2 which hydrolyzes arachidonic
acid from membrane phospholipids, while corticosteroids inhibit it.
Function of prostaglandins



1.
2.
3.
Different prostaglandins have different (and
sometimes opposite) functions depending
on tissue location.
Prostaglandins Increase cAMP in many
endocrine glands; such as pituitary, thyroid
and parathyroid; leading to increased
hormone production by these glands.
On other hand, they decrease formation of
cAMP in some tissues such as:
Adipose tissues leading to decreased
lipolysis
The stomach leading to decreased gastric
HCL secretion, and
The pancreas leading to decreased insulin
secretion .
Function of prostaglandins(continue)

Some prostaglandins cause relaxation of smooth
muscles; especially of bronchi and blood vessels(
vasodilation lowers systemic arterial pressure);
while others cause muscle contraction( stimulate
uterine contraction, hence are used to induce
labour) .
Function of prostaglandins (continue)


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Some inhibit further release of
neurotransmitters, after being released in
response to their presence.
Some are involved in the inflammatory
response, causing oedema, swelling and
prolonged erythema by increasing capillary
permeability.
Some have an effect on platelet aggregation.
Some play a role in temperature control.

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Examples
of
clinically
significant
prostaglandins:
1-PGD2 secreted primarily from the mast
cells and inhibits platelets aggregation and
induces vasodilatation
2-PGE2 secreted by most cells especially the
kidney,, the platelets and the heart, increases
cAMP production, causes vasodilatation, and
platelet aggregation. Used to induce uterine
contraction and labour.
3-PGF2ά secreted by most cells, especially
the lung, spleen, uterus and heart, causes
vasoconstriction, broncho-constriction and
smooth muscle contraction e.g. uterine
contractions.
Function of prostacyclins
Prostacyclin(PGI2);
produced
and
secreted
primarily
by
vascular
endothelial cells( especially heart) ;
 It increases cAMP in platelets, and
inhibit platelets aggregation,
 It prevents platelets adherence to
healthy blood vessels wall, and
 It also produces vasodilatation, hence
lowers the blood pressure
 Thus, it impedes thrompogenesis

Function of Thrompoxanes

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Thromboxanes: are produced and secreted primarily by
the platelets
They cause mobilization of intracellular calcium,
vasoconstriction, and contraction of smooth muscles.
They also decreases production of cAMP in platelets
and cause platelets aggregation,thus promoting the
formation of blood clots (thrombi) ( opposite effect to
PGI. This limit formation to site of vascular injury)
Examples of clinically important TXs:
TXA2: secreted from platelets, induces platelets
aggregation and vasoconstriction, hence increase BP.
TXB2:
secreted from
platelets
and
induces
vasoconstriction
Function of Leukotrienes




Leukotrienes produced by leukocytes, platelets,
mast cells and heart and lung vascular tissues, are
involved in the inflammatory responses such as
erythema, oedema and hyperthermia.
In skin they are responsible for the ‘weal and flare’
response seen in some allergic responses.Some
could lead to fatal side effects of vaccinations,e.g.
LTC4, LTD4, LTE4, are components of slow reacting
substance of enaphylaxis (SRS-A),
induce
contraction of smooth muscles, vasoconstriction,
bronchoconstriction, and increased vascular
permeability.
LTB4 increases chemotaxis of polymorphonuclear
leukocytes, causes release of lysosomal enzymes,
and adhesion of WBCs
Prostaglandins, inflammation steroidal and
non-steroidal anti-inflammatory drugs.

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Prostaglandins released by damaged cells
and nearby macrophages, cause changes in
adjacent
cells that carry specific
prostaglandin receptors in their membranes.
The influence, which prostaglandins have,
depends upon the type of tissue they are
acting upon.
Such action may be direct, or as a result of
modifying the actions of other signaling
molecules.
One of their effects is to stimulate pain
receptors (nociceptors).

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At the same time they intensify the effects of
other chemical mediators such as histamine
and bradykinin leading to vasodilatation and
an increase in the permeability of capillaries
supplying the damaged area, helping the
migration of phagocytes from the blood
through capillary walls into the damaged
tissue.
As a result of these changes, the blood
supply to the area increases, the tissues
swell,
and
pain
occurs
(signs
of
inflammation).
To combat this their production must be
stopped
Synthesis of prostaglandins and thromboxanes from arachidonic acid.
Many stimuli (e.g. epinephrine, thrombin and bradykinin) activate
phospholipase A2 which hydrolyzes arachidonic acid from membrane
phospholipids, while corticosteroids inhibit it.
 The
corticosteroidal drugs e.g. cortisol,
prednisolone, act to inhibit phospholipase
A2, thereby inhibiting the release of
arachidonate
from
membrane
phospholipids
and
the
subsequent
synthesis of eicosinoids.
 They also inhibit COX-2
 Thus, they have anti-pyretic and antiinflammatory action.
 However, they have many undesirable side
effects because they prevent the synthesis
of the eicosinoids needed for normal,
healthy
body
functions.
Another
class,
the
non-steroidal
antiinflammatory drugs (NSAIDs) ,all act upon the
cyclooxygenase activity, inhibiting both COX-1 and
COX-2. Examples include: ibuprofen, naproxen,
indomethacin,
phenylbutazone
(
reversible
inhibition), and aspirin (irreversible inhibition)
 Low-dose aspirin therapy is used to lower the
risk of stroke and heart attacks by decreasing
formation of thrombi.
Because of the non selective inhibition of COX-1
activity in the gut , these drugs are associated with
gastric ulcerations.
Systemic inhibition of COX-1, with subsequent
damage to the stomach and the kidneys ,and
impaired clotting of blood, is the basis of aspirin’s
toxicity.

Therefore, Another group of drugs was
developed with selective inhibition on
COX2 only, e.g. Celebrex (celecoxib),
Prexige (lumiracoxib) , Vioxx (rofecoxib)
and Bextra (valdecoxib)
 They are designed to reduce pathologic
inflammatory processes while
maintaining the physiologic function of
COX-1.