MEDIATORS DERIVED FROM

MEMBRANE PHOSPHOLIPIDS

 EICOSANOIDS

 Prostanoids
 Leukotrienes

 PLATELET ACTIVATING FACTOR

 MEMBRANE PHOSPHOLIPID

PLC
PLA2

IP3 DAG

DAG lipase

Lyso-PAF Arachidonic acid

PAF EICOSANOIDS
(Prostanoids, leukotrienes)
 Membrane Phospholipid

Phospholipase A2

9 8 6 5 1
COOH
7 4 3 2
10 13 16 18 20

11 12 14 15 17 19

Arachidonic acid

5, 8, 11, 14-Eicosateraenoic acid

 Membrane Phospholipid
NSAIDs
PLA2

Arachidonic Acid
Lyso-PAF
Lipoxygenase Cyclooxygenase (COX-1,COX-2)

Other products Endoperoxides

PAF LTA4 (PGG, PGH)
LTB4
LTC4 PGI synthase TXA synthase
LTD4
LTE4
Prostacyclin Prostaglandins Thromboxane
LTF4 (PGI2) (PGE2, PGF2α, PGD2) (TXA2)
Leukotrienes

Figure 1: Biosynthesis of Eicosanoids

EICOSANOID SYNTHETIC ENZYMES

Prostanoids
COX-1 (constitutive)
COX-2 (induced)
Leukotrienes
5-lipoxygenase - Leukotrienes
12-lipoxygenase - 12-HETE
15-lipoxygenase - Lipoxins A & B
 MAJOR CELLULAR SOURCES
Prostanoids
TXA2 - Platelets
PGI2 - Endothelial cells
PGD2 - Mast cells
PGE2 - Macrophages and monocytes
Leukotrienes
LTB4 - Neutrophils
Cyst-LTs - Mast cells/basophils and
eosinophils
 INACTIVATION OF EICOSANOIDS
Prostanoids
 Rapid inactivation in Lungs by PG-specific
enzymes; half-life = 1-2 min.
 Over 95% inactivated/passage through
pulmonary circulation.

 TXA2 and PGI2 highly unstable.

(TXA2 TXB2); half-life = 30 sec.
(PGI2 6-oxo-PGF1α ); half-life = 5 min.
 INACTIVATION OF
EICOSANOIDS (cont’d)

Leukotrienes

LTB4 20-carboxy- LTB4

LTC4 LTD4 LTE4 (urine)

 EICOSANOID RECEPTORS

Prostanoid Receptors
Receptor type Typically activated by

EP (EP1, EP2, EP3) PGs of the E series

DP PGD2
FP PGF2a
IP PGI2
TP TXA2
 EICOSANOID RECEPTORS (cont’d)

Leukotriene Receptors

Receptor type Typically activated by

B-LT LTB4

Cys-LT LTC4, LTD4, LTE4

 BIOLOGICAL ACTIVITIES OF
PROSTANOIDS
PGE2
 bronchodilation (EP2)
 vasodilation (EP2)
 uterine muscle contraction (EP3)
 hyperalgesia (EP2)
 Inhibits gastric acid secretion (EP3)
 Increases gastric mucus secretion (EP3)
 mediation of fever (EP1/2)
PGD2
 bronchoconstriction (TP receptors?)
 inhibition of platelet aggregation
PGF2α
 contraction of uterine muscles
 bronchoconstriction
PGI2

 inhibition of platelet aggregation

 vasodilation
TXA2

 platelet aggregation
 bronchoconstriction
 vasoconstriction
 ROLE OF PROSTANOIDS IN
INFLAMMATION

Pro-inflammatory Roles

 Vasodilation (PGE2 and PGI2)

 Hyperalgesia (PGE2)

 Platelet aggregation (TXA2)

 Pyrexia (PGE1 and PGE2)

Anti-inflammatory roles

PGE2
 release of lysosomal enzyme and oxygen
radicals from neutrophils
 histamine release from mast cells
 macrophage activation and cytokine release

PGI2
 platelet aggregation
 CLINICAL USES OF PROSTANOIDS

Obstetrics: [Dinoprost (PGF2α), Dinoprostone (PGE2)]

 To induce abortion
 To induce labour at term
 To stop post-partum bleeding (oxytocin
preferred)
GIT [Misoprostol (PGE1 analogue) ]

To treat peptic ulcers

To prevent gastric erosion in NSAID therapy

Dialysis [ Iloprost (PGI2) ]

To prevent platelet aggregation in dialysis
CP bye-pass &
CVS [ Alprostadil (PGE1) ]

 To maintain a patent doctus arteriosus

pending surgery

Urology (PGE1)

 To treat impotence
 BIOLOGICAL ACTIONS OF
LEUKOTRIENES

LTB4
Powerful chemotactic agent (very important
mediator of inflammation)
Cyst-LTs
 Potent bronchoconstrictors. (important
mediators of asthma)
 Vasodilation (constricts coronary)
 Increased vascular permeability
 PLATELET ACTIVATING FACTOR
(PAF)

 Generated from phospholipid by PLA2

 Released during injury, antigen-antibody

reactions etc

 Generated mainly by inflammatory cells

 Potent mediator of inflammation

Biological Activities of PAF

 Vaodilation and vascular permeability

 Chemotactic for many cells

 Leukocytes and platelets activator

 Indirect bronchoconstrictor
(via eicosanoids?)

 Induces AHR
 LEARNING OBJECTIVES

List the major effects of individual .1

.eicosanoids and PAF

List the major sources or sites of synthesis .2

of PGI2, TXA2 and LTs

Describe the role of COX-1 and COX-2 in .3

health and inflammatory conditions

List the targets (receptors and enzymes) of .4

anti-leukotriene drugs

Describe the clinical uses of prostanoids .5

and anti-leukotriene drugs