Lipid-Derived Autocoids

Eicosanoids and Platelet-Activating Factor

Lipid-Derived Autocoids

Membrane lipids supply the substrate for the synthesis of

eicosonoids and PAF.

Eicosonoids-arachidonate metabolits, including PGs,

PGI2, TxA2, LTs, lipoxins and hepoxilins, are not stored

but are produced, by most cells, when a variety of

physical, chemical, and hormonal stimuli activate acycl

hydrolases that make arachidonate available.

Lipid-Derived Autocoids

Membrane glycerophosphocoline derivatives can be

modified enzymathically to produce PAF.

PAF is formed by a smaller number of cell types,

principally Leucocytes, Platelets, and endothelial

cells.

Lipid-Derived Autocoids

Eicosanoids and PAF lipids contribute to

inflammation, smooth muscle tone, hemostasis,

thrombosis, parturition, and GI secretion.

Lipid-Derived Autocoids

Several classes of drugs, most notably Aspirin, the

tNSAIDs and spicific inhibitor of COX-2, such as

the Coxibs, owe their principle therapeutic effects

to blockade of eicosanoid formation.

EICOSANOIDS

History

1930 Kurzrok and Lieb

1935 von Euler Prostaglandin

1962 Samuelsson, Bergström PGE1 PGF1α

1964 Bergstrom and Van Dorp biosynthesis of

PGE2

1971 Vane, Smith and Willis, Aspirin and

NSAIDs

PGs, LTs, and related compounds are called

eicosanoids, Precursor essential fatty acids contain 20

carbons and 3,4,5 double bonds:

8,11,14-eicosatrienoic acid (dihomo--linolenic acid)

5,8,11,14-eicosatetraenoic acid (AA)

5,8,11,14,17-eicosapentaenoic acid (EPA)

Eicosanoids Biosynthesis

Phosphatidylcholine and phosphatidylethanolamine

cPLA2 (cytosolic, Ca2+_dependent)

sPLA2 (secratory)

iPLA2 (Ca2+ _independent)

COXs, Lipoxygenases (LOXs), and CYPs

Products of PG G/H synthases

Complex microsomal enzymes

COX and hydroperoxidase (HOX) activities

Prostanoids (PGs, Prostacyclin, PGI2, and TxA2)

COX-1 and COX-2

Products of Lipoxygenases (LOXs)

HPETE → HETE

These are five active human LOXs-

5(S)-LOX, 12(S)-LOX,12(R)-LOX;

15(S)-LOX-1, and 15(S)-LOX-2

5-LOX pathway leads to the synthesis of the LTs.

FLAP

LTC4, LTD4, and LTE4 (SRS-A)

Products of CYPs

epoxyeicosatrienoic acids (EETs)

endothelial cells (EDHFs)

Other Pathways

non-enzymatic free radical catalyzed oxidation of

AA

Isoprostanes

their formation is suppressed by antioxidants.

endocannabinoids arachidonylethanolamide

(anandamide) and 2-arachidonoylglycerol

Inhibitors of Eicosanoid Biosynthesis

PLA2 - Glucocorticoids (annexins )

COX-2 – induced expression – Glucocorticoides

COXs- Aspirin and tNSAIDs

COX and 5-LOX – Licofelone

COX-2 – Coxibs

TX synthase

LOXs - Zileuton

Eicosanoid Catabolism

pulmonary circulation - PGE2

TXA2 – (t1/2 – 30 seconds)

PGI2 – (t1/2 – 3 minutes)

LTs – long acting

Pharmacological Properties of Eicosanoids

Prostaglandin Receptors

Cell Signaling Pathways and Expression

Receptors for LTs

Endogenous PGs, Txs, and LTs:

- Functions in Physiological and Pathological Processes

Platelets Platelet aggregation leads to activation of membrane

PLs → AA → eicosanoids

In human platelets, TxA2 and 12-HETE

Low dose Aspirin

TxB2 – unstable angina, MI, and stroke

PGI2 – Inhibition platelet aggregation and disaggregation

performed clumps

Vascular injury

COX-2 inhibitors

Vascular Tone

Prostanoids modulate vascular tone locally COX-2 derived PGI2

PGI2 – Pulmonary hypertension

PGE2 – maintenance of renal blood flow

PGI2 and PGE2 – septic shock

PGs – maintanence of placental blood flow

COX-2 derived PGE2 (DA)

EETs - hypertension

Inflammatory Vascular Disease

TxA2 - atherogenesis

PGI2 - atheroprotective

COX-2 - abdominal aortic aneurism formation

LTs

Lung

A complex mixture of autacoids is released when sensitized

lung tissue is challenged by the appropriate antigen.

COX-derived (PGE2, PGF2α, TxA2, PGD2 ,and PGI2).

CysLTs probably dominate during allergic constriction of

the airway.

CysLT-receptor antagonists and 5-LOX inhibitors are

effective in the treatment of human asthma.

slow LT metabolism in lung.

Kidney

Long-term use of all COX inhibitors is limited by the

development of hypertension, edema, and congestive heart

failure in a significant number of patients.

COX-2 derived PGE2 and PGI2 (RBF and salt excretion).

Biosynthesis of PGE2 and PGI2 is increased by factors that

reduce renal blood flow.

Bartter's syndrome

inhibition of COX-2

Inflammatory and Immune Responses

PGs and LTs are synthesized in response to a host of stimuli

that elicit inflammatory and immune responses, and contribute

significantly to inflammation and immunity.

Prostanoids generally promote acute inflammation.

LTs are potent mediators of inflammation.

LTB4 in chemotaxis, adhesion, and recruitment of leukocytes.

Increased vascular permeability

Heart

PGI2 and PGE2 protect against oxidative

injury in cardiac tissue.

Reproduction and Parturition

PGF2α appears important for luteolysis.

COX-2 generates prostanoids (PGF2α and TxA2)

that are important in the final stages of

parturition.

Cancer

COX-2 - in models of colon, breast, lung, and other

cancers.

NSAIDs and cancers.

PGE2 and TxA2 - pro-carcinogenic mediators.

CysLTs and LTB4

Pharmacological Effects

Cardiovascular System Eye

Platelets CNS

Inflammation and Immunity Endocrine system

Smooth Muscle Bone

Kidney

Cardiovascular effect

local vascular tone and renal actions.

PGE2, PGI2, and PGD2 elicit vasodilation and a drop in

blood pressure .

PGD2 (flushing, nasal stuffiness, and hypotension)

TxA2 – potent vasoconstrictor

LTC4 and LTD4 – Hypotension, permeability

EET - EDHFs

Platelets

LD of PGE2 - aggregation

HD of PGE2 – Inhibition of aggregation

PGI2 and PGD2 - Inhibition of aggregation COX-1 is dominant COX-2 - Megakaryocytes and immature platelet TxA2

the major product of COX-1 in platelets

thrombin and ADP

endogenous inhibitors, NO and PGI2

Inflammation and Immunity LTs - pro-inflammatory lipoxins - anti-inflammatory prostanoids (PGE2 and PGI2) both kinds of activity LOX-2 is dominant PGs – inhibit lymphocyte function and proliferation DP2 (most cells) – is a potent leukocyte chemoattractant

LTB4 -is a potent activator and chemotactic agent for neutrophils, T lymphocytes, eosinophils, monocytes, dendritic cells, and mast cells

LTB4 - aggregation of eosinophils and promotes degranulation and the generation of superoxide.

LTB4 - promotes adhesion of neutrophils to vascular endothelial cells (transendothelial migration)

LTB4 - stimulates synthesis of pro-inflammatory cytokines from macrophages and lymphocytes.

Mast cell–generated LTB4 also may contribute significantly to T lymphocyte migration

Smooth Mucsle

Bronchial and Tracheal muscle.

TxA2, PGF2α, and PGD2 contract

PGE2 and PGI2 relax

CysLTs Bronchoconstrictors

Bronchial mucus secretion

(muscle edema)

Smooth Mucsle

Uterus PGF2α, and PGE2

Together with Oxytocin is essential for the onset of

parturition.

Uterine responsiveness to PGs increases as pregnancy

progresses but remains smaller than the response to Oxytocin.

Gastrointestinal Muscle PGEs and PGFs stimulate contraction of the main longitudinal muscle from

stomach to colon

PGs reduce transit time in the small intestine and colon.

Diarrhea, cramps, and reflux of bile have been noted in response to oral

PGE.

PGEs and PGFs stimulate the movement of water and electrolytes into the

intestinal lumen (watery diarrhea).

PGE2 appears to contribute to the water and electrolyte loss in cholera

(therapy with tNSAIDs).

The LTs have potent contractil effect.

Gastric and Intestinal Secretions

PGE2 and PGI2 increased mucus secretion (cytoprotection), reduced acid

secretion, and reduced pepsin content.

PGE2 and PGI2 - vasodilatory properties and direct effects on secretory

cells

PGE2 and its analogs also inhibit gastric damage caused by a variety of

ulcerogenic agents and promote healing of duodenal and gastric ulcers.

COX-1 -dominant source (physiological conditions)

COX-2 - predominates during ulcer healing.

CysLTs – constrict blood vessels (gastric damage)

Kidney

Both the renal medulla and cortex synthesize prostanoids.

PGE2 and PGI2 – (COX-2 derived) increase medullary blood flow and inhibit

tubular sodium reabsorption.

Expression of medullary COX-2 is increased during high salt intake.

COX-1-derived products promote salt excretion in the collecting ducts

PGE2 and PGI2 increase renal BF and GF through their local vasodilating

effects (marginally functioning kidneys and volume-contracted states).

PGE2 and PGI2 - increase renin release

Eye

PGF2α - decreases intraocular pressure (IOP) effective

in the treatment of open-angle glaucoma

CNS The induction of fever by a range of endogenous and exogenous pyrogens appears to be

mediated by PGE2

The body tempreture set points, is elevated by endogenous pyrogens (IL-1β, IL-6, TNF-

α, and Interferone)

The initial phase of thermoregulatory response to pyrogens is mediated by ceramide

release in neurons of the preoptic area in the anterior hypothalamus.

the late response in the endothelium of blood vessels in the preoptic hypothalamic area

to form PGE2.

PGE2 can cross the blood-brain barrier and acts on thermosensitive neurons.

PD2 – increase extracellular adenosin. Facilitates induction of sleep.

COX-2-derived prostanoids are implicated in several degenerative disorders (e.g. AD,

PD).

Pain Inflammatory mediators, (LTs and PGs) increase the sensitivity of

nociceptors and potentiate pain perception.

Both PGE2 and PGI2 reduce the threshold to stimulation of nociceptors

(peripheral sensitization).

Both COX-1 and COX-2 are expressed in the spinal cord under basal

conditions and release PGs in response to peripheral pain stimuli.

PGE2, PGD2, PGI2, and PGF2α, can increase excitability in pain transmission

neuronal pathways in the spinal cord, (hyperalgesia and allodynia).

LTB4- hyperalgesia

Amplification system for the pain mechanism (in inflammatory process)

Endocrine System PGE2 increases ACTH, growth hormone, prolactin, and

gonadotropins.

Other effects (steroid production, insulin release, and

thyroid-like effects).

Critical role of PGF2α (induce an oxytocin-dependent

decline in progesterone levels).

PGE2 - positive-feedback loop to induce oocyte maturation

required for fertilization during and after ovulation.

Bone PGs are strong modulators of bone metabolism.

COX-1 is expressed in normal bone

COX-2 is upregulated in certain settings (inflammation and

mechanical stress).

PGE2 - bone formation and Bone resorption

Therapeutic Uses Stable agonists, inhibiting eicosanoid formation, and antagonizing eicosanoid

formation

Therapeutic abortion (Dinoprostone, misoprostol, and carboprost)

Gastric cytoprotection (misoprostol)

Impotence (PGE1)- second line treatment of erectile dysfunction.

Maintenance of PDA – congenital heart disease (PGE1)

Pulmonary Hypertension – long term therapy with PGI2 (epoprostenol)

Glaucoma – long term PGF2α derivative (latanoprost)