Lipid-Derived Autocoids Eicosanoids and Platelet-Activating Factor.
-
Upload
angelica-edwards -
Category
Documents
-
view
224 -
download
4
Transcript of Lipid-Derived Autocoids Eicosanoids and Platelet-Activating Factor.
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)