Role of Eicosanoids in Inflammatory Response

Saturday, August 6, 2016 Rajesh Chaudhary 1

 Lower FA vs. Higher FA?
Unsaturated FA
Mono unsaturated FA
Polyunsaturated FA
Linoleic acid
(2 double bonds)
Linolenic acid
(3 double bonds)
Arachidonic acid
(4 double bonds)

 1. Linoleic acid
 2. a-linolenic acid
Supplied through the diet. Found only in the oils originating from plant.

Cardiovascular System
Department of Biochemistry, Nepalgunj Medical College, Nepal
Saturday, August 6, 2016 4Rajesh Chaudhary

 Role in inflammatory response: redness, swelling, pain.
 Destroy invading organisms and helps in repair.
 Helps in smooth muscle contraction.
 Increase water and sodium excretion.
 Acts as a modulator – bronchoconstrictor,
bronchodialator

 Eicosa: (Greek) = 20.
 Precursor of eicosanoids: Polyunsaturated fatty acids.
 Are chemical messengers.
 Chemical messengers: neurotransmitters, cytokines,
hormones, retinoid, eicosanoids, and growth factors.
 Needs receptors: either plasma membrane or intracellular
binding protein.
 E.g. Ion-channel receptor, tyrosine kinase receptor.

 Produced only when necessary
 Not stored in body
 Extremely short half-life
 Biological action mediated by G-protein coupled
receptor – different in different cells
 Acts locally

 Required for synthesis of prostaglandin, thromboxane, leukotriene,
and lipoxin.
 Compromises mitochondrial membrane integrity.
 Low level of DHA: RETINITIS PIGMENTOSA.
 EFA deficiency is exacerbated by trans-fatty acids.
 EFA deficiency can be reversed by administering Vitamin B / fat-free
liver extract in diet.
 Source of trans-fatty acids: ruminant fat (E.g. butter: 2-7%)  arise
from action of microorganism present in rumen.
 Main source: vegetable oil (partially hydrogenated vegetable oil)

 Takes part in inflammatory response: infection/injury
 E.g. forming blood clot, pain, swelling, and fever.
 Takes part in smooth muscle contraction (intestine, uterus)
 Increase water retention, sodium excretion, regulation of blood
pressure.
 Acts as modulator (Activator & Repressor)
 Blood vessel constrictor as well as dilator

 Synthesized in small amount
 Action is localized
 Not synthesized by special gland

Functions of TXA2

 PG + third letter.
 PG: Prostaglandin + A, C, D,
F.
 No. represents bonds.
 Nomenclature: 4 things to
care about
 No. of carbon atoms, no. of
bond`s, position of bonds,
carbon no. containing bond.

 From Archidonic acid (5,8,11,14-eicosatetraenoic acid)
 Epinephrine or Bradykinin binds with receptor 
induce Phospholipase A2 secretion  releases
Archidonic acid from membrane bound phospholipids
 Oxidation and cyclization of Archidonic acid to PGG2 
converted to PGH2 (Enzyme: glutathoine-dependent
peroxidase)

 Pathways: 3 pathways
 1. Cyclooxygenase pathway (prostaglandins,
thromboxanes)  TX1 series
 2. Lipoxygenase pathway (leukotrienes) – TX2 series.
 3. Cytochrome p450 pathway
 Derived from: linoleate, a-linoleate, dietary archidonate,
ecosapentaeonate.
 Isoprostanes: new class of eicosanoids, similar to
prostaglandins – may play role in inflammatory response.

 Divided into 3 categories
Prostanoids
Eicosanoids
Leukotrienes (LTs) Lipoxins (LXs)
Prostaglandins, Prostacyclins, Thromboxanes
1 2 2

 5 carbon ring structure
 Originated from arachidonic acid
 Name derived from prostate gland
 2 groups of prostaglandins were originally defined as
PGE (Ether-soluble) and PGF (Buffer-soluble)
 Each group contains numerous subtypes: PGE1, PGE2,
PGF …

 Six membered, ring containing an ether
 Are produced by platelets (called
thrombocytes)
 Act in formation of blood clot
 And reduction of blood flow to the site of clot

 First found in leukocytes
 Contains 3 conjugated double bonds
 They are powerful biological signals
 For example: leukotriene D4 derived from leukotrienes
A4, helps induces contraction of smooth muscle lining,
the muscle lining of airways to lungs.
Over production of leukotrienes causes asthmatic
attacks. Leukotrienes production is the one target of
antiasthmatic drugs.

 Synthesized by almost all cells.
 From: Polyunsaturated fatty acids with 20-carbon atom.
 Fatty acids esterified with membrane phospholipids
 Dietary precursor of prostaglandin: Linoleic acid
 Linoleic acid  elongation  desaturation

 Most common: Archidonic acid
 E.g. Eicosatetraenoic acid (Polyunsaturated, 20 carbons, 4
double bonds)
 Archidonic acid is not synthesized in body, have to be
supplied in diet.
 Dietary source: Linoleate  present in plant oils.
 Diet affect cell membrane composition.

 3 pathways: COX, LOX, cytochrome p450
 COX  prostaglandin and thromboxane
 LOX  leukotriene, lipoxin and HETE
Structure of Prostaglandin and Thromboxane

In polymorphonuclear
leukocytes
In platelets
In eosinophilic
leukotyces

Trihydroxy
derivative of
arachidonic acid.

 Synthesis of prostaglandin are partially controlled.
How?
 Self-catalyzed destruction  switch off PG synthesis.
 Function of 15-hydroxyprostaglandin dehydrogenase
 Inaction of 15-hydroxyprostaglandin dehydrogenase:
sulfasalazine/ indomethacin.

 Half-lives (t1/2) = seconds to minute
 Oxidation of hydroxy group  ketone group
 Double bond at C13 is reduced.

 Inhibited by structurally unrelated compounds
 E.g. Corticosteroids (Cortisol)
 Non-steroidal anti-inflammatory drugs
 Aspirin inhibits PG synthesis
 Aspirin – irreversibly blocks synthesis of
cyclooxygenase
 Indomethacin & Phenylbutazone – reversibly blocks
synthesis of cyclooxygenase.

 Short half life – may be minutes or so.
 Site of degradation: liver and lungs.
 Enzymes responsible: 15-a-hydroxy PG
dehydrogenase and 13-PG reductase  converts
hydroxyl group at C15 to keto group then C13 and C14
dihydroxy derivatives.

 Prostacyclin: vasodilator, inhibits platelets formation
 PGF2 stimulates uterine muscle  termination of pregnancy
 PGF  constrictor of broncho smooth muscle
 PGE: Bronchodilator
 PGE2 and D2  inflammatory response, capillary permeability
 PGs in general inhibits gastric secretion
 PGE2  lipolysis, calcium mobilization, glycogen synthesis

Glucocorticoids
administration
Induce production
of lipocortin /
macrocortin
Inhibit activity of
phospholipase A2
Synthesis of
leukotrienes &
Prostaglandins is
decreased
Inflammatory
response
decreased

Signaling molecule  binds to cell-surface receptor 
signals release of phospholipase  phospholipase
cleaves phospholipids of cell membrane  production of
eicosanoids

Role of Eicosanoids in Inflammatory Response

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Andere mochten auch

Andere mochten auch (20)

Ähnlich wie Role of Eicosanoids in Inflammatory Response

Ähnlich wie Role of Eicosanoids in Inflammatory Response (20)

Mehr von Nepalgunj Medical College and Teaching Hospital

Mehr von Nepalgunj Medical College and Teaching Hospital (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

Role of Eicosanoids in Inflammatory Response