Lec 28- The Eicosanoids Flashcards Preview

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Flashcards in Lec 28- The Eicosanoids Deck (18)
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1
Q

Introduction

A
  • Eicosanoids are 20 carbon fatty acids from membrane phospholipids which are oxygenated and polyunsaturated
  • Eicosanoids is the family for prostaglandins (PG), thromboxjnes and leukotrienes
  • Precursor of all molecules is arachidonic acid
2
Q

Where are they produced and how

A
  • Platelets, mast cells, endothelial cells, macrophages/ monocytes, neutrophils, eosinophils
  • In response to GPCR activation e.g. bradykinin; IL-1 and TNF on inflammatory cells
  • Phospholipase A2 activation
  • Arachidonic acid release is the first and rate limiting step
3
Q

Bradykinin (important in inflammation and respiratory tract; slows the heart) cascade

A

1) tissue injury and collagen exposure
2) Activation of blood clotting cascade
3) Kallikrein is produced; kininogen (precursor for bradykinin) interacts with kallikrein to produce bradykinin
- Activation of sensory nerve endings (Pain) and increase in vascular permeability, (also slows the heart) Eicosanoid synthesis (activates phospholipase A2 via GPCR’s)
4) bradykinin then reacts with kininases which creates an inactive peptide

4
Q

Arachidonic acid-

A

1) stimulus occurs e.g. TNF-a or IL-1
2) Phospholipase A2 (PLA2) then cleaves arachidonic acid from phospholipid membrane
- PLa2 activity can be inhibited by steroids and by endogenous protein called lipocortin. This is also done by phospholipase C
3) arachidonic acid can then react with either COX (to form PG and thromboxane) OR 5-lipoxygenase (to form the leukotrienes)

5
Q

How are PG and TXs formed (thromboxane)

A
  • Not stored- biosynthesis precedes release
  • Made by COX (addition of 2 oxygens across the double bonds
  • COX-1= constitutive, widespread
  • COX-2= inducible in inflammatory cells (cytokines switch on production of COX-2- this is therefore the main target for anti-inflammatory’s)
  • Products of COX are termed prostanoids
6
Q

PG’s and TX’s- synthesis

A

1) arachidonic acid –> (COX)
2) PGG2 then rapidly –> PGH2
- PGH2 is the prostanoid that can then be converted into many different types of PG and TX via prostanoid synthetases

7
Q

PG’s and TX’s- different types

A
  • TXA2 and TXB2- platelets
  • PGD2- Mast cells
  • PGE2- Macrophages and neutrophils
  • PGF2-a- Macrophages, uterus
  • PGI2 (prostacyclin)- Endothelial cells
8
Q

Prostanoid receptors

A
  • Specific receptors exist for each prostanoid as determined by agonists
  • Receptors classified as DP for PG D,FP for PGF
  • Basically each PG has its own receptors
9
Q

PG’s and TX’s- biological activities

A
  • PGD2 (mast cells)- vasodilator
  • PGE2 (Macrophages, neutrophils)- inflammatory mediator and vasodilator
  • PGF2-a: Smooth muscle contraction; gonadotrophin and prolactin release from corpus lute
  • PGI2- vasodilation and decreases platelet aggregation
  • TXA2/B2- induces platelet aggregation and Vaso and broncho constriction
10
Q

PGE2 receptor and effects

A
  • EP1- smooth muscle contraction
  • EP2- Smooth muscle relaxation, increase GI fluid secretion
  • EP3- smooth muscle constriction decrease in acid secretion, increase in mucous secretion
11
Q

Pathophysiological role

A
  • Key inflammatory mediators
  • Effect acute and chronic inflammation
  • Effect on smooth muscle
  • PGD2 and E2 from macrophages, mast cells, neutrophils–>vasodilation, oedema
  • PGE2 –> pain and fever if injected intradermally - via EP2 receptors
12
Q

PGE2 in inflammation

A
  • Causes pain and sensitises sensory nerves (makes body more aware of painful stimuli) to other painful stimuli (e.g. bradykinin)
  • Enhances bond turnover and cartilage degradation in arthritis
  • Acts on cold sensitive neurones in hypothalamus- fever (this is how paracetamol works inhibit COX-1 so inhibit production of PGE2)
  • Modulation of prostanoid synthesis is an important goal in control of inflammation
13
Q

How are PG’s metabolised

A

t1/2 - 1 min, plasma [100pg/ml]

  • Broken down enzymically by oxidation, by enzyme present in kidney and lung
  • 15-hydroxyprostaglandin dehydrogenase (15-pgdh)
14
Q

Can prostanoids be used therapeutically

A
  • Obs and gynae- to induce abortion or labour e.g. dinoprostone (PGE2 analouge)
  • GI protection- misoprostol (PGE2 analogue)- to prevent gastric ulcers in NSAID users
  • CVS- epoprostenol (PGI2)- inhibit platelet aggregation
  • Glaucoma- latanoprost (PGF2a analogue) increases aqueous humour outflow
15
Q

Lipo-oxygenases

A
  • Lipoxygenases are activated by Ca2+, ATP and FLAP (5-lipoxygenase activating protein)
  • First product from 5-HPETE is LTA4- unstable epoxide- all LT’s derive from this produced by leukocytes
  • LTB4= simple lipid from neutrophils
  • LTC4 (eosinophils), D4 and E4= sulphide-peptidyl LT’s formed by glutathione S-transferase
16
Q

LT formation

A

1) Arachidonic acid–> (5-lipo-oxygenase)
2) 5HPETE –>
3) LTA4 (equivalent to PGH2) –>
4) LTB4 (neutrophils) OR
5) pepidyl LT
- LTA4 reacts with glutathione-S-transferase (this protects against free radicals as well) this molecules links with LTA4 to form LTC4
6) LTD4 is LTC4 with 1 less amino acid
7) LTE4 is LTD4 with 1 less amino acid

17
Q

Physiological role of LT’s

A
  • LTB4; neutrophil activation
  • LTC4, D4 increase vasodilation (not coronary), permeability and bronchoconstriction
  • LTC4,D4,E4 increase mucous secretion
  • LTB4 raised in acute inflammation psoriasis, RA then levels subside
  • All sulphide-LT’s= SRS-A, slow reacting substance of anaphylaxis- more potent and longer lasting than histamine as bronchoconstrictor- Asthma
18
Q

Other lipid mediators

A
  • Lipoxins; anti-inflammatory mediators made from arachidonic acid
  • Platelet activating factor (PAF); vasodilator, increases vascular permeability, bronchoconstrictor, made by PLa2