Lipid mediators of Inflammation

Question 1

What is eicosanoids?

Answer 1

collective name for prostaglandins, thromboxane and leukotrienes

Question 2

What 2 things can eicosanoids be split into?

Answer 2

cylooxegenases and lipooxygenases

Question 3

What are cylooxegenases?

Answer 3

prostaglandins, thromboxanes

Question 4

What are lipooxygenases?

Answer 4

leukotrienes-lipoxins

Question 5

What are eicosanoids targets for?

Answer 5

NSAIDs−glucocorticoids−lipoxygenase inhibitors−leukotriene antagonists

Question 6

What is a prostanoid?

Answer 6

prostaglandin and thromboxane

Question 7

What are prostanoids generated from?

Answer 7

arachidonic acid

Question 8

How is arachidonic acid produced?

Answer 8

2 pathways:
1 step pathway
direct conversion of phospholipids into arachidonic acid

2 step pathway
-phospholipids are converted to diacyl glycerol (by phospholipase C) or to phosphatidic acid (by phospholipase D)
-diacyl glycerol is converted to arachidonic acid by DAG lipase, and phosphatidic acid is converted to arachidonic acid by phospholipase A2
−these two pathways are triggered by many agents eg thrombin acting on platelets, and antigen-antibody reactions, by action of bradykinin and adrenaline

Question 9

What enzyme is needed to convert arachidonic acid to prostanoids?

Answer 9

Cyclooxegenase (COX)

Question 10

What is COX?

Answer 10

fatty acid attached to ER

Question 11

What are the 2 isoforms of COX?

Answer 11

COX1 and COX2

Question 12

What is COX 1 and what does it do?

Answer 12

always active

regulation of peripheral vascular resistance (thromboxane A2), renal blood flow (prostaglandinE2), platelet aggregation (thromboxane A2), gastric protection (prostaglandin E2)

Question 13

What is COX 3?

Answer 13

variant of COX 1

involved in pain perception in CNS

Question 14

What is COX 2?

Answer 14

not always active
needs to be stimulated (byIL-1b and TNF alpha)

responsible for the role of prostaglandin/thromboxane in the inflammatory response such as pain and fever

Question 15

What is the role of COX?q

Answer 15

convert arachidonic acid to two prostaglandin endoperoxides

PGG2 and PGH2, PGG2 is not stable and is converted to PGH2

Question 16

How is PGH2 converted to prostanoids?

Answer 16

isomerase enzyme

Question 17

What does thromboxane synthase do?

Answer 17

converts PGH2 to thromboxane A2

−this is important in platelet aggregation

Question 18

What is TXA2 important for?

Answer 18

platelet aggregation

Question 19

What does prostacyclin synthase do?

Answer 19

converts PGH2 to prostacyclin PGI2

Question 20

What is PGI2 important in?

Answer 20

vasodilation

Question 21

What does PGE2 do?

Answer 21

vasodilator

promotes labour through cervix dilation

Question 22

What does PGD2 do?

Answer 22

bronchoconstriction

inhibits platelet aggregation

Question 23

What does PGF2a do?

Answer 23

bronchoconstriction and uterine contraction

Question 24

What do Bradykinin and adrenaline do?

Answer 24

initiators of the cascade by initiating phospholipase action at the cell membrane.

Question 25

What can inhibit the cycloxegenase pathway?

Answer 25

aspirin

Question 26

What happens if you inhibit the cycloxegenase pathway?

Answer 26

initiate the lipoxygenase pathway bc arachidonic acid needed to make leukotrines and lipoxins

Question 27

How do you get Leuketriene A4 from arachidonic acid?

Answer 27

5-lipoxygenase with the help of FLAP converts arachidonic acid to 5-HPETE which results in the first leukotriene: leukotriene A4

Question 28

What does leukotriene A4 become?

Answer 28

amino acids can be added to leukotriene to produce leukotrienes C4, D4, and E4 leukotriene A4 can also be converted to lipoxins by other lipoxygenases

Question 29

What does PPAR gamma do?

Answer 29

reduces levels of some inflammatory mediators

Question 30

What do lipoxins recruit?

Answer 30

monocytes to clear the inflammation

Question 31

What do CyPGs do?

Answer 31

- work with lipoxins and prostaglandin D2 - promote Phagocytosis of apoptotic cells by macrophages - Ihibit macrophage activation thus reducing uncontrolled tissue damage - reduce NF kappa B activation (by controlling the levels of I kappa B alpha which is an inhibitor of NK kappa B) which helps to reduce activation of inflammatory genes

Question 32

What do mast cells make?

Answer 32

PGD4

Question 33

wHAT DO ENDOTHELIAL CELLS MAKE?

Answer 33

PGI2, PGE2

Question 34

What do eicosanoids act on?

Answer 34

G coupled receptors

Question 35

Which receptors do prostaglandins act on?

Answer 35

E4 receptors E2 receptors are involved in bronchodilation E3 receptors are involved inb ronchoconstriction

Question 36

What receptors do thromboxane act on?

Answer 36

TP receptors

Question 37

What does leukotriene B4 act on?

Answer 37

t BLT receptors

Question 38

What does LTB4 do?

Answer 38

leukotriene C4, D4, and E4 act onCys-LT receptors LTB4 is chemotactic, leads to bronchoconstriction, increases vascular permeability, increases oedema, and increases secretion of thick viscous mucous

Question 39

Why shouldn't you prescribe aspirin to someone with asthma?

Answer 39

since COX gets blocked by aspirin arachidonic acid goes on to produce leukotrienes through the lipoxygenase pathway bronchoconstriction

Question 40

What problems do Cys leukotrienes (LTC4, LTD4, LTE4) cause?

Answer 40

airway oedema, secretion of thick mucous, and smooth muscle contraction

Question 41

What are antagonists for the CysLT receptor?

Answer 41

Montelukast, pranlukast, and zileuton

Question 42

What do the CysLT receptor anatagonists help with?

Answer 42

prevention of mild to moderate asthma early to late bronchoconstriction effects of allergens exercise induced asthma and asthma provoked by NSAIDs (like aspirin)

Question 43

What are the effects of LTD4?

Answer 43

increased cellular infiltration of eosinophils and neutrophils increased mucus secretion increased bronchoconstriction increased airway oedema

Question 44

What can bradykinin and serotonin activate?

Answer 44

thromboxane A2 in endothelial cells

Question 45

What can shear stress cause?

Answer 45

activate prostaglandin I2 in endothelial cells this acts on IP receptor and cause vascular smooth muscle relaxation by increasing cAMP prostaglandin I2 will also reduce platelet aggregation

Question 46

What does prostaglandin E2 act on?

Answer 46

E3 receptors on parietal cells in the stomach (these cells secrete HCl)= REDUCES HCL SECRETION Prostaglandin E2 acts on E3 receptors on mucus secreting cells in the stomach = INCREASES ITS PRODUCTION

Question 47

What does fish oil contain?

Answer 47

eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that play significant roles in inflammation (anti inflam actions)

Question 48

What does poly unsaturated fatty oild (from fish) do?

Answer 48

reduces arachidonic acid this leads to an increase in EPA and DHA in the body lipoxygenase and cyclooxygenase enzymes now act on the EPA and DHA and produce structures that are slightly different to the normal PGs, TXs and LTs−there is lesser production of PGE3, TXB2, LTB4, 5-HETE, and LTE4 the consequence of this is as follows−there is an increase in production of LTB5, TXA3, LTE4, and 5HPETE in different structural forms-LTB5 is 10-100 times less chemotactic to neutrophils-ie it does not attract neutrophils

Question 49

What do E-series resolvins do?

Answer 49

E-series resolvins (resolvin D1-D4; EPA-derived mediators) have anti-inflammatory actions

Question 50

What do docosatrienes and neuroprotectins do?

Answer 50

Docosatrienes and neuroprotectins (D-series resolvins; DHA-derived mediators) have anti-inflammatory effects