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Physiology & Science: Therapeutics > Lipid mediators of inflammation > Flashcards

Lipid mediators of inflammation Flashcards

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1
Q

What are prostaglandins, thromboxanes, lipoxins and leukotrienes referred to as collectively?

A

Eicosanoids

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2
Q

How are the eicosanoids divided up?

A

2 branches:

  • -> prostaglandins + thromboxanes (prostanoids) via cyclooxygenases (cyclic)
  • -> leukotrienes + lipoxins via lipooxygenases (linear)
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3
Q

Eicosanoids are molecules with powerful inflammatory actions. Therefore, they are targets of which major anti-inflammatory drugs?

A
  • NSAIDS
  • Glucocorticoids
  • Lipoxygenase inhibitors
  • Leukotriene antagonists
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4
Q

What is a key difference between the formation of prostanoids (PG + TX) and histamine?

A

Prostanoids are not ‘ready-to-go’ unlike histamine

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5
Q

What is the rate-limiting step of prostanoid formation?

A

Prostanoids are generated from arachidonic acid (AA, poly-unsaturated fatty acid) - this is rate limiting.

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6
Q

How are AAs (arachidonic acids) produced?

A
  • Produced from phospholipids (PLs) via 1-step/2-step pathways
  • Steps triggered by many agents eg. thrombin on platelets and antigen-antibody rxns on mast cells
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7
Q

What impact do bradykinin and adrenaline have on formation of prostanoids?

A

They are known initiators of the cascade in production of AAs and can initiate phospholipase action at the cell membrane

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8
Q

Describe the enzyme responsible for converting AA to prostanoids

A
  • Cyclooxygenase
  • Two main isoforms: COX-1 + COX-2
  • COXs are fatty acids, attached to endoplasmic membrane
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9
Q

What are key characteristics of the COX-1 enzyme?

A
  • Constitutively active - already there
  • Responsible for ‘physiological’ roles of PGs/TXs such as…
    • regulation of peripheral vascular resistance
    • renal blood flow
    • plateley aggregation
    • gastric cytoprotection
  • So COX-1 produces PGE2 and TXA2
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10
Q

What are key characteristics of the COX-2 enzyme?

A
  • Needs to be stimulated by IL-1, TNF-a
  • Responsible for role of PGs/TXs in inflammatory responses:
    • pain
    • fever
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11
Q

What are key characteristics of the COX-3 enzyme?

A
  • Variant of COX-1
  • Pain perception of CNS
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12
Q

Leukotriene A4 can be converted to Leukotriene B4 by a hydrolase. What is the role of Leukotriene B4 (LTB4)?

A
  • Very important chemoattractant
  • Attracts cells to site of inflammation
  • To remove debris/bacteria
  • Needs to be controlled otherwise start eating healthy cells
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13
Q

Which molecule are most of the end prostanoids derived from?

A

PGH2

it makes PGI2, TXA2, PGD2, PFG2a, PGE2

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14
Q

What is epoprostenol?

A
  • Synthetic PGI2
  • Important vasodilator
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15
Q

What are tissue-specific isomerases?

A

Tend to be synthases of some sort - mainly PGD2, PGE2, PGF2a synthases.

They help to form those above from PGH2

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16
Q

What is the role of PGD2?

A
  • Bronchoconstriction
  • Inhibits platelet aggregation
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17
Q

What is the role of PGF2a?

A
  • Bronchoconstrictor
  • Uterine contraction
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18
Q

What does Thromboxane A2 do and what drug inhibits it?

A
  • TXA2 found on activated platelets -> cause platelet aggregation
  • For homeostatic balance
  • Formation inhibited by aspirin
19
Q

What are functions of PGE2?

A
  • Promotes labour - softens cervix + stimulates uterine contractions
  • Induces fever
  • Promotes duct-dependent congenital heart diseases
  • Promotes vasodilation - relaxes smooth muscle
  • Promotes resolution of inflammation by suppressing T cell receptor signalling
20
Q

What is 5-lipooxygenase and what is FLAP?

A
  • 5-lipooxygenase forms LTA<strong>4</strong> (leukotrienes) from AA
  • FLAP is a protein needed to activate 5-lipooxygenase
  • FLAP engages with AA first
21
Q

What are the sulphidopeptide leukotrienes?

A
  • LTC4, LTD4, LTE4
  • Contain amino acids in structure
  • Formed from LTA4
22
Q

What is the general role of lipoxins and cyPG during resolution?

A

There is a switch for PG synthesis from pro-inflammatory (PG + LTs) at onset of inflammation to anti-inflammatory lipoxins and cyPG during resolution.

23
Q

How do lipoxins bring about resolution in their anti-inflammtory role?

A
  • Lipoxins recruit monocytes
  • To clear site of necrotic apoptotic neutrophils
  • Regulate activation levels of neutrophils
  • And dampen their damaging effects (inc phagocytosis of neutrophils)
24
Q

How does cyPG act in concert with lipoxins to bring about an anti-inflammatory effect?

A
  • cyPGs promote phagocytic clearance of apoptotic cells by macrophages -> resolution of inflammation
  • cyPG - inhibits macrophage activaiton -> decrease uncontrolled tissue damage; decrease NF-kB activation
  • This helps to decrease activation of inflammatory genes
25
Q

What cells are specialised to make PGD2?

A

Mast cells

26
Q

What cells are specialised to make PGI2 and PGE2?

A

Endothelial cells

27
Q

What cells are specialised to make TXA2?

A

Platelets

28
Q

What type of receptor do eicosanoids act at?

A

Act at specific G-protein-coupled receptors. They exert diverse and often contradictory actions of inflammation and are subject to local inactivation.

29
Q

Where do PG subtype eicosanoids act?

A

Act at DP, FP, IP & EP (EP1,2,3) receptors

30
Q

Where do TXs act at?

A

TP receptors

31
Q

Where do LTs act act and what physiological actions does this induce?

A
  • LTB4 - at BLT receptors
  • LTC4, LTD4, LTE4 at Cys-LT receptors
    • -> chemotactic; bronchoconstrictor; inc vasc perm; oedema; inc secretion of thick, viscous mucus
32
Q

PG receptors are found in lungs, vessels, gut, CNS, kidney and uterus. What is the physiological action of the following PG receptors:

  • DP
  • FP
  • IP
A
  • DP receptors: vasodilatation, decrease platelet aggregation, bronchoconstriction
  • FP receptors: contraction of myometrial sm muscle, bronchoconstriction
  • IP receptors: vasodilatation, decrease platelet aggregation, renin release
33
Q

What is the physiological actions of the EP1,2,3 receptors?

A
  • EP1 : contraction of bronchiole/GIT smooth muscle
  • EP2 : bronchodilation, vasodilation, relaxation of GIT smooth muscle, inc intestinal fluid secretion (watery/bicarb)
  • EP3 : contraction of intestinal sm muscle, inc gastric mucus secretion, decrease gastric acid secretion, pyrexia
34
Q

Thromboxane receptors (TP receptors) are found in vessels + platelets. What physiological action is induced by binding of the TP receptors?

A

TP : vasoconstriction, inc platelet agregation

35
Q

Leukotrienes are for general inflammation and in lungs/vascular for acute allergy responses. What are the actions of the BLT and Cys-LT receptors?

A
  • BLT (1,2) : chemotaxis + proliferation of immune cells, inc adhesion
  • cysLT (1,2) : bronchoconstriction, vasodilation, inc vascular perm
36
Q

For, leukotriene receptor antagonists, give the following:

  • Which LTs act at which type of receptor
  • Action of LTs
  • When is receptor blockade useful
  • Side-effects
  • Examples
A
  • cys-LT receptors - (LTC4, LTD4, LTE4 etc)
  • These LTs cause aiway oedema, secretion of thick mucus + sm muscle contraction
  • Blockade useful in following:
    • prevention of mild to moderate asthma
    • early to late bronchoconstrictor effects of allergens
    • exercise-induced asthma + asthma provoked by NSAIDs
  • Side effects include GI upset, irritability, dry mouth/thirst + rashes/oedema
  • Examples: zafirlukast, montelukast, pranlukast, zileuton
37
Q

How is asthma provoked by NSAIDs?

A
  • There are 2 routes of eicosanoids being made
  • Aspirin (and NSAID) will block only the COX route
  • But not the LOX (lipoxygenase) route
  • Lipoxygenase route therefore makes leukotrienes
  • Leukotrienes -> bronchconstriction, airway mucus etc -> asthma!
38
Q

What is the difference of action between leukotrienes (LTD4, LTDC4, LTE4) and histamine in the lung?

A
  • Leukotrienes are much more potent (contraction) than histamine
    • Order: LTD4, LTC4, LTE4, histamine
  • They increase cellular infiltration of eosiniphils + neutrophils
  • Increase mucus secretion
  • Increase bronchoconstriction
  • Increase airway oedema
39
Q

Which eicosanoids are important for haemostatic balance?

A
  • TXA<strong>2</strong> : promotes platelet aggregation, binds to TP receptor -> inc [Ca2+] -> contraction
  • PGI<strong>2</strong> : inhibits platelet aggregation, binds to IP receptor -> inc cAMP -> relaxation

Have opposite effects + released by endothelial cells

40
Q

In gastric acid secretion, histamine is released from ECL cells to act on what receptor + cell?

A
  • Histamine acts on parietal cells
  • by binding to H2 receptor
  • promotes acid (H+) secretion
41
Q

What receptor(s) does PGE2 bind to in mediating gastric acid secretions? What is the action of this?

A
  • PGE2 binds to EP3 receptors on
    • parietal cell -> inhibit acid secretion
    • mucus secreting cell -> stimulate mucus/bicarb secretion
42
Q

Why are poly-unsaturated fatty acids of interest to us?

A
  • PUFAs; omega-3 essential fatty acids
  • Perceived beneficial effects for our health
  • EPA - eicosapentaenoic acid
  • DHA - docosahexaenoic acid
  • Derivatives of EPA and DHA (resolvins/neuroprotectins) have anti-inflammatory actions
43
Q

What happens to the pathway when you take PUFA (poly-unsaturated fatty acids)?

A
  • PUFA intake (fish oil supplementation) increase
  • -> Decrease in arachidonic acid (AA)
  • Replaced with an increase in EPA + DHA
  • EPA + DHA become substrates for COX
  • Generates alternative eicosanoids
  • Decrease in PGE2, TXB2, LTB4, 5-HETE, LTE4
  • Increase in LTB5, TXA3, LTE4, 5-HPETE (these eicosanoids diff structure to those generated from AA)
    • LTB5 is 10-100 less chemotactic to neutrophils
44
Q

A number of novel group of mediators have also been identified from COX-mediated action on EPA and DHA. What are they?

A
  • E-series resolvins (resolvin D1-D4; EPA-derived mediators) have anti-inflammatory actions
  • Docosatrienes + neuroprotectins (D-series resolvins; DHA-derived mediators) also have anti-inflammatory effects

Physiology & Science: Therapeutics (6 decks)

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