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MODA Inflammation and immunosuppression > Lecture 2 > Flashcards

Lecture 2 Flashcards

1
Q

Bradykinin synthesis pathway

A
  1. Hageman factor becomes activated by contacting neg charged surfaces e.g LPS when leaking out of vessels during inflammation
  2. Activated hageman factor converts plasma prekallikrein to kallikrein
  3. Kallikrein cleaves HMW kininogen to bradykinin

(LMW kininogen to kalidin)

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2
Q

Inactivation of bradykinin

A
  • Kininase 1 removes C terminal arg to form des-arg-bradykinin (an agonist at B1 receptors). Mediated by several peptidases including serum carboxypeptidase
  • Kininase 2 is a peptidyl dipeptidase. Removes 2 C terminal amino acids (aka ACE)
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3
Q

Bradykinin receptors

A
  1. B1 upregulated in infalmmation (activated by cytokines esp IL-1) reponds primarily to des-arg-bradykinin
  2. B2 constitutively expressed and potently activated by bradykinin and kallidan

Both Gq coupled GPCRs

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4
Q

Activation of bradykinin receptors

A
  • Activation causes inc Ca2+ which activates cystolic phospholipase A2 (cPLA2)
  • Prostacyclin (PGI2) and NO diffuse to vascular smooth muscle layer and induce vasodialtation by inc cAMP and cGMP respectively
  • Also results in nociceptor activation since Gq activation leads to PKC activation which phosphorylates numerous ion channels involved in the sensation of pain (dry cough)
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5
Q

Hereditary angioedema (HAE) pathology

A

Caused by mutation in the gene encoding c1-INH (a c1 esterase inhibitor which inhibits kallirein). Mutation reduces inhibition so kallirein is over-expressed and patients present with severe and painful swelling.

  • Type I HAE from mutations that compromise CI-INH synthesis/secretion
  • Type II from mutations that poduce inactive C1-INH
  • ACE inhibitor associated angioedema may be linked to variation in genes that regulate the immune system (higher prevalence in African americans)
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6
Q

Treatment of HAE

A
  • Recombinant C1-INH
  • Kallikrien inhibitors
  • B2 antagonist icatibant

Predominant treatment in the UK is icatibant

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7
Q

Chemokines

A

Chemoattractant cytokines

  • CCL3 induces mast cell degranulation by acting at CCR1 receptors
  • Chemokine receptors are GPCRs (differ from cytokine receptors which are tyr kinases)
  • Nomenclature governed by N terminus cysteine e.g CXC = single amino acid between 2 cysteines
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8
Q

Colony stimulating factors

A

Stimulate formation of maturing colonies of leukocytes

Primarily used to overcome deficits in a persons WBC count following chemotherapy

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9
Q

Nerve growth factor and drugs that target it

A

NGF is a potent sensitising agent released from mast cells and macrophages. It activates signalling pathways that result in a lesser stimulus causing pain (5 degree decrease in pain threshold following an NGF injection)

  • Effects mediated by high affinity TrkA (receptor tropomyosin-related kinase A)
    • Theoretically NGF mABs that sequester NGF should reduce pain. TANEZUMAB has been developed but i still in trials
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10
Q

Annexin-A1

A

Anti-inflammatory

  • Produced by many cells and downregulates both inflammatory cell activation and mediator release
  • Actions mediated by binding to the GPCR formylpeptide receptor 2 (FPR2)
    • FPR2 is also the receptor for lipoxin
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11
Q

Production of lipid mediators of inflammation

A

e.g. leukotrienes, platelet activating factor and prostanoids (prostaglandins and thromboxane)

cPLA2 activation by Ca2+ and phosphorylation

  • Bradykinin at B2 = Ca2+ release
  • TNFa at TNFR1 promotes MAPK phos of cPLA2 at ser 505 and ser727
  • TNFa at TNFR2 = Ca2+ release

Liberation of arachodonic acid from phospholipid membrane (rate limiting step) producing leukotrienes and prostaglandins

PLA2 action on membrane also produces lysoglycerlphosphorylcholine (precursor of PAF)

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12
Q

leukotriene synthesis

A
  • Arachodonic acid → 12-HETE via 12-lipoxygenase
  • Arachodonic acid → leukotriene A4 (LTA4) via 5-lipoxygenase
  • LTA4 →LTB4 via LTA4 hydrolase
  • LTA4→LTC4, LTD4, LTE4 via LTC4 synthase

LTC-LTE4 known as the cysteinergic leukotrienes (CysLTs)

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13
Q

Leukotriene receptors

A

All LT receptors are GPCRs

LTB4 acts on BLT1 and BLT2 receptors (Gq or Gi)

CysLTs act at CysLT1 and CysLT2 receptors (always Gq)

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14
Q

Efficacy of CysLTs at different receptors

A

CysLT1: D > C > E

CysLT2: D = C > E

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15
Q

Actions of CysLTs

A

All cause bronchoconstriction, increase vascular permeability and mucus secretion

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16
Q

Montelukast

A

CysLT1 receptor antagonist used in the maintenance of asthma

CysLTs are released from mast cells and eosinophils in the airways of athmatics

17
Q

Action of LTB4

A

Potent chemoattractant and activator of neutrophils and macrophages

-upregulates neutrophil adhesion molecule expression and promotes macrophage cytokine release

  • LTB4 found in the exudate in many conditions making LTA4 hydrolase the target of many anti inflammatory drugs
  • One agent with this function was withdrawn due to causing dermatitis
18
Q

Lipoxin synthesis

A

2 main pathways:

  • 12 lipoxygenase conversion of LTA4 to LXA4
  • 15 lipoxygenase conversion of arachodonic acid to 15-S-HETE then converted to LXA4 by 5-lipoxygenase
19
Q

Actions of LXA4

A

Binds to formylpeptide receptor 2 (FPR2) which is Gi coupled

Reduced neutrophil chemotaxis and degranulation

Acts as an antagonist of CysLT1 receptors

20
Q

Platelet activating factor (PAF)

A

Formed throught the action of acetyltransferase on lyso-PAF

Acts on various GPCRs to increase thromboxane production in platelets

Chemotactic for neutrophils and can activate PLA2

21
Q

Metabolism of arachodonic acid

A

Metabolised to prostaglandins by cyclooxygenases (COX)

COX catalyses 2 reactions:

  1. arachidonic acid is cyclised and oxygenated to form the endoperoxide PGG2
  2. peroxyl in PGG2 is reduced to form PGH2
22
Q

Sources of prostanoids in inflammation

A
  • PGE2 and PGI2 tend to be produced locally by tissues and blood vessels
  • PGD2 released from mast cells
  • PGE2 and TXA2 released by macrophages in chronic inflammation
23
Q

Prostanoid receptor

A

Prostanoids act at GPCRs and some PGs can act at multiple receptors

  • DP1, EP2, EP4 and IP3 are Gs coupled and therefore inc cAMP
  • EP1, FP, TP are Gq coupled therefore inc Ca2+
  • DP2, EP3 = Gi coupled, dec cAMP
24
Q

PGD2

A
  • DP1 vasodilatation, inhibition of platelet aggregation and relaxation of GI/uterine smooth muscle
  • TP = bronchoconstriction
25
Q

PGE2

A
  • EP1 = bronchial/GI muscle contraction
  • EP2 = bronchodilatation, vasodilatation and relaxation of GI muscle
  • EP3 = GI contraction, fever, reduced gastric acid secretion, increased gastric mucus
  • EP4 sensitisation of nociceptors
26
Q

PGI2

A

Vasodilatation and inhibition of platelet aggregation

27
Q

TXA2

A

Vasoconstriction, bronchoconstriction and platelet aggregation

28
Q

PGF2a

A

Uterine contraction

29
Q

Platelet aggregation

A

Balance between pro-aggregation (TXA2) and anti-aggregation (PGI2)

In endothelial damage balance shifts towards TXA2

  • use of anti-platelet agents e.g low dose aspirin in secondary prevention of stroke
  • fish oil reduces risk of MI as it is high in eicosapentanoic acids e.g. PGI3 and TXA3
  • PGI3 more potent than PGI2
  • TXA3 less potent than TXA2
30
Q

NSAID mechanism of action

A

Inhibit COX by entering a hydrophobic channel on the enzyme and forming hydrogen bonds with an arginine residue at position 120

This prevents entrance of fatty acids (e.g. arachidonic acid) into the catalytic domain thus inhibiting PG production

Inhibition is reversible (except for aspirin)

31
Q

side effects of NSAIDs

A

Most common side effec tis GI bleeding (approx 5000 deaths pa)

People at risk of GI bleeding (age, history of gastric ulceration) given NSAIDs in combo with PPIs e.g. omeprazole or PGE1 inhibitor misopristol

32
Q

COX-2 selectivity

A

It was thought that cox2 selectivity would reduce inflammation without the side effects

The hydrophobic channel in the enzyme that NSAIDs enter is narrower in cox1 than in cox 2

Drugs were developed with bulky side chains that could pass through cox2 but not cox1

most NSAIDs e.g. ibuprofen are small and non-selective

drugs ending in -coxib tend to be cox2 selective eg etoricoxib

33
Q

Problems with cox-2 selectivity

A

Although cox2 is upregulated in inflammation it is also constitutively expressed in some endothelial and vascular mooth muscle cells

  • Inhibition = reduced PGI2 = reduced vasodilatation/ increased platetlet aggregation
  • also inhibits eNOS = less NO = less vasodilatation

Some associated with myocardial risk - ROFECOXIB withdrawn from the market

Still associated with GI risk. possibly due to interference of healing of pre-existing ulcers (NB risk is reduced with selectivity)

34
Q

Capsaicin

A

Applied topically as a cream 3/4 times a day. Activated TRPV1 on nociceptors.

Constant presence of agonist after an initial warming sensation induces a depolarising block of nociceptors as well as nocicpetor degeneration leading to pain relief

35
Q

anti-NGF drug trial

A

TANEZUMAB

mAB against NGF. High levels of NGF found in CSF of OA patients. Tanezumab used in trial for OA but trial uspended due to some subjects developing rapdily progressing OA and requiring joint replacement

It was subsuquently shown that the rate of joint replacement was the same in placebo so trial has been allowed to continue

36
Q

Naproxen and cardiovascular risk

A

Non selective NSAID

Relatively similar cardiovascular risk in naproxen, ibuprofen adn cox2 selective inhibitor

MODA Inflammation and immunosuppression (6 decks)

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