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INFECTION AND IMMUNOLOGY > ML Watson Lec 3 & 4 > Flashcards

ML Watson Lec 3 & 4 Flashcards

1
Q

1) What are Eicosanoids the product of?

2) What is the main Eicosanoid precursor in mammals?

A

1) The oxidation product of 20-Carbon fatty acids

2) Arachidonic acid

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2
Q

What are the 4 CLASSICAL eicosanoids?

A

1) Prostaglandins (E2)
2) Prostacyclins (I2)
3) Leukotrienes
4) Thromboxanes

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3
Q

What are the 4 NON-CLASSICAL eicosanoids?

A

1) Lipoxins
2) Resolvins
3) Isoprostanes
4) Endocannabinoids

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4
Q

PAF is an inflammatory mediator - what does it stand for?

A

Platelet activating factor

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5
Q

Explain in 3 steps how Phospholipids become either prostaglandins or thromboxanes

A

1) Cell damage activates PLA2
2) PLA2 liberates Arachidonic acid from phospholipid
3) Arachidonic acid is metabolised by COX-1 and COX-2 to form prostaglandins (PGI2, PGE2) and thromboxanes (TxA2)

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6
Q

Explain in 3 steps how Phospholipids become leukotrienes, lipoxins or other compounds

A

1) Cell damage activates PLA2
2) PLA2 liberates arachidonic acid from phospholipids
3) Arachidonic acid is metabolised by lipoxygenases to form leukotrienes (LTB4, LTC4, LTD4) lipoxins or other compounds

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7
Q

How is PAF derived?

A
  • Derived from phospholipid precursors by PLA2 to give lyso-PAF
  • Acetylation of lyso-PAF gives PAF
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8
Q

What do prostaglandins act via?

A
  • Specific GPCRs on target cells (cell membrane receptors)
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9
Q

What is the receptor for prostacyclin (PGI2)

A

IP

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10
Q

There are 4 PGE2 receptors EP1-4 and an IP receptor. Which of these are vasodilators?

  • What do these do?
  • How are they coupled?
A
  • EP2 and IP receptors
    (receptors on smooth muscle)
  • Enhance plasma extravasation
  • Gs coupled to adenylyl cyclase, increases cAMP (SM relax and inc blood flow)
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11
Q

What does the Thromboxane (TP) and PGF2 (FP) receptor do?

A
  • Cause SM contraction

- Gq coupled to PLC - IP3 and calcium

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12
Q

TXA2 activates ____ and increases airway obstruction by inducing ____ muscle ____ and ____ cell mucus secretion

A

1) leukocytes
2) smooth
3) contraction
4) goblet

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13
Q
  • Which of the following statements applies to COX-1
    1) Is present in most cells as a constitutive enzyme that produces prostanoids that act as homeostatic regulators (e.g modulating vascular responses)
    2) Is not normally present (at least in most tissues) but it is strongly induced by inflammatory stimuli and therefore believed to be more relevant to inflammation therapy
A

Statement 1:

COX-1 is present in most cells as a constitutive enzyme that produces prostanoids that act as homeostatic regulators (e.g modulating vascular responses)

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14
Q

How does PGE2 work?

- Inflamm

A

1)

  • Promotes vasodilation
  • Activates cAMP coupled EP2 receptors on vasc SM
  • Inc vasc permeability by enhance release of histamine and other mediators from tissue leukocytes e.g mast cells
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15
Q

Prostaglandins sensitise peripheral _-____. This ____ pain response to other agents and ____ algesic response to C____

A

1) C-Fibres
2) Increases
3) Increases
4) Capsaicin

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16
Q

Which receptors in the dorsal root ganglia play a role in the pain pathway?

A
  • EP1 receptors

- EPI receptor knock out mice have decreased inflammatory pain responses

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17
Q

How is fever regulated in relation to prostaglandins?

Which receptor plays a role?

A
  • Production and action of PGE2 in the anterior hypothalamus
  • Role for the EP3 receptor
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18
Q

Is fever regulated by PGE2 sensitive to NSAIDs or paracetamol?

A
  • NO
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19
Q

Which of the following are induced by TNF-alpha, IL-1 and repressed by glucocorticoids?

COX-1 or COX-2?

A

COX-2

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20
Q

What is the definition of COX-2 specificity?

A
  • Inhibition of COX-2 but not COX-1, across the entire therapeutic dose range
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21
Q

Arachidonic acid interacts with COX-1 and 2 by binding to a crucial residue in the binding site. Is arachidonic acid specific or non specific and why?

A
  • NON-SPECIFIC

- There are no side chains to sit deep into the pocket so no specificity to either active site

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22
Q

____ is selective for COX-2.

Naproxen or Celecoxib

WHY?

A

Celecoxib.

It has a long side chain that sits deep into the pocket where the critical residence resides, giving specificity to the active site of COX-2

Naproxen has no such side chain making it non-specific

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23
Q

How can NSAID selectivity for COX-1 and COX-2 be studied?

A
  • As a ‘potency ratio’

- The IC50 values for blocking the two enzymes

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24
Q

Put the following in order of COX-2 selectivity…

Ibuprofen
Rofecoxib
Celecoxib
Aspirin

A

1) Rofecoxib (COX-2)
2) Celecoxib (COX-2)
3) Ibuprofen (MIXED)
4) Aspirin (LOW DOSE COX-1)

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25
Q

What PGs are responsible?

1) Initiation of labour
2) Inhibition of gastric acid secretion, increased gastric mucus production
3) Inhibition of platelet aggregation and vasodilation
4) Platelet aggregation and vasoconstriction

A

1) PGF2-alpha and PGE2
2) PGE2
3) PGI2 from endothelium
4) TXA2 from platelets

26
Q

What are some side effects of aspirin like drugs?

A
  • GI irritation and bleeding
  • Renal toxicity
  • Bleeding due to blocking housekeeping COX-1
27
Q

What was the issue with Rofecoxib?

HINT: PGI2 vs TXA2

A
  • Rofecoxib is a COX-2 selective NSAID
  • PGI2 is responsible for inhibition of platelet aggregation and vasodilation BUT is derived mostly from COX-2
  • Rofecoxib suppresses PGI2 but has no effect on TXA-2 that is from COX-1

THUS… PGI-2 decreased (less inhibition of aggregation)
TXA-2 remains (so net increase of blood clotting)

Means increased incidence of thromboembolic events!

28
Q

How does aspirin exert an anti-thrombotic action?

A
  • Aspirin acetylates COX thus platelet TXA2 production ceases for the life of the platelet
  • BUT endothelial cells make new endothelial COX so PGI2 is still released as it recovers rapidly compared to platelet COX

SO PLATELET COX-1 INHIBITION IS BENEFICIAL IN THROMBOSIS

29
Q

Why are selective COX-2 inhibitors BAD?

A
  • They affect PGI2 more than TXA2

- THUS, less anti platelet aggregation but same platelet aggregation and vasoconstriction

30
Q

Leukotrienes are formed by 5-lipoxygenase conversion of arachidonic acid.

Which Leukotrienes are responsible for bronchoconstriction?

A
  • LTC4 and LTD4

- They also increase effects of other constrictor agents

31
Q

Which Leukotrienes are responsible for Oedema?

- Are they neutrophil dependent or independent?

A
  • LTC4 and LTD4
  • Stimulate increased vascular permeability (independent)
  • LTB4
  • Simulate increased vascular permeability (dependent)
32
Q

Which Leukotrienes are responsible for Chemotaxis of inflammatory cells?

A
  • LTB4 on the BLT1 receptor
33
Q

Are there HIGH or LOW levels of leukotrienes in RA patients?

A
  • HIGH
34
Q

How do glucocorticoids inhibit COX?

A
  • The indirectly inhibit COX by inhibiting PLA2 transcription
  • Also induce synth of PLA2 inhibitor LIPOCORTIN
  • ALSO inhibit COX-2 synthesis
  • Therefore, PLA2 cannot liberate arachidonic acid from membrane phospholipids to make prostaglandins and leukotrienes
35
Q

How does Zileuton work?

A
  • It inhibits 5-lipoxygenase

- Prevents conversion of arachidonic acid to leukotrienes

36
Q

How does Zafirlukast and montelukast work?

A
  • These leukotriene antagonists inhibit action of LTC4 and LTD4
  • Used in asthma
37
Q

How do NSAIDs work?

A
  • Inhibit COX

- Prevent Arachidonic acid conversion to Prostaglandins

38
Q

Why are eicosanoids important?
List the ones responsible for the following…

1) Vasodilation (___,___)
2) Vascular permeability (__’s)
3) Synergy with other mediators e.g
____
____
____
4) Pain (___,___)
5) Fever (____)

A

1) PGE2, PGI2
2) LT’s
3)
Histamine
Bradykinin
Chemotaxins
4) PGE2, PGI2
5) PGE2

39
Q

What is EPA (omega 3 fatty acid) metabolised by and to?

A
  • BY COX

- TO PGI3 (potent pro-aggregatory) and TxA3 (weak pro-aggregatory)

40
Q

Leukocytes move from the ____ to sites of ____ and ____ activation.

A

1) Blood
2) Inflammation
3) Immune

41
Q

Directional control of Leukocytes is co-ordinated by tissue expression of ____ molecules and ____ stimuli for Leukocyte migration.

A
  • Adhesion

- Chemical

42
Q

What are the 4 steps in Leukocyte diapedesis?

A

1) Circulation e.g of neutrophils
2) Tethering/rolling
3) Firm adhesion
4) Transmigration

43
Q

Explain the 4 steps in Leukocyte diapedesis…

A
  • Inflammatory signals induce endothelial cells to exocytose P selection and synthesis PAF which appears on cell surface
  • P selection molecules bind oligosaccharide groups at leukocyte cell surface
  • Weak adhesion causes rolling along endothelial cells
  • Leukocytes also have PAF receptors and integrins.
  • Receptor binding to PAF results in activation of integrins
  • Causes integrins to bind iCAM molecules expressed on endothelial cells
  • Leukocyte then tightly adheres to endothelium
  • Migrates between endothelial cells to reach underlying tissue
44
Q

E-selectin expression on endothelial cells is induced by ____ or _ _ _

A

Cytokines or LPS

45
Q

Expression of E selection is inhibited by ______

A

glucocorticoids

46
Q

What does LAD II stand for?

A
  • Leukocyte adhesion deficiency-II
47
Q

What is LAD II?

A
  • Patients suffer recurrent infections and die
  • No pus and neutrophilia
  • Leukocytes do not express selection ligands
  • Decreased rolling response on E or P selections
  • Severely impaired neutrophil accumulation in skin inflammation
48
Q

Integrins are expressed on the surface of _____

A

Leukocytes

49
Q

Leukocyte B2 interns can form _ heterodimers

A

3
alphaL/B2
alphaM/B2
alphaX/B2

50
Q

Leukocyte activation induces ______ change - affinity

Leukocyte activation induces clustering of ___ - avidity

A

1) conformational

2) integrins

51
Q

LAD I is…

A
  • Patients suffer recurrent bacterial infections without pus
  • Leukocytes do not adhere to extracellular material or endothelium in vitro
  • Leukocytes deficient in B2 integrin
52
Q

Which of the following integrins is induced by cytokines IL-1 and TNF?

ICAM-2 or ICAM-1

A

ICAM-1

ICAM-2 is basally expressed on endothelium

53
Q

VLA-4 expressed on eosinophils, monocytes and _ cells

What is it induced by?

A

T

Induced by cytokines

54
Q

Natalizumab is an anti _ _ _ - _ antibody

What does it do?

A

VLA-4

Prevents new inflammatory lesions. Dampens down inflammation by preventing T cell infiltration

55
Q

Transmigration involves chemoattractants (chemotaxins) and ___s

A

CAMs - cellular adhesion molecules

56
Q

Give some examples of non-selective chemotaxins…

A

1) LTB4
2) C3a, C5a
3) formyl peptides

57
Q

Chemokines are SELECTIVE GPCRs and are produced in response to __, __ and ___

A

IL-1, TNF, bacteria

58
Q

CXC chemokines are mainly _____ attractants

A

Neutrophil

59
Q

CC chemokines are NOT neutrophil attractants! They target Eosinophils, Basophils, ____ and activated T cells

A

MONOCYTES

60
Q

Which of the following are involved in chronic inflammation?

Neutrophils, monocytes, lymphocytes

A

Monocytes and lymphocytes

Neutrophils are involved in acute inflammation

61
Q

Match the following

1) Different selection and CAM expression
2) Different chemokine expression

1) Different integrin expression
2) Different chemokine receptor expression

Tissues, Leukocytes

A

First two statements = Tissues

Second two statements = Leukocytes

INFECTION AND IMMUNOLOGY (14 decks)

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