Inflammation Part 2

Question 1

What does NSAIDs stand for?

Answer 1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Question 2

List the four types of NSAIDs

Answer 2

COX-1 inhibitors
Non-selective NSAIDs
Older COX-2 inhibitors
Newer COX-2 inhibitors (aka coxibs)

Question 3

State mechanism of action for aspirin

Answer 3

Inhibits COX-1 and COX-2 enzymes

Question 4

Define COX-1 and COX-2

Answer 4

Rate limiting enzymes for prostaglandins

Question 5

Describe COX-1 and state the three functions

Answer 5

Constitutively expressed in most tissues

Functions include platelet aggregation, mucus production, gastric cytoprotection

Question 6

Describe COX-2

Answer 6

Induced by inflammation, soft tissue damage/injury and cancer

Question 7

Describe the two consequences of LPS-TLR4-NF-kB activation

Answer 7

Activation of this signalling pathway increases COX-2 expression

COX-2 in turn converts prostaglandin G2 to prostaglandin H2

Question 8

Define and describe the location and function of prostacylin (PGI2)

Answer 8

Found in endothelium, kidneys and brain

Anti-inflammatory

Functions: vasodilation; inhibits platelet aggregation; mucus production

Question 9

Define and describe the location and function of thromboxane A2

Answer 9

Found in platelets, macrophages, kidneys, smooth muscle

Pro-inflammatory

Functions: platelet aggregation/vasoconstriction

Question 10

Define and describe the location and function of prostaglandin E2

Answer 10

Found in brain, kidneys, smooth muscle

Pro-inflammatory

Functions: involved in fever and pain
Reduces perception of pain however doesn’t eliminate

Question 11

Define and describe the location and function of prostaglandin F2-alpha

Answer 11

Found in brain, kidneys, smooth muscle

Parturition; inflammatory response

Question 12

Name the four prostanoids

Answer 12

Prostacylin (PGI2)
Thromboxane A2
Prostaglandin E2
Prostaglandin F2-alpha

Question 13

Describe two consequences of selective COX-2 inhibition

Answer 13

When balance tipped in favour of TXA2 formation after COX-2 inhibition: vasoconstriction and platelet aggregation likely to occur

Increased risk of CV events such as myocardial infarction and stroke

Question 14

Describe mechanism of action of aspirin

Answer 14

Reduces production of prostaglandins (ie antipyretic, desensitised pain reception)

Inhibits COX-1 in platelets, decreases AA metabolism (steric hinderance), prevents thromboxane A2 synthesis

Question 15

What is a low dose aspirin and describe its uses

Answer 15

Mini-aspirin = 75-150 mg

Used for angina, myocardial infarction and prevention of thromboembolism after CV surgery

Question 16

Name and explain a common drug that interacts with aspirin

Answer 16

Prior use of ibuprofen will competitively inhibit aspirin action

Ibuprofen analogue (eg Loxoprofen) can be taken 6 hours before aspirin

Question 17

What is prednisone a prodrug of?

State it’s comparison to cortisol

Answer 17

Prednisolone

4-5x more anti-inflammatory than cortisol

Question 18

Describe the function of prednisone

Answer 18

Prednisone itself is inactive

Must first be converted to prednisolone (hepatic 11-beta hydroxysteroid dehydrogenase 1)

Prednisolone binds to glucocorticoid receptors

Question 19

State the five major examples of the use of prednisone

Answer 19

Endocrine disorders
Rheumatic disorders (eg RA and acute gout)
Collagen disorders
Dermatologic diseases
Allergic states (eg asthma)

Question 20

Describe and explain the first step of the glucocorticoid receptor signalling pathway- interactions with LPS/TLR4 cascades

Answer 20

1. Glucocorticoids diffuse through plasma membrane and bind to cytosolic glucocorticoid receptors inducing conformational change

Question 21

Describe and explain the second step of the glucocorticoid receptor signalling pathway with interactions- LPS/TLR4 cascades

Answer 21

2. HSP90 is released (which stabilises unbound inactive glucocorticoid receptors) uncovering two nuclear localisation motifs of glucocorticoid receptors

Question 22

Describe and explain the third step of the glucocorticoid receptor signalling pathway- interactions with LPS/TLR4 cascades

Answer 22

3. These two sites (nuclear localisation motifs of GRs) are then bound by nucleoporin and importin

Question 23

Describe and explain the fourth step of the glucocorticoid receptor signalling pathway- interactions with LPS/TLR4 cascades

Answer 23

4. Glucocorticoid receptor dimer translocates into nucleus and binds to glucocorticoid receptor DNA elements leading to upstream of glucocorticoid receptor target genes (“promoter”)

Question 24

Describe and explain the fifth step of the glucocorticoid receptor signalling pathway- interactions with LPS/TLR4 cascades

Answer 24

5. This transactivates glucocorticoid receptor target genes (eg GILZ; IkB)

Question 25

What is the timescale of the glucocorticoid receptor signalling pathway interaction with LPS/TLR4 cascades?

Answer 25

Cellular responses takes hours to days

Question 26

What does GILZ stand for?

Answer 26

Glucocorticoid-Induced Leucine Zipper

Question 27

Describe and explain the mechanism of action of GILZ

Answer 27

GILZ binds to NF-kB via the PER (proline and glutamic acid rich region) domain at the C-terminus of GILZ

Inhibits NF-kB nuclear translocation thereby inhibiting inflammation

Question 28

State the main mechanism of action of glucocorticoids as anti-inflammatory

Answer 28

Mainly via a genomic mechanism (altering gene expression via blocking gene transcription and activating anti-inflammatory factors)

Question 29

Describe and explain the three main mechanisms of action of glucocorticoids as anti-inflammatory

Answer 29

1. Inhibits PLA2 and COX-2 via inhibition of COX-2 transcription
2. Downregulates expression of inflammatory cytokines (eg IL-1; IL-6)
3. Alters the expression of numerous genes in many tissues (eg GILZ)