Innate Immunity: Inflammation

Question 1

Describe histamine

Answer 1

Synthesised from histidine, stored and released from: Mast cells, basophils, neurons, ECLs
Pre-made in secretory heparin granules
Also released by complement C3a and C5a, thru rise in [Ca2+]i.
Metabolised by INMT and diamine oxidase
Histamine inhibited by β-adrenoceptor stimulation
4 types of receptors: H1-4

Question 2

What is the effect of H1 and H2 receptor stimulation on the CVS?

Answer 2

If H1 is stimulated:
-vasodilation
-Increased venule permeability, which decreases blood volume
If H2 is stimulated:
-Increase in HR
-Decrease BP due to decrease in vascular resistance

Question 3

Give the other effects of H1 and H2 stimulation

Answer 3

Contraction (H1)
Algesia: Pain, itching, sneeze via sensory nerve stimulation(H1)
↑ exocrine secretions due to increased BF
↑ gastric acid secretion (H2 –mediated)

Question 4

Describe the triple response

Answer 4

Antidromic impulses cause vasodilation distant from the site of irritation.
This leads to the third phase of inflammation= flare
Flare, flush, wheal, reddening

Question 5

Give the 1st Generation H1 antagonists

Answer 5

mepyramine, promethazine, diphenhydramine

Question 6

Give the 2nd Generation H1 antagonists

Answer 6

Terfenadine: pro-drug w cardiac arrhythmia actions in high concs ↑ w grapefruit juice (inhibits P450 drug metabolism)
Fexofenadine = active, non-toxic metabolite of terfenadine
These drugs do not cross the BBB

Question 7

What are the theraputic and side effects of H1 antagonists?

Answer 7

Reduce minor inflammation (insect bites, hayfever), BUT NO significant value in asthma
1st gen drugs cross the BBB and are sedative, causing drowsiness
Some (e.g. promethazine) are anti-emetic
Anti-muscarinic actions (common in 1st gen drugs) e.g. atropine-like effects of blurred vision, constipation, etc.

Question 8

Describe the H2 antagonists and how they are used in gastric problems, giving the side effects

Answer 8

Cimetidine, ranitidine reduces HCl secretion in treatment of ulcers and Zollinger-Ellison
Increase INMT activity so more rapid histamine breakdown
Side effects: confusion, dizziness, tiredness & diarrhoea
Cimetidine decreases cP450 activity so potential adverse drug interactions; gynecomastia

Question 9

Give the pharmacological effects of bradykinin

Answer 9

Increases vascular permeability
Vasodilation (↓BP)
Pain, dry cough
Contracts gut and bronchial sm
Generates prostanoids→ release lipid inflammatory mediators
Chemotactic to leukocytes, which defend against infections

Question 10

Describe the metabolism of bradykinin

Answer 10

Metabolism of bradykinin: kininases, I and II (ACE, aminopeptidase P, carboxypeptidase)

Question 11

Describe the distribution of 5-HT- which cells and areas of the body are they found in?

Answer 11

Platelets (release 5-HT and TXA2) → platelet aggregation
ECF cells of GI tract (mediates gut movement, diarrhoea)
Brain (cognition, aggression, mating, feeding, sleep, pain, vomiting)
Some tumours (e.g. carcinoid) secrete excess 5-HT →↑ proliferation, and cell survival

Question 12

Describe the inflammatory actions of 5-HT

Answer 12

Increases mast cell number, adhesion and migration at injury site
Enhances inflammation of skin, lungs and gut
May synergise with TXA2 to stimulate platelets + vasoconstriction
Release of 5-HT from platelets plugs the injured site, which briefly constricts injured arteries/oles

Question 13

What are Eicosanoids?

Answer 13

Question 14

Why are eicosanoids important?

Answer 14

Molecules with powerful inflammatory actions
Targets of major anti-inflammatory drugs:
NSAIDs
Glucocorticoids
Lipoxygenase inhibitors
Leukotriene antagonists

Question 15

How are prostanoids formed? What are they made from?

Answer 15

Prostanoids are not ‘ready-to-go’, like histamine
They’re made from arachidonic acid (rate-limiting step)
AAs are produced from phospholipids via 1-2-step pathways, triggered by many agents:
eg thrombin on platelets and Ag-Ab reactions on mast cells

Question 16

Conversion of AA to prostanoids requires the COX enzyme, which has isoforms COX-1 and COX-2 (and COX-3)

Describe these isoforms

Answer 16

COX-1: Constitutively active, more involved physiologically
eg regulates peripheral vascular resistance, renal BF, platelet aggregation, gastric cytoprotection
COX-2: Needs to be stimulated (e.g. by IL-1 beta, TNFa)
Responsible for PGs/TXs in pain and fever
COX-3: Variant of COX-1; pain perception of CNS

Question 17

Draw out the cyclooxygenase pathway

Answer 17

White font= enzymes
Yellow= different products

Question 18

Draw out and label the lipooxegnase pathways

Answer 18

Question 19

PG synthesis switches from pro-inflammatory (PG & LTs) at onset of inflammation to anti-inflammatory lipoxins and (cyPG) during resolution
Describe how this happens

Answer 19

Lipoxins recruit monocytes/macrophages to clear apoptotic neutrophils which resolves inflammation
They regulate neutrophil activation, dampen damaging effects
CypG inhibits macrophage activation, ↓NF-kB activation (helps to ↓ activation of inflammatory genes)

Question 20

Which cells make which eicosanoids?

Answer 20

mast cells: PGD2
platelets: TXA2
endothelial cells: PGI2, PGE2

Question 21

Where do the eicosanoids act to exert diverse+contradictory actions in inflammation?

Answer 21

PGs act at DP, FP, IP and EP (EP3 for PGI2) receptors
TXs at TP receptors
LTB4 at BLT receptors
LTC4, LTD4 & LTE4 at Cys-LT receptors. This is chemotactic, so bronchoconstrictor & ↑ vascular permeability, oedema, ↑thick mucus secretion

Question 22

Describe actions of eicosanoids at DP, FP and IP receptors

Answer 22

DP receptors: Vasodilatation, ↓ platelet aggregation, bronchoconstriction
FP receptors: Contraction of myometrial smooth muscle, bronchoconstriction
IP receptors: Vasodilatation, ↓ platelet aggregation, renin release

Question 23

Describe actions of eicosanoids at EP receptors
also remember…

Answer 23

EP1 receptors: Contraction of bronchiole/GIT smooth muscle
EP2 receptors: Bronchodilation, vasodilatation, relaxation of GIT sm, ↑ intestinal fluid secretion
EP3 receptors : Contraction of intestinal sm, ↑ gastric mucus secretion, ↓ gastric acid secretion, pyrexia

Remember PGE2 acts at EP3 receptors!

Question 24

Describe the action of TXs and LTs on their different receptors

Answer 24

TXs on TP receptors: Vasoconstriction, ↑ platelet aggregation

LTs on BLT (1 & 2) receptors:Chemotaxis and immune cell proliferation
On CysLT (1 & 2) receptors: Bronchoconstriction, vasodilatation, increased vascular permeability

Question 25

What is the effects of the mediators on bronchospasm?

Answer 25

Question 26

What are leukotrine receptor antagonists?

Answer 26

Eg: Zafirlukast, montelukast, pranlukast
Block cysteinyl LT receptors (LTC4, LTD4, LTE4, etc.)
These LTs cause airway oedema, thick mucus secretion and sm contraction

Receptor blockade prevents: mild/moderate asthma
Early to late bronchoconstrictor effects of allergens
Exercise and NSAID induced asthma

Question 27

Give the side effects for leukotriene receptor antagonists

Answer 27

GI upset
Dry mouth, thirst
Rashes, oedema
Irritability

Question 28

Use this diagram to explain why aspirin is not good for asthmatics

Answer 28

Aspirin blocks the Cox pathway, so the arachidonic acid is going to go through the lipoxygenase pathway.
This pathway leads to powerful inflammatory mediators, causing broncoconstriction, increased chemotaxis, ↑mucus secretion, ↑ vascular permeability

Question 29

How are NSAIDs associated w GI bleeds?

Answer 29

NSAIDs is a COX inhibitor, which stops prostanoid synthesis (PGs and TXA2)
(PGs) protect the epithelial cells of the stomach by:
Stimulating HCO3- which neutralises gastric acid
Reducing H+ secretion
Stimulating mucus production and vasodilation
Thus GI bleed can be from aspirin overdose

Question 30

Explain the effects of local hormones on permeability and blood flow

Answer 30

Histamine increases BOTH blood flow and permeability
PGs increase blood flow
Bradykinin increases permeability