Innate Immunity: Inflammation Flashcards
Describe histamine
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
What is the effect of H1 and H2 receptor stimulation on the CVS?
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
Give the other effects of H1 and H2 stimulation
Contraction (H1)
Algesia: Pain, itching, sneeze via sensory nerve stimulation(H1)
↑ exocrine secretions due to increased BF
↑ gastric acid secretion (H2 –mediated)
Describe the triple response
Antidromic impulses cause vasodilation distant from the site of irritation.
This leads to the third phase of inflammation= flare
Flare, flush, wheal, reddening
Give the 1st Generation H1 antagonists
mepyramine, promethazine, diphenhydramine
Give the 2nd Generation H1 antagonists
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
What are the theraputic and side effects of H1 antagonists?
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.
Describe the H2 antagonists and how they are used in gastric problems, giving the side effects
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
Give the pharmacological effects of bradykinin
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
Describe the metabolism of bradykinin
Metabolism of bradykinin: kininases, I and II (ACE, aminopeptidase P, carboxypeptidase)
Describe the distribution of 5-HT- which cells and areas of the body are they found in?
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
Describe the inflammatory actions of 5-HT
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
What are Eicosanoids?
Why are eicosanoids important?
Molecules with powerful inflammatory actions
Targets of major anti-inflammatory drugs:
NSAIDs
Glucocorticoids
Lipoxygenase inhibitors
Leukotriene antagonists
How are prostanoids formed? What are they made from?
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
Conversion of AA to prostanoids requires the COX enzyme, which has isoforms COX-1 and COX-2 (and COX-3)
Describe these isoforms
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
Draw out the cyclooxygenase pathway
White font= enzymes
Yellow= different products
Draw out and label the lipooxegnase pathways
PG synthesis switches from pro-inflammatory (PG & LTs) at onset of inflammation to anti-inflammatory lipoxins and (cyPG) during resolution
Describe how this happens
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)
Which cells make which eicosanoids?
mast cells: PGD2
platelets: TXA2
endothelial cells: PGI2, PGE2
Where do the eicosanoids act to exert diverse+contradictory actions in inflammation?
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
Describe actions of eicosanoids at DP, FP and IP receptors
DP receptors: Vasodilatation, ↓ platelet aggregation, bronchoconstriction
FP receptors: Contraction of myometrial smooth muscle, bronchoconstriction
IP receptors: Vasodilatation, ↓ platelet aggregation, renin release
Describe actions of eicosanoids at EP receptors
also remember…
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!
Describe the action of TXs and LTs on their different receptors
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
What is the effects of the mediators on bronchospasm?
What are leukotrine receptor antagonists?
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
Give the side effects for leukotriene receptor antagonists
GI upset
Dry mouth, thirst
Rashes, oedema
Irritability
Use this diagram to explain why aspirin is not good for asthmatics
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
How are NSAIDs associated w GI bleeds?
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
Explain the effects of local hormones on permeability and blood flow
Histamine increases BOTH blood flow and permeability
PGs increase blood flow
Bradykinin increases permeability
