Inflammation Flashcards
What is inflammation? What are the signs of inflammation?
It is the body’s defence response to:
- invasion – pathogens (disease-causing), allergens (non-disease)
- injury - heat, ultraviolet, chemicals
signs of inflammation
calor - increased blood flow, warmth/heat
rubor - increased blood flow, redness
dolor - pain, activation of sensory nerves
tumor - swelling, increased post capillary venule permeability
function laesa - loss of function
What are NSAIDS?
NSAIDS are Non-Steroidal Anti-inflammatory Drugs
- analgesic (prevention of pain)
- anti-pyretic (lowering of raised temperature, fever)
- anti-inflammatory (decrease an immune response)
What are NSAIDS used to treat?
NSAIDS are used to treat:
- low grade pain (chronic inflammation, e.g. arthritis)
- bone pain (cancer metastases)
- fever (associated with infections)
- inflammation ( symptoms- oedema, redness, itch)
What are local hormones?
local hormones are also known as autocoids
- produced in response to a wide range of stimuli
- synthesised or released only as and when required
- local release for local action
- inactivated locally to minimise systemic effects
What is histamine? How is it synthesised, stored and released?
synthesis
- synthesised from histidine amino acid by histidine decarboxylase
- metabolised by imidazole-N-methyltransferase (INMT) and diamine oxidase
stored and released from
- mast cells, which express receptors for IgE on cell surface (connective tissues)
- basophils (blood)
- neurons in brain
- histaminergic cells in gut = histamine secreting cell
pre-made, ‘ready-to-go’ in secretory granules composed of heparin and acidic proteins
How is histamine release stimulated by allergens?
mast cells expresses IgE and its receptors on its surface
- allergens crosslink with IgE on the mast cell surface
- crosslink causes release of mediators (histamine) from the mast cell
= degranulation of the mast cell/release of vesicles is calcium dependent
What is the triple vascular response?
redness - depends on chemical mediator
flare
wheal - raised or swollen marks left behind
What are the types of histamine receptors?
H1, H2, H3 and H4
- are all G protein coupled receptors
H1 and H2 are clinically important
What is the effect of stimulating H1 and H2 receptors?
cardiovascular
- dilates arterioles and reduces TPR = H1
- increased permeability of post capillary venules = H1
- increased HR = H2
- decrease blood pressure = H2
non-vascular smooth muscle = airways, gut
- contraction = H1 (bronchoconstriction)
algesia
- pain, itching, and sneezing caused by stimulation of sensory nerves = H1
gastric acid
- increased secretion = H2
associated exocrine secretions
- increased due to increased blood flow
What are the physiological effects of histamine (via the stimulation of histamine receptors)?
- gastric acid production
signal sent to the brain from the gastric vagus nerve
stimulates gastrin secretion by the G cells
gastrin
- can act on/bind to the histamine secreting cell (HSC) to stimulate histamine release . histamine can bind to H2 receptors on the parietal cell simulating gastric acid secretion
- can also act directly on the parietal cell to stimulate gastric acid release
acetylcholine
- can act on/bind to the histamine secreting cell (HSC) to stimulate histamine release . histamine can bind to H2 receptors on the parietal cell simulating gastric acid secretion
- can also bind to muscarinic receptors on the parietal cell stimulating gastric acid secretion
What are the physiological effects of histamine (via the stimulation of histamine receptors)?
- gastric acid inhibition
prostaglandin E2
- can inhibit the parietal cell and stop gastric acid secretion
- can stimulate the mucus secreting cell to produce mucus = protects lumen of the stomach from acdo
- can promote bicarbonate secretion = neutralises gastric acid
What are the effects of H1 and H2 antagonists? What are examples of H1 and H2 antagonists? What are their effects and side effects?
H1 antagonist
- 1st generation = mepyramine
- 2nd and 3rd generation = terfenadine
reduces inflammatory responses = treats acute inflammation
- anti-emetic (treat motion sickness) or anti-muscurinic ( have atropine like effects)
H2 - cimetidine ranitidine - reduce/inhibit gastric acid secretion = increase breakdown of histamine - mental confusion, dizziness
What are the lipid mediators of inflammation?
collectively known as eicosanoids
are split into
- cyclo-oxygenases pathway which includes prostanoids
= prostanoids are prostaglandins and thromboxanes
- lipo-oxygenases pathway which includes leukotrienes and lipoxins
What are eicosanoids? Why are they important?
are lipid mediators of inflammation
are targets of anti-inflammatory drugs
How are prostanoids generated?
are not ready to go unlike histamine
are generated from arachidonic acid
- arachidonic acids are generated from phospholipids
What is COX? What are the different types? What is its function?
conversion of arachidonic acid into prostanoids (prostaglandins and thromboxanes) requires the enzyme cyclooxygenase (COX)
- two main forms COX1 and COX2
COX 1
- constitutively active
- responsible for ‘physiological’ roles of PGs/TXs
= regulation of peripheral vascular resistance, renal blood flow
COX 2
- needs to be stimulated
- responsible for role of PGs/TXs in inflammation responses (pain and fever)
COX 3
- variant of COX-1; pain perception of CNS
What is the cyclo-oxygenase pathway?
arachidonic acid is converted into prostaglandin endoperoxides (PGG2, PGH2) by cyclooxygenase
prostaglandin endoperoxides can be converted into
- thromboxane A2 by thromboxane synthase
= can be inhibited by aspirin
- prostacyclin (PGI2) by prostacyclin synthase
- classical prostaglandins
What are the functions of prostaglandin and thromboxane?
prostaglandin, PGE2
- vasodilator in the gut
- gastric acid secretion
prostacyclin, PGI2
- vasodilator
- inhibits platelet aggregation
thromboxane, TXA
- increases platelet aggregation
What is the cyclo-oxygenase pathway?
arachidonic acid is converted into
- 5-HPETE by 5-lipoxygenase then into leukotrienes by 5-lipoxygenase
- lipoxins by other oxygenases
What cells makes TXA, PGE , PGD and PGI?
TXA - platelets
PGD - mast cells
PGI, PGE - endothelial cells
act at specific GPCR
What is the difference between leukotrienes and prostanoids? What is their effect?
Why should leukotrienes be given to asthmatics?
leukotrienes are more potent than prostanoids (prostaglandins + thromboxanes)
leukotrienes airway oedema, secretion of thick mucus and smooth muscle contraction
What is the effect of 5-HPETE?
5-HT promotes inflammation by increasing the number of mast cells at the site of tissue injury
5-HT stimulates mast cell adhesion and migration
5-HT enhances inflammatory reactions of skin, lungs and gut
