Give examples of immune-driven responses to inflammation
What are the molecular and cellular mechanisms of acute inflammation?
What are the cellular mediators of acute inflammation?
Remember: platelets contain serotonin
You need activation of these cells to produce granules that will result in increase in concentration resulting in quick clearance.
Prostaglandins/Leukotrienes/Platelet activating factors are newly synthesised.
What are the mediators of acute inflammation produced by the liver?
Explain how immune response to inflammation results in end fibroplast activation:
Dendritic cells: cytokines, chemokines, costimulatory molecules
Mast cells: Histamine, Proteases, Prostaglandins, Leukotrienes, Chemokines, Cytokines
In Blood Vessel:
Macrophages: Nitric Oxide, Cytokines, Chemokines Proteases, Leukotrienes --> Fibrobplast Activation
Explain the role of arachidonic acid in dampening the immune response
Lipoxins, resolvins, protectins, maresins all designed to dampen down the inflammatory response
One of the things about these mediators is that they need to be metabolised first. What does this is arachidonic acid.
Explain the process of phospholipid metabolism in the inflammatory response:
Phospholipid can be metabolised to Arachidonic acid by phospholipase A2
Arachidonic acid can be shunted to form lipoxins, leukotrienes etc.
Where do the NSAIDs target?
This pathway is important because of NSAIDs.
Prostacyclin and thromboxane - important for platelet function.
Prostaglandins - for stomach function.
COX-2 is inducible only in the inflammatory response.
Proteases drive the formation of free radicals, and inflammatory prostaglandins which drive the inflammatory response.
Give examples of some NSAIDs
They have anti-inflammatory, analgesic and andtipyretic effects.
How does Aspirin work?
- only NSAID to irreversibly inactivate both isoforms of COX
- Acetylates the catalytic serine residue in position 529
- Affects COX-2 expression and both transcriptional and posttranscriptional levels
- This means that arachidonic acid is now shunted preferentially to the generation of lipoxins (which resolve inflammatory response)
- COX-2 acetylation modifies the enzyme in such a wy that it performs an incomplete reaction ultimately resulting in the formation of lipoxins.
- Inhibits IkB kinase and prevents NF-kB activation
- Acetylates many proteins and RNA.
How does Aspirin block the COX enzymes?
- Aspirine blocks the active site by causing acetylation of the serine, so arachidonic acid can no longer access the active site.
What do NSAIDs do to platelets and vascular endothelial cells?
1. Platelet cannot make thromboxane
2. Means that cant form thrombus so no stopping of bleeding.
In endothelial cells, this means reduced formation of Prostacyclin (PHI2).
At low dose, aspirin has preferential effect on blocking platelet function.
High dose aspirin = more preferentially take out Prostacyclin, increasing chance of MI.
Therefore dosing is critical.
What's the difference between Aspirin and Ibuprofen binding to COX?
1. Ibuprofen will bind active site of COX enzyme - aspirn will not.
BUT ibuprofen is reversible, so will come off the COX.
Ibuprofen blocks activity of aspirin - therefore will block platelet effect. So give aspirin first, so can irreversibly block, then ibuprofen.
What are the side-effects of Aspirin?
What are Coxibs?
- Family of drugs more targeted towards COX-2
- Introduced to minimise gastric problems
- Cox2 in cancer cells/vascular endothelium/kidney
- Celecoxib is an example.
What are the risks of using Celecoxib?
Can increase risk of
3. Hyperkalaemia (high potassium levels)
What are glucocorticoids (SAIDS)?
- Based on adrenal steroids
- Synthesised from cholesterol
- Released as needed under the influence of ACTH
- Used clinically in many inflammatory diseases
- Topical use, low toxicity.
- Acute use: acceptable toxicity
- Chronic use: severe side effects and toxicity
How do steroids work?
Steroid receptors are found in the cytoplasm complexed with a heat shock protein, Hsp90.
Steroids cross the cell membrane and bind to the steroid receptor complex, releasing Hsp90.
The steroid-receptor complex can now cross the nuclear membrane.
In the nucleus the steroid receptor binds to specific gene regulatory sequences and activates transcription.
Steroids tend to have quite a global non-specific anti-inflammatory effect.
What are the problems with using glucocorticoids?
The more you use them, the more the patients adrenal glands shrink, so patient becomes dependent on them.
- Suppression of response to infection
- Suppresion of endogenous GC synthesis
- Metabolic actions (affecting carb and protein metabolism)
- Iatrogenic cushing's syndrome
In the phospholipid pathway where to GC target?
What ways can the complement system drive an acute inflammatory response?
C3a and C5a are the main ways that the complement system can drive an accute inflammatory response.
What effects does histamine have on inflammation?
What systemic effects does histamine have?
Histamine produces its action by its effect on histamine receptors H1 H2 H3 H4 GPCRs
- Stimulation of gastric acid secretion.
- Contraction of smooth muscle (other than that of blood vessels)
- Cardiac stimulation
- Increased vascular permeability
Histamine is released from mast cells by exocytosis during inflammatory and allergic reactions.
Give examples of sedating anti-histamines
Give examples of no-sedating anti-histamines
- Reduces the increased vascular permeability caused by histamine.
- As an adjunct to adrenaline in emergency treatment of anaphalaxis.
Give an example of some immunsuppressive drugs
- Cyclosporine A
Describe the mechanism of action of Clycosporine/Tacrolimus
Inhibits calcineurin which binds Nf-ATC, which drives IL-2 gene transcription, IL-2 is important in T-cell activation, so blocking calcineurin means less T cell activation.
Describe the mechanism of action of Rapamycin
Rapamycin binds FKBP, & mTOR
Critical for actin cytoskeleton and spreading migration tissue immune response
- Therefore can have migratory effect on immune cells, stopping them from getting in the right place
-MtOR can also have an effect on the cell cycle. So can block cell cycle progression and can have profound effect on immune system.
Explain the mechanism of action of Basiliximab
- Basiliximab is a monoclonal antibdoy
- It will bind directly onto receptor (antagonist) and prevent signalling downstream of the receptor (JAK/STAT) and therefore have an effect on the immune system (IL-2)