Flashcards in 8.0 Inflammation Deck (60)
What is the triple response of Lewis?
Local vasodilation within seconds (due to histamine)
Neurogenic imflammation within 30-60 seconds
Increase vascular permeability causes plasma leakage
What is dermatographic urticaria?
"Exaggerated triple response
May be triggered by drugs (e.g. penicillin)
Treatment = antihistamines + Omalizumab"
What is the effect of prostaglandins (PGE2 + PGI2)?
What is the effect of histamine?
Vasodilation and ↑ vascular permeability
What is the effect of TNF-a/IL-1?
More cytokine release
Express adhesion molecules
Mast cell stimulation
Activates mast cells
1 of each factor apart from C9 (12-18 C9s)
What do mast cells release following stimulation?
4) Nerve growth factor
5) Preformed cytokines
What cells contain histamine?
1) Mast cells - found in acidic granules with HMW heparin
2) Basophils - found in acidic granules with HMW heparin
3) Enterchromaffin-like cells
4) Histaminergic neurons of the brain
What particles cause mast cell degranulation?
Role and GPCR for the 4 histamine receptors?
- Smooth muscle contraction (ileum + bronchioles)
- Blood vessel dilation
- Triple response
- Increase heart rate
- Increase gastric acid secretion
What 2 enzymes metabolise histamine?
- Deaminates histamine → imidazole acetaldehyde
- Transfers methyl group to nitrogen on imidiazole ring → N-methylhistamine
Imidazole acetaldehyde + N-methylhistamine are inactive at H receptors
What is mastocytosis?
Whats the problem with 1st generation antihistamines?
Crossed BBB → drowsiness
Whats the problem with 2nd generation antihistamines?
Had an effect on hERG → long QT syndrome
What cells in the stomach secrete HCl?
What is the pathway of HCl secretion?
Synthesis pathway for bradykinin:
What inhibits kallikrein?
C1 esterase inhibitor
Deficiency in this → hereditary angioedema
What inactivates bradykinin?
Kinase 1 → des-Arg-bradykinin
Kinase 2 (ACE) → Inactive kinin
What are the receptors for bradykinin and what are their agonists?
B1 (↑ in inflammation) : agonist = des-Arg-bradykinin
B2 (constitutive) : agonist = bradykinin + Kallidin
Structure of arachidonic acid:
20 carbon unsaturated fatty acid
4 double bonds
Mechanism of COX inhibition for most NSAIDs?
- Enter hydrophobic channel in enzyme
- Hydrogen bond with Arg120
- This interaction prevents arachidonic acid from entering the catalytic domain
Differences between COX1 + COX2 hydrophobic channels?
COX1 = narrow hydrophobic channel
COX2 = wide hydrophobic channel
How is selective COX-2 inhibition achieved?
Drugs contain a bulky sulphur side chain - thus the drug is too big to fit into the narrow hydrophobic channel of COX-1
COX-2 selective inhibitors tend to end in -coxib
Where is serotonin found?
- Released by platelets during activation and aggregation
- Causes further aggregation of platelets and vasoconstriction
2) Intestinal enterochromaffin cells
3) Serotonergic neurons (ENS + CNS)
What are the metabolic actions of steroids?
o ↓ uptake of glucose by muscles/fat
o ↑ gluconeogenesis
o ↑ protein catabolism
o ↓ protein anabolism
o Redistribution of fat
What are the anti-inflammatory actions of steroids?
• Anti-inflammatory actions:
o ↓ influx/activity of leukocytes
o ↓ activity of monocytes
o ↓ clonal expansion of T and B cells
o Switch from Th1 to Th2 response
o ↓ pro-inflammatory cytokine production/action (e.g. IL-1, IL-2, IL-5, TNF-α)
o ↓ eicosanoid production
o ↑ release of anti-inflammatory factors (IL-10, IL-1ra, lipocortin 1, secretory leukocyte inhibitory protein and IkB)
• Overall → ↓ activity of innate and acquired immune system (beneficial in some conditions)
What are the side effects of steroids?
"•Side effects (seen with large + prolonged doses):
o Opportunistic infection (∵ ↓ immune system)
o Impaired wound healing
o Oral thrush (candidiasis)
o Hyperglycaemia (∵ glucose metabolism effects)
o Muscle wasting
o Cushing's syndrome (see diagram)
- Class = Human monoclonal antibody
- Target = TNF α
- Mechanism = sequesters excess TNFa in rheumatoid arthritis
Treatment: Rheumatoid arthritis