E1 Eicosanoids Flashcards
give examples of mediators
hormones, cytokines, nucleosides, nucleotides, basic amines, lipids/fatty acids, enzymes and peptides etc….
Criteria for establishing a substance as a mediator are:
- It is released from local cells in sufficient quantity to mediate biological activity on target cells within an appropriate time frame
- Application of an authentic sample of the proposed mediator reproduces the biological effect
describe eicosanoids
- storage (time)
- signaling
Group of mediators that are generated from FA precursors (arachidonic acid)
Not stored ‘pre-formed’ in the cell: Degraded quickly so they cannot travel far in the body (within 30s-5mins)
can mediate paracrine and autocrine signaling but NOT endocrine signaling (as degraded)
what is the rate limiting step in eicosanoid synthesis
catalyst = phospholipase A2-mediated release of fatty acids (arachidonic acid) from phospholipids
what enzymes are involves in metabolisation of arachidonic acid
epoxygenase, cyclo-oxygenase (COX) and lipoxygenase (LOX) —> results in generation of a host of eicosanoids
what does the eicosanoid produced depend on
cell type and isomerases/synthases enzymes present
what inhibits both COX1 & COX2 irreversibly
Aspirin - anti-inflammatory and anti-platelet agent via blocking platelet TXA2 synthesis via inhibition of COX1 (reduces the risk of thrombosis)
Name the 5 different prostanoids receptors identified
All GPCRs
- Prostaglandin D2(PGD2)receptors: DP1 and DP2
- Prostaglandin E2receptors: EP1-EP4
- Prostaglandin F receptor: FP
- Prostaglandin I2 (prostacyclin) receptors: IP1 and IP2
- Thromboxane receptor(TP): TPα (TXA2) and TPβ
describe NSAIDs
- what do they inhibit
- what does that prevent
non-steroidal anti-inflammatory drugs - main COX inhibitors COX1 & COX2
- inhibit prostaglandin and thromboxane synthesis
- reduces inflammation
- antithrombotic (low dose aspirin) and analgesic effects
patients lacking COX1 have what disorder
mild bleeding disorder
NSAIDs - inhibition of COX1 gives what side effects
inhibition of COX2…
inhibition of COX-1 can give associated: side effects (ulcers, prolonged bleedingtime, kidney problem)
inhibition of COX-2 accounts for the anti-inflammatory features of NSAID however side effects: (hypertension, acute kidney problems)
Name some side effects of COX inhibition
NSAIDs are acidic & damage the GIT + irritation of gastric mucosa
COX inhibition: Prostaglandins normally have a protective role in the gastrointestinal tract (GIT) – (PGE1, PGE2 and PGI2 inhibit gastric acid secretion and prevent gastric ulcers)
COX-2 inhibitors have been found to increase the risk of thrombosis, heart attack and stroke even with short-term use
describe LOX
Lipoxygenase (LOX)
Peroxidation of AA by 5-lipoxygenase (5-LO)
- Leukotrienes (LTA4) –> LTA4 is converted to LTB4 & cysteine leukotrienes: LTC4, LTD4, LTE4
- Hydroxyeicosatetraenoic acid (5-HETE)
- Lipoxins
what cells synthesize leukotrienes
what do leukotrienes signal via
WBCs, mast cells & platelets
Via GPCRs: principally coupled to Gαi and Gαq G proteins
Leukotrienes in Inflammatory Diseases (7)
- Asthma (Cys-LTs)
- Atherosclerosis (LTB4 and Cys-LTs)
- Rheumatoid arthritis (LTB4)
- Inflammatory bowel disease (LTB4 and Cys-LTs)
- Cancer (LTB4)
- Inflammatory pathways in obesity (LTB4)
Other emerging roles:
- Insulin resistance (LTB4)
