Lipid mediators of inflammation Flashcards
What are eicosanoids?
- PGs, Thtomboxanes and leukotrienes are collectively known as eicosanoids
- There are two pathways:
- cyclic (cycloxygenase) pathway -> Prostanoids (PGs and TXs)
- Lipoxygenase pathway -> LTs and lipoxins
Why are eicosanoids important?
- They have powerful inflammatory actions
- targets of major anti-inflammatory drugs
Give 4 examples of anti-inflammatory drug types
- NSAIDs (aspirin)
- Glucocorticoids (methotrexate)
- Lipoxygenase inhibitors
- Leukotriene antagonists - expensive but very good for aspirin-induced asthma
What is the process of prostanoid formation?
- Prostanoids are not ‘ready-to-go’ (unlike histamine)
- Prostanoids are generated from arachidonic acid (AA, poly-unsaturated fatty acid). This is rate-limiting step
- AAs are produced from phospholipids (PLs) via 1-step/2-step pathways
- These steps are triggered by many agents, e.g. thrombin on platelets and antigen-antibody reactions on mast cells
How is AA made?
1 step
- PLs (via Phospholipase A2) –> AA
2 step
- PLs (Via PLC) –> DAG (via DAG lipase) –> AA
- PLs (Via PLD) –> phosphatidic acid (via PLA2) –> AA
What sort of stimulus causes AA to come out of esterification with the membrane phospholipid?
- Inflammatory stimuli such as Bradykinin and adrenaline
What are cyclooxygensases?
- Enzyme that converts AA to prostanoids
- Two main isoforms (COX-1/2)
COX-1 vs COX-2 vs COX-3
COX-1
- Constitutively active
- Responsible for physiological roles of PGs/TXs such as regulation of TPR, renal blood flow, platelet aggregation, gastric cytoprotection
COX-2
- Needs to be stimulated (by inflammatory cytokines such as IL-1b or TNFa)
- Responsible for roles of PGs/TXs in inflammatory responses (pain and fever)
COX-3
- Variant of COX-1
- Pain perception of CNS
What is the cyclooxygenase pathway?
DRAW IT
- AA (via COX) –> PGG2
- PGG2 is very unstable and so is quickly converted to PGH2
- PGH2 -> Thrombxane synthase -> TXA2
- PGH2 -> tissue-specific isomerases (mPGES-1) -> PGD2/PGE2/PGf2a
- PGH2 -> prostacyclin synthase -> PGI2
What do the specific prostanoids do?
- TXA2 = platelet aggregator
- PGD2 = allergic responses, bronchoconstrictor, inhibits platelet aggregation
- PGE2 = myometrium contraction in labour
- PGF2a = bronchoconstrictor and uterine contraction
- PGI2 = inhibits platelet activation and vasodilator
What is homeostatic balance?
- TXA2 is a platelet aggregator
- PGD2 and PGI2 inhibit platelet aggregation and activation
- The balance between them means that your blood isnt always clotted
Give 2 drugs that inhibit thromboxane synthase
- Aspirin
- picotamide
- Ifetroban
- Terutroban
Give 2 drugs that inhibit prostacyclin synthase
- Epoprostenol
- Iloprost
- Treprostinil
What is the lipoxygenase pathway?
DRAW IT
- FLAP (5-lipoxygenase activator protein) acts on AA
- 5-lipoxygenase then acts on it to produce 5-HPETE
- 5-lipoxygenase then acts again to produce LTA4
- In turn, glutathiones transpeptidases and various AAs (e.g. glycine and cysteine) are all added to produce sulphidopeptide LTs (LTC4, LTD4, LTE4)
- If LTA4 hydrolase acts on LTA4 instead, then it produces LTB4
- other lipoxygenases can act on AA/LTA4 to make lipoxins
What are some anti-inflammatory lipid mediators?
- Lipoxins
- Cyclopentenone PGs (CyPGs)
How do Lipoxins and CyPGs carry out the anti-inflammatory actions?
- Lipoxins recruit monocytes to clear the inflamed site of necrotic/apoptotic neutrophils - regulate the activation of neutrophils and increase their phagocytosis
- Acting with CyPG, they promote phagocytic clearance of apoptotic cells by macrophages
- CyPGs inhibit macrophage activation, which decreases uncontrolled tissue damage, and decreases NF-kB activation
- This helps to decrease activation of inflammatory genes and dampen down inflammation
What cells make the particular eicosanoids?
- Mast cells = PGD2, LTs
- Platelets = TXA2
- Endothelial cells = PGI2, PGE2
- Neutrophils/ Basophils/ Eosinophils = LTs
What receptors do the eicosanoids act on?
- PGs (lungs, vascular, gut, CNS, kidney, uterus) = DP, FP, IP, EP1,2,3
- TXs (vascular/platelets) = TP
- LTs (general inflammation, lungs/vascular in acute allergy) = BLT (1&2) and CysLT (1&2)
What do DP receptors do?
Vasodilation, decreased platelet aggregation, bronchoconstriction
What do FP receptors do?
Contraction of myometrial smooth muscle, bronchoconstriction
What do EP receptors do?
EP1 = bronchioconstriction, GIT smooth muscle constriction EP2 = Bronchodilation, vasodilation, relaxation of GITSM and increase intestinal fluid EP3 = Contraction of GITSM, increase gastric mucus secretion, decrease gastric acid, pyrexia
What do TP receptors do?
- Vasoconstriciton and platelet aggregation
What do BLT receptors do?
Chemotaxis and proliferation of immune cells, increased adhesion
- LTB4 is a very potent chemotactic for neutrophils
What do CysLT receptors do?
Bronchoconstriction, vasodilation, increased vascular permeability
Give 4 examples of LT receptor antagonists
Zafirlukast
Montelukast
Pranlukast
Zileuton
Block receptor for Cysteinyl LTs (C,D,E)
What do CysLTs do in general?
Cause airway oedema, secretion of thick mucus and smooth muscle contraction
Why are LT antagonists useful?
- Prevent mild to moderate asthma
- Early to late bronchoconstrictor effects of allergens
- Exercise induced asthma and NSAID induced astham
How can NSAIDs lead to asthma?
- Aspirin blocks COX, however the lipoxygenase pathway is still active
- Therefore we still produce LTs
- This give thick sticky mucus, bronchoconstriction, cellular infiltration of eosinophils + neutrophils
What are some side effects of LT antagonists?
GI upset
Irritability
Dry mouth, thirst
Rashes, oedema
Give the order of potency of bronchoconstriction (least to highest)
Histamine
LTE4
LTC4
LTD4
What type of receptors are EP receptors?
GPCRs
- EP1 = Gq
- EP2 = Gs
- EP3 = Gi
How does PGI2 carry out its actions?
- Inhibits platelet aggregation
- Also acts on IP receptors on SM in response to shear stress -> Increase cAMP -> relaxation
How does PGE2 protect our stomach?
- Acts on EP3 receptors on parietal cells to reduce gastric acid secretion
- EP3 receptors on mucus secreting cells to increase the mucus secretion along with bicarbonate
Why are fish oils beneficial for our health?
- Provide substrates for the generation of alternative eicosanoids
- Increasing PUFA uptake means that more ecosapentoic acid (EPA) and docosahexaenoic acid (DHA) is produced, essentially replacing AA
- Less AA available to less PGE2,TXB2, LTB4, 5-HETE, LTE4 produced
- EPA and DHA are used as substrates for alternative eicosanoids
- Increases production of LTB5, LTE4, 5-HPETE (with different strcture to ones produced from AA)
- LTB5 is 10-100x less chemotactic to neutrophils
What anti-inflammatory metabolites can be made by COX activity EPA and DPA?
- E-series resolvins (resolvin D1-4, EPA-derived mediators) have anti-inflammatory actions
- Docosatrienes and neuroprotectins (D series resolvins, DHA-derived mediators) also have anti-inflammatory effects
