Lipid mediators of inflammation Flashcards
What are prostaglandins, thromboxanes, lipoxins and leukotrienes referred to as collectively?
Eicosanoids
How are the eicosanoids divided up?
2 branches:
- -> prostaglandins + thromboxanes (prostanoids) via cyclooxygenases (cyclic)
- -> leukotrienes + lipoxins via lipooxygenases (linear)
Eicosanoids are molecules with powerful inflammatory actions. Therefore, they are targets of which major anti-inflammatory drugs?
- NSAIDS
- Glucocorticoids
- Lipoxygenase inhibitors
- Leukotriene antagonists
What is a key difference between the formation of prostanoids (PG + TX) and histamine?
Prostanoids are not ‘ready-to-go’ unlike histamine
What is the rate-limiting step of prostanoid formation?
Prostanoids are generated from arachidonic acid (AA, poly-unsaturated fatty acid) - this is rate limiting.
How are AAs (arachidonic acids) produced?
- Produced from phospholipids (PLs) via 1-step/2-step pathways
- Steps triggered by many agents eg. thrombin on platelets and antigen-antibody rxns on mast cells
What impact do bradykinin and adrenaline have on formation of prostanoids?
They are known initiators of the cascade in production of AAs and can initiate phospholipase action at the cell membrane
Describe the enzyme responsible for converting AA to prostanoids
- Cyclooxygenase
- Two main isoforms: COX-1 + COX-2
- COXs are fatty acids, attached to endoplasmic membrane
What are key characteristics of the COX-1 enzyme?
- Constitutively active - already there
- Responsible for ‘physiological’ roles of PGs/TXs such as…
- regulation of peripheral vascular resistance
- renal blood flow
- plateley aggregation
- gastric cytoprotection
- So COX-1 produces PGE2 and TXA2
What are key characteristics of the COX-2 enzyme?
- Needs to be stimulated by IL-1, TNF-a
- Responsible for role of PGs/TXs in inflammatory responses:
- pain
- fever
What are key characteristics of the COX-3 enzyme?
- Variant of COX-1
- Pain perception of CNS
Leukotriene A4 can be converted to Leukotriene B4 by a hydrolase. What is the role of Leukotriene B4 (LTB4)?
- Very important chemoattractant
- Attracts cells to site of inflammation
- To remove debris/bacteria
- Needs to be controlled otherwise start eating healthy cells
Which molecule are most of the end prostanoids derived from?
PGH2
it makes PGI2, TXA2, PGD2, PFG2a, PGE2
What is epoprostenol?
- Synthetic PGI2
- Important vasodilator
What are tissue-specific isomerases?
Tend to be synthases of some sort - mainly PGD2, PGE2, PGF2a synthases.
They help to form those above from PGH2
What is the role of PGD2?
- Bronchoconstriction
- Inhibits platelet aggregation
What is the role of PGF2a?
- Bronchoconstrictor
- Uterine contraction
What does Thromboxane A2 do and what drug inhibits it?
- TXA2 found on activated platelets -> cause platelet aggregation
- For homeostatic balance
- Formation inhibited by aspirin
What are functions of PGE2?
- Promotes labour - softens cervix + stimulates uterine contractions
- Induces fever
- Promotes duct-dependent congenital heart diseases
- Promotes vasodilation - relaxes smooth muscle
- Promotes resolution of inflammation by suppressing T cell receptor signalling
What is 5-lipooxygenase and what is FLAP?
- 5-lipooxygenase forms LTA<strong>4</strong> (leukotrienes) from AA
- FLAP is a protein needed to activate 5-lipooxygenase
- FLAP engages with AA first
What are the sulphidopeptide leukotrienes?
- LTC4, LTD4, LTE4
- Contain amino acids in structure
- Formed from LTA4
What is the general role of lipoxins and cyPG during resolution?
There is a switch for PG synthesis from pro-inflammatory (PG + LTs) at onset of inflammation to anti-inflammatory lipoxins and cyPG during resolution.
How do lipoxins bring about resolution in their anti-inflammtory role?
- Lipoxins recruit monocytes
- To clear site of necrotic apoptotic neutrophils
- Regulate activation levels of neutrophils
- And dampen their damaging effects (inc phagocytosis of neutrophils)
How does cyPG act in concert with lipoxins to bring about an anti-inflammatory effect?
- cyPGs promote phagocytic clearance of apoptotic cells by macrophages -> resolution of inflammation
- cyPG - inhibits macrophage activaiton -> decrease uncontrolled tissue damage; decrease NF-kB activation
- This helps to decrease activation of inflammatory genes
What cells are specialised to make PGD2?
Mast cells
What cells are specialised to make PGI2 and PGE2?
Endothelial cells
What cells are specialised to make TXA2?
Platelets
What type of receptor do eicosanoids act at?
Act at specific G-protein-coupled receptors. They exert diverse and often contradictory actions of inflammation and are subject to local inactivation.
Where do PG subtype eicosanoids act?
Act at DP, FP, IP & EP (EP1,2,3) receptors
Where do TXs act at?
TP receptors
Where do LTs act act and what physiological actions does this induce?
- LTB4 - at BLT receptors
- LTC4, LTD4, LTE4 at Cys-LT receptors
- -> chemotactic; bronchoconstrictor; inc vasc perm; oedema; inc secretion of thick, viscous mucus
PG receptors are found in lungs, vessels, gut, CNS, kidney and uterus. What is the physiological action of the following PG receptors:
- DP
- FP
- IP
- DP receptors: vasodilatation, decrease platelet aggregation, bronchoconstriction
- FP receptors: contraction of myometrial sm muscle, bronchoconstriction
- IP receptors: vasodilatation, decrease platelet aggregation, renin release
What is the physiological actions of the EP1,2,3 receptors?
- EP1 : contraction of bronchiole/GIT smooth muscle
- EP2 : bronchodilation, vasodilation, relaxation of GIT smooth muscle, inc intestinal fluid secretion (watery/bicarb)
- EP3 : contraction of intestinal sm muscle, inc gastric mucus secretion, decrease gastric acid secretion, pyrexia
Thromboxane receptors (TP receptors) are found in vessels + platelets. What physiological action is induced by binding of the TP receptors?
TP : vasoconstriction, inc platelet agregation
Leukotrienes are for general inflammation and in lungs/vascular for acute allergy responses. What are the actions of the BLT and Cys-LT receptors?
- BLT (1,2) : chemotaxis + proliferation of immune cells, inc adhesion
- cysLT (1,2) : bronchoconstriction, vasodilation, inc vascular perm
For, leukotriene receptor antagonists, give the following:
- Which LTs act at which type of receptor
- Action of LTs
- When is receptor blockade useful
- Side-effects
- Examples
- cys-LT receptors - (LTC4, LTD4, LTE4 etc)
- These LTs cause aiway oedema, secretion of thick mucus + sm muscle contraction
- Blockade useful in following:
- prevention of mild to moderate asthma
- early to late bronchoconstrictor effects of allergens
- exercise-induced asthma + asthma provoked by NSAIDs
- Side effects include GI upset, irritability, dry mouth/thirst + rashes/oedema
- Examples: zafirlukast, montelukast, pranlukast, zileuton
How is asthma provoked by NSAIDs?
- There are 2 routes of eicosanoids being made
- Aspirin (and NSAID) will block only the COX route
- But not the LOX (lipoxygenase) route
- Lipoxygenase route therefore makes leukotrienes
- Leukotrienes -> bronchconstriction, airway mucus etc -> asthma!
What is the difference of action between leukotrienes (LTD4, LTDC4, LTE4) and histamine in the lung?
- Leukotrienes are much more potent (contraction) than histamine
- Order: LTD4, LTC4, LTE4, histamine
- They increase cellular infiltration of eosiniphils + neutrophils
- Increase mucus secretion
- Increase bronchoconstriction
- Increase airway oedema
Which eicosanoids are important for haemostatic balance?
- TXA<strong>2</strong> : promotes platelet aggregation, binds to TP receptor -> inc [Ca2+] -> contraction
- PGI<strong>2</strong> : inhibits platelet aggregation, binds to IP receptor -> inc cAMP -> relaxation
Have opposite effects + released by endothelial cells
In gastric acid secretion, histamine is released from ECL cells to act on what receptor + cell?
- Histamine acts on parietal cells
- by binding to H2 receptor
- promotes acid (H+) secretion
What receptor(s) does PGE2 bind to in mediating gastric acid secretions? What is the action of this?
- PGE2 binds to EP3 receptors on
- parietal cell -> inhibit acid secretion
- mucus secreting cell -> stimulate mucus/bicarb secretion
Why are poly-unsaturated fatty acids of interest to us?
- PUFAs; omega-3 essential fatty acids
- Perceived beneficial effects for our health
- EPA - eicosapentaenoic acid
- DHA - docosahexaenoic acid
- Derivatives of EPA and DHA (resolvins/neuroprotectins) have anti-inflammatory actions
What happens to the pathway when you take PUFA (poly-unsaturated fatty acids)?
- PUFA intake (fish oil supplementation) increase
- -> Decrease in arachidonic acid (AA)
- Replaced with an increase in EPA + DHA
- EPA + DHA become substrates for COX
- Generates alternative eicosanoids
- Decrease in PGE2, TXB2, LTB4, 5-HETE, LTE4
-
Increase in LTB5, TXA3, LTE4, 5-HPETE (these eicosanoids diff structure to those generated from AA)
- LTB5 is 10-100 less chemotactic to neutrophils
A number of novel group of mediators have also been identified from COX-mediated action on EPA and DHA. What are they?
- E-series resolvins (resolvin D1-D4; EPA-derived mediators) have anti-inflammatory actions
- Docosatrienes + neuroprotectins (D-series resolvins; DHA-derived mediators) also have anti-inflammatory effects
