Eicosanoids & Prostaglandins Flashcards
Histamine
Released from white cells known as “mast cells”
Degranulation of mast cells occurs in response to injury or presence of an allergen
Blood vessels dilate, capillaries become more permeable
Redness, swelling, itching
Prostaglandins
Made at site of tissue damage or infection
Made from arachidonic acid
Found in cell membranes
Cause blood vessels to dilate and capillaries to become more permeable
Affect blood pressure and sensation of pain, others work in opposite ways
Can promote clotting (thromboxane) or reduce clotting (prostacyclin)
eicosanoids
Signaling molecule
They exert complex control over many bodily systems; mainly in growth during and after physical activity, inflammation or immunity after the intake of toxic compounds and pathogens, and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body.
How are various prostaglandins made different from each other structurally?
Substitutions on the 5 membered cyclopentane ring
Can RBC make prostaglandins?
No
What releases arachidonic acid?
Phospholipase A2 is a membrane-bound enzyme that acts on membrane phospholipid to release arachidonic acid (phospholipase C can also release it but from a different site)
NSAIDs
Exert their effects through inhibition of COX
No COX–>No PGE2–>No stomach protection (gastric mucosa)–>ulcers
Lungs inactivate PG’s how?
How is Thromboxane and prostacyclin inactivated?
Lungs inactivate any PG’s that are floating around via 15-OH-PGDH
Thromboxane and prostacyclin inactivated via WATER
Prostacyclins
vasodilators and inhibit the aggregation of blood platelets
Thromboxanes
(produced by platelet cells) are vasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (thrombosis).
What are eicosanoids?
Family of lipid mediators derived from oxidative transformation of 20-carbon polyunsaturated fatty acids. Eicosanoids include prostaglandins, thromboxane and leukotrienes as the main family members. Eicosanoids are autacoid mediators
Autacoids
Short lives
Localized
Made all over body by nearly all tissues (unlike hormones)
What pathways use autacoid mediators?
Autocrine and paracrine
Cofactors for COX
Iron, O2
What is required for prostaglandin and thromboxane synthesis?
O2 and arachidonic acid (AA)
PGE2/PGI2 + EP2, EP4, IP= affect on smooth muscle
AC–>cAMP–>relaxing smooth muscle (vasodilating blood vessels)
PGF2+FP or TXA2+TP effect on smooth muscle
Assemble –> IP3–>↑Ca 2+ in cytosol–> contract (constrict smooth muscle)
Excess TxA2: TP
Deficient PGI2:IP
Excess TxA2–> Angina pectoris (coronary vasoconstriction)
Symptoms: pain in chest
Excess of PGE2 (GI)
Diarrhea, cramps
Deficit of PGE2 (GI)=ulcers
Prostaglandins active in the reproductive system and role
PGE2:EP
PGF2α:FP
Dilate the cervix, contract the uterus, parturition (delivery)
Deficit: delayed birth
Excess: pre-mature labor, pre-mature birth
PG active in neonatal development and role
PGE2:EP (EP4)
Maintains ductus arteriosus in the fetus which allows maternal blood to bypass immature fetal lungs. Mature neonatal lungs will metabolize PGE2 which will close the ductus arteriosus
Prostaglandins in renal physiology and role
COX-2 always present in kidney along with COX-1.
PGE2/EP receptor role: renal blood flow, filtration and Na + H2O excretion in the kidney
Decifit of PG (kidney)
Leads to Na+ and H2O retention (edema), mild hypertension (elevated blood pressure)
Prostaglandin role in inflammation
PGI2 (prostacyclin) causes vasodilation and decreased platelet aggregation
PGE2 increases vascular permeability, causes pain sensitization, and can cause fever
Negative effects of PG in inflammation
Erythema, edema, pain.
If COX-2 is induced all symptoms are increased, thus NSAIDs inhibit COX activity
What stimulates platelets to make TxA2?
Collagen
Blood platelets get exposed to collagen–>collagen stimulates TxA2 formation by platelets
What stops the process of clotting from spreading throughout the blood stream? What keeps it local?
The stimulus (collagen) is local…and another eicosanoid- PGI2 (prostacyclin)-made by endothelial cells opposes the actions of TxA2 on blood vessels and platelets
What is the importance of COX-2 in thrombosis?
Endothelial cells have a nucleus and can therefore induce production of COX-2 which will increase production of prostacyclin. This will vasodilate and inhibit platelet aggregation allowing blood flow past plaque. Platelets cannot induce production of COX-2 and therefore cannot counteract this benefit
True or False
Platelets have the capability for de novo translation of proteins
False
True or False
Endothelial cells have the capability of de novo transcription and translation of proteins
True
COX-2 can be induced in endothelial cells
How can the build up of PGI2 preventing thrombosis be a negative?
Part of underlying disease progression in atherosclerosis…inflammation.
If endothelial cells’ COX-2 and COX-1 fails to maintain adequate PGI2 synthesis, it may tip the balance in favor of vessel occlusion (the blockage or closing of a blood vessel) if a plaque ruptures…this is what causes heart attacks
What is the benefit of eating an omega 3 fatty acid diet on heart disease?
Some eicosapentaenoic acid eventually replaces some arachidonic acid which weakens the effects of thromboxane A2 which leads to weaker vasoconstriction and weaker platelet aggregation
Eicosapentaenoic acid–>TxA3 (weaker vasoconstricter than TxA2)
Heart disease=too much TxA2
COX1, PGs and Inflammation
- Inflammation stimulates AA release
- COX-1 converts AA into PGE2
- PGE2 causes symptoms
- Inflammation induces COX-2
- Converts AA into PGE2
- Amplifies symptoms
- makes it worse but good for infections
- Symptoms of inflammation: erythema (redness), edema (swelling), pain
Balance: PGI2 (endothelial cells) vs TxA2 (platelets)
PGI2__________TxA2
Δ
PGI2: endothelial (relax blood vessels, inhibit platelet formation)
TxA2: platelets (constrict blood vessels, amplifies platelet aggregation) Too much=block blood vessel
Endothelial cells vs Platelets
Endothelial Cells vs Platelets
COX-1 / COX-1
PGI2 synthase / Tx Synthase
PGI2 / TxA2
TP & IP receptors / “ “
Vasodilation (BP down)/ Vasoconstriction (BP up)
Inhibits platelet aggregation/ Causes platelet aggregation
Atherosclerosis
The build-up of fats, cholesterol, and other substances in and on the artery walls.
Atherosclerosis can cause more PGI2 formation
(to try to unclog artery)
Renal physiology
Filtering blood is so important in KIDNEY that both COX1/COX2 are used
PGE2:EP
Deficit: Na+ & H2O retention(edema)–>Mild hypertension
*More common in elderly
