Eicosanoids and their Physiological role

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Eicosanoids are metabolites of Arachidonic acid which is a fatty acid component of phospholipids in plasma membrane of almost all cells. They primarily play a critical role in cardiovascular, inflammatory and reproductive physiology.

Arachidonic acid is synthesized from essential fatty acid "Linoleic acid" obtained from dietary sources. Usually Arachidonic acid exists in esterified form with membrane phospholipids, mainly Phosphatidylcholine and Phosphatidylethonalamine. The action of the enzyme Phospholipase A2 releases the Arachidonic acid and is a rate limiting step in the generation of Eicosanoids.

Arachidonic acid is metabolized primarily through four pathways (Cyclooxygenase, lipoxygenase, epoxygenase and Isoprostane pathways) which give rise to various Eicosanoids that are involved in important physiological roles. Mainly

  • The Cyclooxygenase pathway gives rise to mediators such as Prostaglandins, prostacyclins and thromboxanes.
  • The Lipoxygenase pathway leads to mediators such as Leukotrienes and Lipoxins.
  • The Epoxygenase pathway produces Epoxyeicosateraenoic acids.

CYCLOOXYGENASE PATHWAY

  • Cyclooxygenases or often called as Prostaglandin H synthases are membrane bound heme containing enzymes that are omnipresent in animal cells.


  • There are two main isoforms of the enzyme namely COX-1 and COX-2 that are found in humans and mainly differ in their cellular, genetic, physiologic, pathologic and pharmacologic functions.


  • They catalyze sequential reactions; the first (Cyclooxygenase) reaction is an oxygen-dependent cyclization of Arachidonic acid to prostaglandin G2 (PGG2); the second (peroxidase) reaction is the reduction of PGG2 to PGH2.


  • The role of COX-1 is protection and maintenance. It mediates various functions such as vascular homeostasis, maintenance of renal and gastrointestinal blood flow, renal function, intestinal mucosal proliferation, platelet function, and antithrombogenesis.


  • Whereas COX-2 is involved in functions such as inflammation, fever, pain, transduction of painful stimuli in the spinal cord, mitogenesis (particularly in the gastrointestinal epithelium), renal adaptation to stresses, deposition of trabecular bone, ovulation, placentation, and uterine contractions of labor.

Prostaglandins:-


  • These are group of structurally similar compounds with potent and specific biological actions. Chemically they are called as prostanoids, and consist of 20-carbon carboxylic acid containing a cyclopentane ring and a 15-hydroxyl group.


  • There are three major sub series of prostaglandins
  1. PG1 series-Derivatives of dihomo-Y=-linoleic acid (eicosatrienoic acid).
  2. PG2 series-These are more prevalent as they are direct derivatives of Arachidonic acid (eicosatetraenoic acid).
  3. PG3 series-Derived from Eicosapentanoic acid (EPA).
  • In this pathway PGH2 is an important product as it is the main precursor for other mediators such as PGD2, PGE2, PGF2a, thromboxane A2 (TxA2), and prostacyclin (PGI2).

Sites and Functions of prostaglandins:

PGD2- Present in mast cells and neurons

-Bronchoconstriction (asthma)

-Sleep control functions

-Alzheimer's disease

PGE2- Present in many tissues which include macrophages and mast cells.

-Potentiation of responses to painful stimuli

-Vasodilation

-Bronchoconstriction

-Cytoprotective: Modulates gastric mucosal acid secretion,mucus, and blood flow

-Vasodilation

-Bronchoconstriction

-Inflammatory cell activation

-Pyrexia

-Mucus production

-Possibly erectile function

PGF2a- Present in Vascular smooth muscle and Uterus smooth muscle

-Vascular tone

-Reproductive physiology (abortifacient)

-Bronchoconstriction

Thromboxane and Prostacyclin:-

  • Thromboxane A2 (TxA2) is the main product in the platelets. It is synthesized with the help of the enzyme "thromboxane synthase" which is expressed in high levels in platelets. It is metabolized into TxB2 which is inactive.


  • TxA2 acts by signaling via 7-transmembrane G protein-coupled Gq mechanism. It functions as a potent Vasoconstrictor and is a promoter of platelet adhesion and aggregation.


  • The vascular endothelium primarily expresses prostacyclin synthase but lacks thromboxane synthase and hence produces PGI2 (Prostacyclin). PGI2 acts by signaling through Gs, and functions as a vasodilator, venodilator, and inhibits platelet aggregation.


  • PGI2 is a physiologic antagonist of TxA2 therefore local balance between these two is necessary in regulation of systemic blood pressure and thrombogenesis. Any imbalance in the levels leads to hypertension, ischemia, thrombosis, coagulopathy, myocardial infarction, and stroke.

LIPOXYGENASE PATHWAY

  • As mentioned earlier this pathway leads to the formation of Leukotrienes and Lipoxins.
  • "Lipoxygenases (LOX)" catalyze the insertion of molecular oxygen into Arachidonic.
  • There are three isoforms of the enzyme,

5 LOX- Present in neutrophils, macrophages, mast cells and eosinophils.

12 LOX- Occurs in platelets, Megakaryocytes, Skin, Macrophages,GI system,Brain

15 LOX- In Macrophages, Monocytes and Airway epithelium.

  • The immediate products of lipoxygenase reactions are hydroperoxyeicosa-tetraenoic acids (HPETE's) which are further reduced to hydroxyeicosatetraenoic acid (HETE's).
  • 5-HPETE by action of 5-LOX on Arachidonic acid is the direct precursor to LTA4, which is in turn the main precursor for all other potent Leukotrienes. Hence 5-LOX is the main isoform that is involved in the production of Leukotrienes.

Leukotrienes:-

  • The first product of leukotriene synthesis is leukotriene A4, synthesized from 5-HPETE by the action of 5-LOX.


  • LTA4 is converted to LTB4 by action of the enzyme LTA4 hydrolase present mainly in neutrophils and erythrocytes.


  • LTA4 converts to LTC4 and this occurs in mast cells, eosinophils, basophils, and macrophages by the addition of a g-glutamylcysteinylglycine tripeptide (glutathione).


  • LTC4, LTD4, LTE4, and LTF4, which represent the cysteinyl leukotrienes, can be interconverted by removal of amino acid portions of the g-glutamylcysteinylglycine tripeptide.

Sites and Functions of Leukotrienes:


  • LTB4 are present in Neutrophils and Erythrocytes. Acts on BLT1 and BLT2 receptors which are G- protein coupled receptors. Leads to proinflammatory sequelae - neutrophils chemotaxis, aggregation and transmigration across epithelium and endothelium. Up-regulates neutrophils lysosomal function and free radical production enhances cytokine production and potentiates the actions of natural killer cells.

  • LTC4, LTD4, LTE4 and LTF4- Are called as"Cysteinyl leukotrienes" and mainly present in Mast cells, Basophils and Eosinophils. They act by binding to CysLT1 receptors. Causes vasoconstriction, bronchospasm, decreased coronary blood flow, decreased cardiac contractility, plasma exudation and increased vascular permeability.

Lipoxins:-

  • The main Lipoxins of biological importance are LXA4 and LXB4. These are modulators of the functions of leukotrienes and cytokines and are important in mitigation of inflammation.


  • LXA4 receptors are mainly present in neutrophils, lungs, spleen and blood vessels.

Functions of Lipoxins:


-Inhibit neutrophil chemotaxis, adhesion, and transmigration through endothelium

-Inhibit eosinophil recruitment

-Stimulate Vasodilation (by inducing synthesis of PGI2 and PGE2)

-Inhibit LTC4- and LTD4-stimulated vasoconstriction

-Inhibit LTB4 inflammatory effects

-Inhibit the function of NK cells

-Stimulate the uptake and clearance of apoptotic neutrophils by macrophages

EPOXYGENASE PATHWAY

  • This pathway is of primary importance in tissues that do not express COX or LOX enzymes. These are microsomal cytochrome P450 epoxygenases and oxygenate Arachidonic acid. The consequent products of this reaction are epoxyeicosatetraenoicacid (EET) and Hydroxyacid derivatives.

  • The dihydro derivatives of EET's are involved in the regulation of vascular tone by inhibiting Na+/K+-ATPase in vascular smooth muscle cells and affect renal function by regulating ion absorption and secretion. They also inhibit platelet COX and expression of intercellular adhesion molecules (ICAM's).

ISOPROSTANES

  • These are the compounds formed by the free radical catalyzed peroxidation of Arachidonic acid without any enzymes. The levels of these compounds are found particularly high during oxidative stress conditions.
  • Main isoprostanes are 8-epi-PGF2a and 8-epi-PGE2, which act as potent vasoconstrictors.

Functions of Isoprostanes:

-As there the rate of formation of isoprostanes depends on cellular oxidation conditions, the isoprostane levels are indicative of oxidative stress.

-Urinary isoprostane levels are used as biomarkers of oxidative stress in ischemic syndromes, reperfusion injury, atherosclerosis and hepatic diseases.

References:

Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition by David E. Golan. Published by Wolter Kluwer/Lippincott Williams & Wilkins.

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Author: Gangadhar Hari

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