Eicosanoid molecules (PGs, TXs, LTs) Objectives: Discover and

Eicosanoid molecules (PGs, TXs, LTs) Objectives: Discover and

Eicosanoid molecules (PGs, TXs, LTs) Objectives: Discover and distinguish relationships between different types of eicosanoid molecules (PGs, TXs, LTs) Gain knowledge of enzymes that create PGs and TXs (COX-1 and -2) Explore physiological functions of these molecules Ascertain how pharmacological inhibitors work to block their activity.

Prostaglandins: -discovered in the 1930s -synthesized in virtually every cell in the body -unsaturated 20 carbon molecules, also contain a 5-member ring -work right within the cells where they are synthesizedact locally -have an extremely short half-life and are not stored

Prostaglandins and related compounds (thromboxanes and other eicosanoids): - Potent cell signalling molecules paracrine hormones - Multiple effects, including pain and inflammation associated with arthritis - Synthesized from essential dietary fatty acids, especially linoleic acid 1

These molecules work generally in immune system, in inflammations, pain calling, muscle contraction, and so on. All of them are derived from the essential fatty acids.

We will study more details about them in Pharmacology and Immunology. Prostaglandins are derived from Arachidonic acid, which is derived from Linoleic acid (an essential fatty acid) They are stimulated by certain drugs and inhibited by others

PGs Prostaglandins TXs Thromboxanes

LTs Leukotrienes They differ from hormones in the following aspects 1.They are produced in small amounts in almost all tissues rather than specialized glands. 2.They act locally rather than after transport to target tissues 3.They are not stored, have extremely short half life, and are metabolized rapidly to inactive products at their site of synthesis.

4.Their biological effects are mediated by plasma and nuclear membrane receptors, which are different in different organ systems. 2 Prostaglandins were first discovered in prostatic fluids. So it was thought that they only were released from the prostate gland, but later on, it was revealed that they are synthesized in all cells in the body.

Prostaglandins are different from hormones. They contain 4 double bonds.

Para next to (beside). Parietal cells in stomach release HCl which will work near these cells to activate pepsin, so this is an example of paracrine action. Hormones take longer time than prostaglandins, for example Insulin takes hours to complete its function.

Hormones move through blood to reach their destination (target cells) Both hormones and PGs have plasma membrane receptors and nuclear membrane receptors Prostaglandins

Two groups: 1. PGE, for ether-soluble, and 2. PGF, for phosphate ( fosfat in Swedish) buffersoluble. Each group contains numerous subtypes, named PGE1, PGE2, and so forth. Prostaglandins act in many tissues by regulating the synthesis of the intracellular messenger 3,5-cyclic AMP (cAMP). Because cAMP mediates the action of diverse hormones, the prostaglandins affect a wide range of cellular and tissue functions.

PGs are divided into 2 groups : E family (PGE) > Ether-soluble F family (PGF) > Phosphate-soluble PGs sometimes decrease and sometimes increase the level of cyclic AMP [cAMP], so they work with both inhibitory and stimulatory G protein (Gs & Gi). 3

Many factors control the synthesis and secretion of different eicosanoids, for example: In pregnancy they are produced under the effect of oxytocin hormone. In the thermoregulatory center of the hypothalamus they are secreted by the effect of pyrogens. Corticotrophin releasing hormone (CRH) stimulates their synthesis while glucocorticoids inhibit their synthesis. Examples of factors that affect eicosanoids synthesis and

secretion Oxytocin works in uterus contraction during labor. Pyrogens are responsible of fever reaction. CRH is released from the hypothalamus, which activates the release of ACTH from the pituitary gland, which goes to the adrenal cortex and causes it to release cortisol. ACTH Adrenocorticotropic Hormone 4 Arachidonic acid is released from

phospholipids in response to specific signals(compare to the formation of second messengers) One of the enzymes responsible of this release is phospholipase A2 whose activity is inhibited by lipocortin, annexins released under the influence of the glucocorticoids ( e.g. cortisol) Many stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 The immediate dietary precursor of arachidonate is linoleic acid.

Linoleic acid (arachidonate precursor) and -linolenic acid linolenic acid (eicosapentaenoate precursor) are essential fatty acids. Minor eicosanoids are derived from eicosapentaenoic acid, e.g.TXA3 All cells with the exception of RBCs can produce eicosanoids. All eicosanoids are locally active compounds and mediate their action through receptor-mediated G-protein linked signaling pathways leading to an increase ( or sometimes a decrease) in cAMP levels. Note from the editor : Lipocortins and Annexins are

the same thing (Remember : they inhibit Phospholipase A2) RBCs don't have a function that needs eicosanoids. Therefore, they dont produce eicosanoids. 5 Biosynthesis of Eicosanoids. Two main pathways are involved in the biosynthesis of eicosanoids.

The prostaglandins, prostacyclin, and thromboxanes are synthesized by the cyclic pathway involving the cyclooxygenases, while The leukotrienes are synthesized by the linear pathway involving lipoxygenases. Both types of enzymes are iron metallo-linolenic acid enzymes. 6

Only for clarification Corticosteroids (inhibit phospholipase A2 production) Sheet : Corticosteroids lead to antiinflammatory and anti-fever effects. Synthesis of prostaglandins prostacyclins and thromboxanes from arachidonic acid. Many stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic

acid from membrane phospholipids, while corticosteroids inhibit it. Cyclooxygenases (COX) Cyclooxygenases (COX) are called thus because they lead to the formation of a cyclopentanoic cycle. They are also called PGH synthases because they lead to formation of prostaglandin H. There are two major different forms (isoenzymes) of cyclooxygenase; cyclooxygenase 1 (COX1) and cyclooxygenase 2 (COX2). The following table summarizes the characters of both of

them: COX 2 Inducible form (not present normally in the cells) and expressed mainly in macrophages and monocytes. COX 1 Continuously produced in

gastric mucosa, kidney, platelets and vascular endothelial cells. Used for signaling pain and inflammation & produces prostaglandins in inflammatory responses. Important for formation of prostaglandins required for

normal physiological functions. Its production is stimulated by inflammatory cytokines (IL-1) and growth factors (e.g. PAF).Inhibited by steroids. It is important in many tissues such as stomach

(production of mucous secretion and regulation of gastric acidity), and in the kidney for water regulation. Another view.. or linoleic acid IL1 Interleukine-1 PAF Platelet Activating Factor

Triple response 1)Pain 2)Heat 3)Swelling Those caused by an infection, inflammation, urticaria or an allergy. Like a mosquito bite for example. 7 Read more about the t riple response of Lewis

Functions of prostaglandins 1. Activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells are mobilized to the site to minimize tissue destruction. 2. Blood clots form when a blood vessel is damaged. Closely related molecules called thromboxanes stimulate constriction and clotting of platelets. Conversely, PGI2 is produced to have the opposite effect on the walls of blood vessels where clots should not be forming. 3. Certain prostaglandins (i.e. PGE2) are involved with induction of labor by inducing uterine contractions.

Some PGs have opposing functions, but it depends on the site of action. e.g : Thromboxanes stimulate clotting in the sites of blood vessel damage, PGI2 works oppositely but in different sites. Both Oxytocin and PGE2 are involved in labor induction. 8 4. Some prostaglandins cause relaxation of smooth muscles; especially of

bronchi and blood vessels( vasodilation lowers systemic arterial pressure); 5. Some inhibit further release of neurotransmitters, after being released in response to their presence. 6. Some are involved in the inflammatory response, causing oedema, swelling and prolonged erythema by increasing capillary permeability. 7. Some play a role in temperature control. 8. Regulate salt and fluid balance in body , increase blood flow in kidneys 9. Increase secretion of protective mucus in GI tract, inhibit acid synthesis in GI tract. 10. Leukotrienes, related molecules, promote constriction of bronchi associated

with asthma. Examples of clinically significant PGs: 1-PGD2 secreted primarily from the mast cells and inhibits platelets aggregation and induces vasodilatation. 2-PGE2 secreted by most cells especially the kidney,, the platelets and the heart, increases cAMP production, causes vasodilatation, and platelet aggregation. Used to induce uterine contraction and labor. 3-PGF2 secreted by most cells, especially the lung, spleen, uterus and heart, causes vasoconstriction,

broncho-linolenic acid constriction and smooth muscle contraction e.g. uterine contractions. Functions of Prostacyclins Prostacyclin(PGI2); produced and secreted primarily by vascular endothelial cells( especially heart) ; It increases cAMP in platelets, and inhibit platelets aggregation, It prevents platelets adherence to healthy blood vessels wall, and It also produces vasodilatation, hence lowers the blood

pressure Thus, it impedes thrombogenesis How do NSAIDs work? Summary Inhibit COX enzymes Reduce production of prostaglandins and thromboxanes Reduce pain, fever and inflammation But Side effects of some NSAIDs in some people - Include gastrointestinal irritation, ulcers,

bleeding, etc. - If untreated, lead to death (~16,000/yr in US) - led to hunt for better anti-inflammatory drugs All of us know the famous drug ASPIRIN and why we use it But do you know how it works? It works by inhibiting an enzyme called cyclooxgenease (it is also called prostaglandin endoperoxide G/H synthetase). Effects of aspirin and other pain killers? Aspirin works on both COX-1 and COX-2 to inhibit

arachidonic acids entry into the active site of the enzyme --acetyl group of aspirin binds to serine in COX -- by blocking the activity of the COX enzymes, this relieves some of the effects of pain and fever --nonselective -- many side effects Tylenolthought to have effects through inhibiting the activity of COX-3, an alternatively spliced form of COX-1 NSAIDS stands for Non-Steroidal Anti-Inflammatory Drugs.

They are over the counter (means they can be sold without a doctors prescription) like paracetamol, aspirin, ibuprofen and so on. Nonselective, means they affect any site of pain blindly. 9 They have serious side effects, for example people with heart diseases who take NSAIDS can die from gastrointestinal bleeding if left untreated. Tylenol is the trade name for paracetamol.

Some doctors recommend people with a cardiac diseases history in their families to take a low dose aspirin (baby or buffered aspirin) constantly. - Low-dose aspirin therapy is used to lower the risk of stroke and heart attacks by decreasing formation of thrombi. Aspirin irreversibly inhibits COX-1 (and COX-2) Has a short half-life New platelets are constantly being made Because of the non selective inhibition of COX-1

activity in the gut , these drugs are associated with gastric ulcerations. Systemic inhibition of COX-1, with subsequent damage to the stomach and the kidneys ,and impaired clotting of blood, is the basis of aspirins toxicity. Freedom from GI side effects make the COX-2 inhibitors very attractive. Thromboxanes They have a six-membered ring containing an ether. They are produced

by platelets (also called thrombocytes) and act in the formation of blood clots and the reduction of blood flow to the site of a clot. It stimulates activation of new platelets as well as increases platelet aggregation. Function of Thromboxanes They are produced and secreted primarily by the platelets . They cause mobilization of intracellular calcium, vasoconstriction, and contraction of smooth muscles.

They also decreases production of cAMP in platelets and cause platelets aggregation, thus promoting the formation of blood clots (thrombi) ( opposite effect to PGI. This limit formation to site of vascular injury) Examples of clinically important TXs: TXA2: secreted from platelets, induces platelets aggregation and vasoconstriction, hence increase BP. TXB2: secreted from platelets and induces v.c. The corticosteroidal drugs e.g. cortisol, prednisolone, act to inhibit phospholipase A2,

thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosinoids. They also inhibit COX-linolenic acid 2 Thus, they have anti-linolenic acid pyretic and anti-linolenic acid inflammatory action. However, they have many undesirable side effects because they prevent the synthesis of the eicosinoids needed for normal, healthy body functions. 10

The side effects of Corticosteroidal drugs like Water retention (Edema) Obesity Osteoporosis. Other problems Leukotrienes First found in leukocytes, contain three conjugated

double bonds. They are powerful biological signals. For example, leukotriene D4, derived from leukotriene A4, induces contraction of the muscle lining the airways to the lung. Overproduction of leukotrienes causes asthmatic attacks, and leukotriene synthesis is one target of anti-asthmatic drugs such as prednisone. The strong contraction of the smooth muscles of the lung that occurs during anaphylactic shock is part of the potentially fatal allergic reaction in individuals hypersensitive to bee stings, penicillin, or other

agents. LTA4 Note the four double bonds, three of them conjugated LTB4 LTC4 is a cysteinyl leukotriene, as are D4 and E4 Function of Leukotrienes

Leukotrienes produced by leukocytes, platelets, mast cells and heart and lung vascular tissues, are involved in the inflammatory responses such as erythema, oedema and hyperthermia. In skin they are responsible for the weal and flare response seen in some allergic responses. Some could lead to fatal side effects of vaccinations, e.g. LTC4, LTD4, LTE4, are components of slow reacting substance of anaphylaxis (SRS-linolenic acid A), induce contraction of smooth muscles, vasoconstriction, bronchoconstriction, and increased vascular permeability.

LTB4 increases chemotaxis of polymorphonuclear leukocytes, causes release of lysosomal enzymes, and adhesion of WBCs Inhaled Corticosteroids for Bronchial asthma treatment End

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