Arachidonic acid, leukotriene

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

Prostaglandins are biosynthesized from the 20-carbon unsaturated fatty acid, arachidonic acid. Leukotrienes and lipoxins... 

Leukotriene (Section 9.16) An unstable and potent biomolecule synthesized in eeUs by the oxidation of arachidonic acid. Leukotrienes are responsible for biological conditions such as... 

Leukotrienes and Prostanoids. Arachidonic acid (AA) (213) and its metabohtes are iavolved ia cellular regulatory processes ia all three principal chemical signaling systems endocrine (see Hormones), immune, and neuronal (62). FoUowiag receptor activation or iacreased iatraceUular... 

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages. Newer drugs are designed to either inhibit the enzyme 5-lipoxygenase, which acts on arachidonic acid in the first stage of leukotriene biosynthesis, or to block leukotriene receptors. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Eicosanoid (Section 27.4) A lipid derived biologically from 5,8.11,14-eicosatetraenoic acid, or arachidonic acid. Prostaglandins, thromboxanes and leukotrienes are examples. 

Aspirin sensitive asthma, affecting about 10% of all asthmatics, is a nonallergic response to aspirin and other agents that inhibit cyclooxygenase-1. Mechanistically, the most likely reasons are lack of bronchoprotective prostaglandin E2 and shunting of arachidonic acid into the leukotriene pathway. 

Cysteinyl leukotriene is a compound synthesized from arachidonic acid in inflammatory cells that contains an amino-acid side chain. 

Calderwood, S.K., Bomstein, B., Famum, E.K.., Stevenson, M.A. (1989). Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell. Physiol. 141, 325-333. 

Contrary to other elicitors of non-immune anaphylactic reactions (radiocontrast media, neuromuscular blocking agents, non-steroidal anti-inflammatory drugs (NSAIDs)) where there are at least hypothetical concepts regarding the pathomecha-nism of these reactions via increased mediator release (e.g. histamine release, shift in arachidonic acid metabolism from prostaglandins towards leukotrienes, etc.) [26], there is almost no literature regarding the pathomechanism of these reactions after LA application. 

Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. These fatty acids are found in high concentrations in vegetable oils (Table 14-2) and in small amounts in animal carcasses. These essential fatty acids are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation (see below), and they also have various other functions which are less well defined. Essential fatty acids are found in the stmctural lipids of the cell, often in the 2 position of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane. 

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

The main problem with any study of prostaglandins (PGs) is that although brain concentrations can exceed 0.1 /rg/g, they appear to be formed on demand, rather than preformed and stored and they have very short half-lives (seconds). Also specific effective antagonists remain to be developed and PGs are widely and evenly distributed, unlike many NTs. Thus any analysis of their central effects rests heavily on either studying PG release, or their effects when applied directly (icv injection). Certainly the brain has the enzymatic ability to synthesise both prostaglandins (cycloxygenase) and leukotrienes (lypoxygenase) from arachidonic acid (AA) (see Fig. 13.8) and a number of central functions have been proposed for them (see Piomelli 1994). 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

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