Arachidonic acid leukotrienes from

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. 

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. 

Stimulated platelets release arachidonic acid rapidly from their phospholipids, apparently as a result of activation of phospholipase A2. The released arachidonate can in turn be metabolized to endoperoxides and thromboxane A2 (Chapter 21). These compounds are also potent activators of platelets and cause a self-activating or autocrine effect.1) While PAF has a beneficial function, it can under some conditions contribute in a dangerous way to inflammation and to allergic responses including anaphylaxis,) asthmag and cold-induced urticaria.1 Although the effect of PAF is separate from those of histamine and of leukotrienes, these agents may act cooperatively to induce inflammation.1... 

Arachidonic acid released from membrane phospholipids or other sources is metabolized by the LO pathway to the smooth muscle contractile and vasoactive leukotrienes (LT), LTC4, and LTD4, as well as to the potent chemoattractant LTB4. These molecules are intimately involved in inflammation, asthma, and allergy, as well as in other multiple physiological and pathological processes. For example, cirsiliol (3, 4, 5-trihydroxy-6,7-dimethoxyflavone) proved to be a potent inhibitor of 5-LO (IC50, 0.1 pM) derived from basophilic leukemia cells and peritoneal polymorphonuclear leukocytes. 

Platelets have been shown to cooperate with leukocytes in production of chemotactic fectors which the cells are unable to synthesize themselves. 12-HETE from platelets are metabolized by unstimulated neutrophils to 12,20-di-HETE (Marcus et al, 1984,1988). Leukocytes produces increased amounts of leukotrienes, because 12-HPETE produced in activated platelets stimulates the activity of leukocyte 5-lipoxygenase (Maclouf et al, 1982 Romano and Sethan, 1992). Neutrophils convert arachidonic acid released from stimulated platelets to produce 5-HETE and leukotriene B4 (LTB ) (Marcus et al, 1982). Platelet activating fector (PAF) are shown to stimulate production of LTB from tiiese cells (Lin et al, 1982). Platelets can also produce the vasoconstrictor leukotriene C4 (LTC4) from leukotriene A4 (LTA4) synthesized by leukocytes (Maclouf and Murphy, 1988). Activated platelets and neutrophils release PAF (Lynch and Henson, 1986) which is a potent mediator of inflammation and asthma. 

Arachidonic acid, derived from membrane phospholipids, is the precursor for synthesis of the leukotrienes. 

For the reasons given above, agents that interfere with leukotriene synthesis or actions, are of great interest in relation to limiting inflammatory reactions. The sites amenable to pharmacological manipulation include (I) the upstream inhibition of arachidonic acid production from phospholipids (which is a rate-limiting step see PHOSPHOLIPASE inhibitors) (2) the inactivation of five-... 

The HPETEs and HETEs are the primary products of the action of lipoxygenase on arachidonic acid, and from them, by further biochemical transformations, are derived all the remaining transmitters with which this review is concerned. In particular, (5S)-HPETE is the starting point from which are derived all of the most important leukotrienes studied to date. 

Fig. 6. Biochemical pathway of the metabolism of arachidonic acid into the biologically active leukotrienes. Arachidonic acid released from phospholipids by cytosolic (c) phospholipase Aja is metabolized by 5-lipoxygenase to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) and leukotriene A4 (LTA4) which is then enzymatically converted into leukotriene B4 (LTB4) or conjugated by glutathione to yield leukotriene C4 (LTC4).

Glutamate-mediated calcium influx results in stimulation arachidonic acid release from neural membrane glycerophospholipids. This release is catalyzed by CPLA2 and PLC/DAG-lipase pathway (McIntosh et al., 1998 Schuhmann et al., 2003 Shohami et al., 1987, 1989 Wei et al., 1982 Dhillon et al., 1996 Homayoun et al., 1997, 2000). Arachidonic acid release occurs in traumatic as well as fluid percussion models of brain injury (FPI). Enzymic oxidation of arachidonic acid generates prostaglandins, leukotrienes, and thromoboxanes whereas non-enzymic oxidation produces isoprostanes and ROS which include superoxide and hydroxyl radicals (Farooqui and Horrocks, 2007). 

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

As part of the response to leukocyte cell activation, cysteinyl leukotrienes are generated de novo from arachidonic acid liberated from cell membrane phospholipid by cytosolic phospholipase A2 (Fig. 3.8). In concert with 5-lipoxygenase-activating protein (FLAP), the enzyme 5-lipoxygenase (5-LO) converts arachidonic... 

The mechanism of NSAID-induced respiratory reactions appears to be due to the redirection of arachidonic acid metabolism from the COX to the lipoxygenase synthetic pathway with associated production of cysteinyl leu-kotrienes. PGE2 normally helps to dampen the production of the leukotrienes. 

Leukotriene biosynthesis depends upon the availability of arachidonic acid (8) as the free carboxylic acid as the 5-LOX substrate, which typically requires the action of cytosolic phospholipase to release arachidonic acid (8) from membrane phospholipids [27]. The name leukotriene was conceived to capture two unique attributes of these molecules. The first relates to those white blood cells derived from the bone marrow that have the capacity to synthesize this class of eicosanoids, for example, the polymorph nuclear leukocyte. The last part of the name refers to the unique chemical structure, a conjugated triene retained within these eicosanoids [29,30]. The first step for the leukotriene biosynthesis is the insertion of molecular oxygen at position 5 of arachidonic add (8) to produce 5-HPETE (17) that can be converted to leukotriene (18) by the second catalytic activity... 

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. 

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. 

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

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

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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