Leukotrienes in inflammation

The effects of LCPUFAs in inflammation have been reviewed by Calder (2006). Briefly, if is h) ofhesized fhaf fhe effecfs of LCPUFA n-3 fatty acids on immune function are mediated by their ability to compete with the metabolism of fhe n-6 fatty AA. AA can be metabolized into the pro-inflammatory prostaglandin-E2 (PGE2) or leukotriene-B4 (LTB4). 

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed in Chapter 18, the cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. 

Prostaglandins have been implicated both in the induction of inflammation and in its relief. In inflammation small blood vessels become dilated, and fluid and proteins leak into the interstitial spaces to produce the characteristic swelling (edema). Many polymorphonuclear leukocytes attracted by chemotactic factors that include LTB4309 (Chapter 19) migrate into the inflamed area, engulfing dead tissue and bacteria. In this process lysosomes of the leukocytes release phospholipase A, which hydrolyzes phospholipids and initiates the arachidonate cascade. The leukotrienes that are formed promote the inflammatory response. However, cAMP can suppress inflammation, and PGE2 has a similar effect. Indeed, E prostaglandins, when inhaled in small amounts, relieve asthma. 

Busse W, Kraft M. 2005. Cysteinyl leukotrienes in allergic inflammation Strategic target for therapy. Chest. 127 1312-1326. 

Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR, Jr. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003 lll(suppl) S18-S36. 

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. 

Besides 12-LOX in platelets, the 5-LOX isoforms are constitutive in neutrophils. Evidences indicate that LOXs are involved in inflammation diseases and in atherosclerosis. 5-LOX is the enzyme that catalyzes the formation of leukotrienes with potential role for leukocytes and platelets interaction and inflammation. After platelet and leukocyte stimulation, products of both COX-1 and 5-LOX pathways increase. COX-1 activity derivatives increase the vascular permeability mediated by prostaglandins and produce platelet aggregation mediated by TXA2. The product of the lipoxygenase pathway, 5-oxo-6,8,1 1,14-eicosatetraenoic acid (5-Oxo-ETE), induces leukocyte chemotaxis and inflammation. 5-Oxo-ETE is formed by the oxidation of 5S-hydroxy-ETE (5-HETE) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH), a microsomal enzyme found in leukocytes and platelets (42). 

Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect. 

Omega-3 fatty acids are long-chain polyunsaturated fatty acids. The parent fatty acid of this group is alpha-linolenic acid, an essential fatty acid that the body is unable to synthesize alpha-linolenic acid can be converted in the body to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In animals and man, these acids reduce the production of several compounds that are involved in inflammation and thrombosis, such as eicosanoids (prostaglandins, thromboxanes, prostacyclin, and leukotrienes) and cytokines (interleukin II-l) (1). The extent of the conversion of alpha-linolenic acid to EPA and DHA is unclear. The conversion process appears to be inhibited by a high intake of linoleic acid, another essential fatty acid (2). In addition, alpha-linolenic acid is found in dark green vegetables and the oils of certain nuts and seeds, especially rape seeds and soya beans. 

Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN (2000) Oxidoreductases in lipoxin A4 metabolic inactivation a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J Biol Chem 275 25372—25380... 

Thunnissen, M.M., Nordlund, P., Haeggstrom, J.Z. 2001. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Nat. Struct. Biol. 8 131-135. 

Montelukast sodium is a leukotriene receptor antagonist that blocks the effects of specific leukotrienes in the respiratory airways, thereby reducing bronchoconstriction, edema, and inflammation. It is indicated in the prophylaxis and chronic treatment of asthma in patients 12 months and older and in relief of symptoms of seasonal allergic rhinitis in patients 2 years and older. 

In response to stress conditions, varions tissnes convert polytmsaturated fatty acids having twenty carbons to a family of componnds called eicosa-noids. Eicosanoids include prostaglandins, thromboxanes, prostacyclins, and leukotrienes, and are generally involved in inflammation and pain sensation. Aspirin, acetaminophen, and other analgesics work by inhibiting the initial reactions required for the conversion of fatty acids to eicosanoids. 

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