Leukotrienes functions

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

J mohara M, Takasaki J, Matsumoto M> Matsumoto S-I, Saito X Soga X Matsushime H, Furuichi K Functional characterization of cysteinyl leukotriene CysLT2 receptor on human coronary artery smooth muscle cells. Biochem Biophys Res Commun 2001 287 1088. 

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. 

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). 

Lung Function concentration of 5-15 mcg/mL holding chamber) OR leukotriene receptor... 

In persistent asthma, inhaled corticosteroids provide the most comprehensive control of the inflammatory process and are the cornerstone of therapy.2 Inhaled corticosteroids are more effective than cromolyn, leukotriene modifiers, nedocromil, and theophylline in reducing markers of inflammation and AHR, improving lung function, and preventing emergency department visits and hospitalizations due to asthma exacerbations.2,25 The primary... 

Leukotriene modifiers (e.g., zafirlukast and montelukast) have not been adequately evaluated in COPD patients and are not recommended for routine use. Small, short-term studies showed improvement in pulmonary function, dyspnea, and quality of life when leukotriene modifiers were added on to inhaled bronchodilator therapy.27,28 Additional long-term studies are needed to clarify their role. 

Topical corticosteroids (Table 16-1) may halt synthesis and mitosis of DNA in epidermal cells and appear to inhibit phospholipase A, lowering the amounts of arachidonic acid, prostaglandins, and leukotrienes in the skin. These effects, coupled with local vasoconstriction, reduce erythema, pruritus, and scaling. As antipsoriatic agents, they are best used adjunc-tively with a product that specifically functions to normalize epidermal hyperproliferation. 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors a role for LTB4 in up-regulation of CCR7 expression and function. Blood 2007 109 ... 

Mellor, E. A., Frank, N., Soler, D., et al.. (2003) Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells functional distinction from CysLTlR. Proc. Natl. Acad. Sci. U. S. Am. 100,11589-11593. 

Cysteinyl leukotriene receptor M201V, SNPs Tristan da Cunha, Caucasian, Loss of function (167,287-292) ... 

Thompson, M. D., Capra, V., Takasaki, J., et al. (2007) A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate. Pharmacogenet. Genomics. 17, 539-549. 

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