Leukotriene effect

Baud L, Perez J, Denis M, Ardailou R. 1987. Modulation of fibroblast proliferation by sulfidopeptide leukotrienes effect... 

Question A program was initiated to produce silent antagonism of leukotriene effect in asthma (no agonist effect, only inhibition of natural agonist in the system). Accordingly, a human leukotriene receptor was expressed in Chinese hamster ovary (CHO) cells this system responded to the natural agonist but it was noted that the natural agonist was not as potent in this recombinant system as it was in samples of human airway tissue. Chemists... 

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. 

Endotoxin and Muramyl Dipeptide Derivatives. Bacterial cell wall constituents such as the Hpopolysaccharide endotoxin and muramyl dipeptide, which stimulate host defense systems, show radioprotective activity in animals (204). Although endotoxin is most effective when given - 24 h before irradiation, it provides some protection when adrninistered shortiy before and even after radiation exposure. Endotoxin s radioprotective activity is probably related to its Hpid component, and some of its properties may result from PG and leukotriene induction (204). 

Leukotriene B5 can be biosynthesized in the body from eicosapentaenoic acid, which is ingested in the form of dietary fish lipid. Synthetic LTB5 was synthesized as outlined below and found to have only 20% of the neutrophil chemotactic activity of LTB4, a fact which may be relevant to the antiinflammatory effect of dietary marine lipid. 

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. 

The effects of leukotrienes can be blocked at several levels. Inhibitors of FLAP or 5-LO inhibit LT synthesis at all levels. However, FLAP antagonists developed to date have been too hepatotoxic for human use. Zileuton, a 5-LO synthase inhibiting drug, also demonstrated some hepatotoxicity in a small percentage of patients, which was nonetheless entirely reversible. However, the short half-life of this compound requires four times daily... 

Triggering of asthma attacks in asthmatics. This side effect is a pseudo-allergic reaction where COX-inhibition increases the availability of substrates for lipoxygenase, which are converted to broncho-constrictive leukotriens... 

Along with the bronchodilators, several types of dragp are effective in Hie treatment of asthma. These include corticosteroids, leukotriene formation inhibitors, leukotriene receptor agonists, and mast cell stabilizers. 

In a third study the time course of the effects of intravenous and intracoronary injections of cysteinyl leukotrienes on metabolic parameters and systemic and coronary hemodynamics was examined in patients with normal coronary arteries [32]. LTD4 (3 nmol, injected into the left coronary artery) induced an early (20 s), transient fall in mean arterial pressure paralleled by rises in heart rate and plasma levels of epinephrine and norepinephrine, all of which had returned to baseline by 10 min. CVR rose at 10 and 15 min and myocardial oxygen extraction at 15 min. Thus, small doses of cysteinyl leukotrienes may induce both an early, transient fall in mean arterial pressure, with secondary sympathoadrenergic activation, and a later increase in small coronary arteriolar resistance. 

Cysteinyl leukotrienes can induce an early, transient fall in arterial pressure associated with sympathoadrenergic activation, plus a late rise in small coronary arteriolar resistance [32]. Using specific antagonists of CysFTi and CysFT2 [63] it will be possible to assess the each receptor s contribution to the cardiovascular effects of these vasoactive mediators. 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

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). 

We have already stressed the potential importance of lipid-rich membranes in the skin as potential targets for ROS-induced damage and ageing of human skin is morphologically identical to changes found by peroxidative processes (Serri et al., 1977). The involvement of AA metabolites in skin disease, and in particular psoriasis, has been the subject of much recent interest. Studies have included topical and intradermal administrations of AA metabolites, and assay of such products in clinical specimens. Results show that concentration of AA, 12-hydroxy-eicosatetraenoic acid (12-HETE), PG and leu-kotrienes are increased in psoriatic lesions (Hammarstrom etal., 1975 Camp etal., 1983 Brain etal., 1984 Duell et al., 1988) and also that full-thickness epidermis from normal and diseased skin has the enzymatic capacity to convert AA to some of the same metabolites (Hammarstrom etal., 1975, 1979 Camp etal., 1983 Brain etal., 1984 Ziboh et al., 1984 DueU et al., 1988). The biological effect of both 12-HETE and leukotrienes was confirmed by both topical application and intradermal injection, which caused epidermal inflammation and... 

Soter, N.A., Lewis, R.A., Corey, E.J. and Austen, K.F. (1983). Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J. Invest. Dermatol. 80, 115-119. 

Findlay, S.R., Barden, J.M., Easley, C.B. and Glass, M. (1992). Effect of the oral leukotriene antagonist ICI 204,219 on the antgen-induced bronchoconstriction in subjects with asthma. J. Allergy Clin. Immunol. 89, 1040-1045. 

Finnerty, J.P., Wood-Baker, R., Thompson, H. and Holgate, S.T. (1992). Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204,219, a potent leukotriene D4 receptor antagonist. Am. Rev. Resp. Dis. 145, 746-749. 

Hui, P.H., Taylor, I.K., Taylor, G.W., Rubin, P., Kesterton, J., Barnes, N.C. and Barnes, P.J. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 46, 184-189. 

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 either inhibit 5-lipoxygenase (zileuton) or competitively antagonize the effects of leukotriene D4 (montelukast and zafirlukast). These agents improve FEV, and decrease asthma symptoms, rescue drug use, and exacerbations due to asthma. Although these agents offer the convenience of oral therapy for asthma, they are significantly less effective than low doses of inhaled corticosteroids.2,33... 

Patients receiving these agents may notice improvement in 1 to 2 weeks, but maximal benefit may not be seen for 4 to 6 weeks. Cromolyn and nedocromil appear to be similar in efficacy to the leukotriene antagonists and theophylline for persistent asthma.18 Both agents are well tolerated with adverse effects limited to cough and wheezing. Bad taste and headache have also been reported with nedocromil. One dose of cromolyn or nedocromil prior to exercise or allergen exposure will provide effective prophylaxis for 1 to 2 hours. Cromolyn and nedocromil are not as effective as albuterol for prophylaxis of exercise-induced asthma. 

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