Leukotriene endotoxin

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). 

Leukotrienes can form in hepatocytes, Kupffer cells and masto-cytes. Their release, induced by endotoxins for example, correlates with the increase in AP, LAP and y-GT. Leukotrienes have a marked inflammatory effect. Enhanced production together with reduced secretion of leukotrienes into the bile can result in severe lesions of the bile ducts. (203)... 

Lipoxygenase Resistant to PAF-induced lethal shock Maintain sensitivity to endotoxin lethality Blocked production of leukotrienes... 

PAF-induced shock (Chen et al., 1994). The knockout mice fail to show PAF-induced bronchoconstriction, vasoconstriction, or the release of peptidyl leuko-trienes (Table 5). This suggests that leukotrienes are important mediators of PAF-, but not of endotoxin-induced shock. 

A diet supplemented with GLA and eicosapentaenoic acids improved oxygen delivery by decreasing vascular resistance and increasing cardiac index in endotoxin-induced lung injury in pigs. This mechanism is thought to involve attenuation of endotoxin-induced thromboxane B2 synthesis (Murray et al., 1995). A study (Mancuso et al., 1997) in endotoxic rats demonstrated that in addition to attenuation of thromboxane B2 production, production of leukotriene B4, leukotriene C/D4, and PGFla,... 

Badr, K., Kelley, V.E., Rennke, H. and Brenner, B.M. (1986). Role for thromboxane A2 and sulfidopeptide leukotrienes in endotoxin-induced acute renal failure. Kidney Int., 30, 474-480... 

At this time, it is difficult to reconcile the results from all the studies in the literature regarding the role of specific eicosanoids or PAF in the development of endotoxin-induced lung injury. The differences in results may be due to the use of inadequate or ineffective inhibitors, different doses and preparation of endotoxin, variable sensitivity of different species of animals to endotoxin effect and differences in eicosanoid metabolism in different species . A final possibility is that perhaps none of the metabolites alone is adequate to cause injury, but mediator chain reactions and synergistic actions of several mediators are important. This might explain why interventions targeting a single mediator (thromboxane or leukotrienes) have so far met with limited success. 

Hagmann, W., Fritz, M.M. and Keppler, D. (1983). Leukotrienes and endotoxin lethality. In Piper, P.J. (ed.) Leukotrienes and Other Lipoxygenase Products, pp. 128-133. (Chichester John Wiley and Sons)... 

Hagmann, W., Denziinger, C. and Keppler, D. (1984). Role of peptide leukotrienes and their hepatobiliary elimination in endotoxin action. Circ. Shock, 14, 223-235... 

Evidence for increased leukotriene formation following endotoxin has been found in the bile of and following enterotoxin in the monkey ... 

Pretreatment with LYl 71883 prevented the endotoxin-induced neutropenia (Figure 5.13), haemoconcentration (Figure 5.14) and acute systemic hypotension observed in rats . The increased haemoconcentration of endotoxic shock, an indirect measure of vascular permeability, suggests enhancement of vascular permeability by endogenous LTD4/E4. It is not clear whether the prevention of neutropenia by LYl 71883 in endotoxaemia is a direct effect of inhibition of the action of sulphidopeptide leukotrienes. For example, these leukotrienes have been shown to stimulate neutrophil adherence to cultured endothelial cells by a platelet activating factor-dependent mechanism. ... 

The relative importance of leukotrienes as pathophysiological mediators may, however, be species dependent. In contrast to rats, pretreatment with this LTD4/E4 antagonist in sheep failed to prevent the endotoxin-induced neutropenia, and pulmonary permeability, but did reduce the pulmonary arterial and microvascular pressures. LYl 71883 failed to prevent the increased rabbit lung permeability induced by oleic acid in the isolated perfused rabbit lung. ... 

Hagmann, W. and Keppler, D. (1982). Leukotriene antagonists prevent endotoxin lethality. Naturwissenschaffen, 69, 594-595... 

Etemai, A.R., Tempel, G.E., Wise, W.C., Halushka, P.V. and Cook, J.A. (1986). The beneficial effects of a leukotriene antagonist on endotoxin induced acute hemodynamic alterations. Circ. Shock, (In press)... 

Tumor necrosis factor-a is an endotoxin (LPS)-inducible cytokine that plays an important role in the inflammatory processes. TNF-a is implicated in the pathobiology of many human diseases such as septic shock, cancer, rheumatoid arthritis, and AIDS. Inhibition of elevated TNF-a levels has been proposed as a strategy for alleviating the progression of these diseases. Eicosanoids derived from AA (20 4n-6), such as leukotrienes and thromboxanes, have been implicated in the inflammatory responses. In this study, the roles of eicosanoids on the inhibition of LPS-induced TNF-a production by n-3 PUFA were investigated in human monocytic THP-1 cells. The n-3 PUFA, EPA and DHA, decreased the production of TNF-a to the greatest extent among various... 

A number of attempts to alter the course of ALI/ARDS pharmacologically have not been proven to be successful. These include the use of exogenous surfactant, glucocorticoids, antioxidant (n-acetylcysteine), prostaglandin and leukotriene synthesis inhibitors (hetoconazole, ibuprofen), prostaglandin El, inhaled nitric oxide, and pentoxifylline (159,160). Trials with antibodies aimed at blocking inflammation provoked by endotoxin, TNF-a, and IL-1 have also not been proven to be successful... 

Tanaka N, Kita T, Kasai K, Nagano T. The immunocytochemical localization of tumour necrosis factor and leukotriene in the rat heart and lung during endotoxin shock. Virchows Arch 1994 424 273-277. 

---