LPS toxicity

In endotoxinemic mice IL-10 treatment inhibits proinflammatory cytokine release and leads to a reduction in LPS toxicity (G8, H28). IL-10 does not influence the LPS-induced production of IL-6 in vivo (M9). This suggests that IL-10 could differentially regulate TNF and IL-6 production by macrophages in vivo, in contrast to data obtained in vitro (Wl), or that cell types other than macrophages are a major source of IL-6 in vivo and are resistant to IL-10 (S23). 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

Several phase I trials have been performed with LPS from Salmonella abortus equi administered i.v. in patients who suffered from disseminated cancer. White blood cell number decreased after each injection and returned to basal level by 24 hours. There were no changes in coagulation parameters, and no disseminated intravascular coagulation was observed. After the first injection of LPS, increases in TNF-a concentration and IL-6 activity in serum were detected. However LPS tolerance which is accompanied by a decrease in TNF-a and IL-6 production depended on the intervals between repeated injections, but it was not determined whether it was a benefit or a draw-back. Injections of IFN-y prevented this decrease in TNF-a and IL-6, and ibuprofen attenuated LPS toxicity [183,186],... 

Ong SY, Clarke SJ, Bishop J, Dodds HM, Rivory LP. Toxicity of irinotecan (CPT-11) and hepato-renal dysfunction. Anticancer Drugs 2001 12(7) 619-25. 

Although endotoxin interacts with many cells throughout the body, and probably does intercalate into membranes in a fairly nonspecific fashion, the lethal effect of LPS seems to be conferred by cells of hematopoietic origin. This fact was revealed by adoptive transfer studies in which crosstransplantation of C3H/HeJ and C3H/HeN hematopoietic stem cells was carried out after lethal irradiation (26). The phenotype of the donor determined the phenotype of the radiation chimera. In separate experiments, it was shown that macrophages were of principal importance in LPS toxicity (27,28). As hematopoietic derivatives, macrophages therefore seem to be the most important responder cells, ultimately conferring the lethal effect of LPS. 

As has been emphasized in this review, LPS is an unusual poison in that its mechanism of toxicity has been preserved by evolution. In effect, the host realizes that LPS is toxic and accepts the risk of toxicity for the greater good of combating infection. A single mutation would suffice to remove the threat of LPS toxicity, and many species seem to have chosen this option. In mammals, however, LPS sensing is acute, and with this faculty has come the burden of LPS toxicity. What is the nature of the tradeoff in mathematical terms Can it be calculated ... 

Beumer, C., Wulferink, M., Raaben, W., Fiech-ter, D., Brands, R., Seinen, W. (2003) Calf intestinal alkaline phosphatase, a novel therapeutic dmg for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets. /. Pharmacol. Exp. Then 307,... 

Lipopolysaccharide (LPS) endotoxins are characteristic Gram-negative outer-cell components which are produced by many cyanobacteria. Although LPS have been characterized and found to be toxic to laboratory animals after isolation from cyanobacteria, their toxicity to rodents is less potent than the endotoxins of enteric pathogens such as Salmonella Typical symptoms of animals suffering from LPS intoxication include vomiting, diarrhoea, weakness and death after hours rather than minutes. 

Several TLR-4 adjuvants for vaccines have been developed to date. An example of these is monopho-sphoryl lipid A (MJPL) a modified version of lipid A found in LPS [4]. It has been used extensively in clinical trials as it is far less toxic than LPS. It is hoped to use MPL in vaccines against infectious diseases, allergies and cancer. Derivatives of MPL have now been... 

FIGURE 7.9 (See color insert) Peroxynitrite production by activated macrophages. Cells isolated from control (CTL) and toxicant (TOX)-treated animals were cultured overnight in the presence of IFNa + LPS. Phorbol myristate acetate was then added. Thirty minutes later, the cells were loaded with DHR 123. After 5 minutes incubation, the cells were rinsed and analyzed for fluorescence associated with peroxynitrite production by confocal microscopy. 

Lesniak W, Bielinska AU, Sun K, Janczak KW, Shi X, Baker JR, Balogh LP (2005) Silver/ dendrimer nanocomposites as biomarkers fabrication, characterization, in vitro toxicity, and intracellular detection. Nano Lett 5 2123-2130... 

Wackett LP (1995) In Young LY, Cerniglia CE (eds) Microbial transformation and degradation of toxic organic chemicals. Wiley-Liss, New York, p 217... 

Table 2 shows the results obtained for four-hour and 24-hour exposure to AmB. LC-AmB had an IC50 above lOOmg/L after 24-hour exposure. This indicates that it has very low toxicity, comparable to the commercial formulation AmBisome (9). The toxicity increased with the time of exposure for all formulations (after a 48-hour exposure, the IC50 of LC-AmB was 86mg/L, data not shown). Very similar results were obtained in the presence of polymyxin B, eliminating the possibility that the toxicity was due to the contamination of the formulations with lipopolysaccharide (LPS) (22). 

Clemens TL, Hill RN, Bullock LP, et al. 1979. Chloroform toxicity in the mouse Role of genetic factors and steroids. Toxicol Appl Pharmacol 48 117-130. 

McCarty LP, Flarmagan DC, Randall SA, et al. 1992. Acute toxicity in rats of chlorinated hydrocarbons given via the intratracheal route. Human Exper Toxicol 11 173-177. 

Xiong DW, Fang T, Yu LP, Sima XF, Zhu WT (2011) Effects of nano-scale TiO(2), ZnO and their bulk counterparts on zebrafish acute toxicity, oxidative stress and oxidative damage. Sci Total Environ 409 1444—1452... 

Seffernick JL, Wackett LP (2001) Rapid evaluation of bacterial catabolic A case study with atrazine chlorohydrolase. Biochemistry 40 12747-12753 Senesi M, Chen Y (1989) Interaction of toxic organic chemicals with humic substances. In Gerstl Z, Chen Y, Mingelgrin U, Yaron B, Toxic organic chemicals in porous media. Springer, Berlin pp 37-91... 

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

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