Endotoxin tolerance

Every marketed product has a level of endotoxin tolerated based on the minimum pyrogenic dose and amount of the drug to be administered as per Food and Drug Administration (FDA) guidelines [19]. However, there are none for the more advanced chemical assays described here. Indeed there are only a few highly specialized university laboratories that currently have experience in trace chemical analysis of LPS and PG. There are no commercial testing laboratories. Simplification and automation will allow more widespread availability of these methods. 

Sano, H., Sata, T., Nanri, H., Ikeda, M., and Shigematsu, A. 2002. Thioredoxin is associated with endotoxin tolerance in mice. Crit. Care Med. 30 190-194. 

Qureshi, S.T., Lariviere, L., Leveque, G., Clermont, S., Moore, K.J., Gros, P., Malo, D. Endotoxin-tolerant mice have mutations in toll-like receptor 4 (TLR4). J Exp Med 189 (1999) 615-625. 

LAL Gelation Leucopenia Leucocytosis Complement Activation Blood Pressure Depression Shwartzman Phenomenon Bone Marrrow Necrosis Prostaglandin Synthesis Endotoxin Tolerance Macrophage Activation... 

Zager RA, Johnson AC, Lund S, Endotoxin tolerance TNF-a hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int, 2007, 71 496-503. 

One such phenomenon is endotoxin tolerance. It is known that LPS stimulation is associated with a prompt response (NF-/cB translocation to the nucleus and cytokine production) followed by a refractory state, wherein a second challenge is far less effective at provoking such a response (97,98). Cross-tolerance has been observed when a primary stimulus with lipopeptides is used in place of LPS (99). Although some have attributed tolerance to the production of antiinflammatory cytokines such as TGF/3 and/or IL-10 (100), it is more widely held that tolerance reflects the activation of a feedback pathway within cells, causing paralysis of the LPS response. One example of tolerance at the cellular level involves the production of NF-kB p50 homodimers, which can bind to diverse promoters within the cell and prevent activation by p50/p65 heterodimers (101). Other levels of blockade are also possible and are currently under investigation. 

M44. Moore, J. N., Cook, J. A., Morris, D. D., Halushka, P. V., and Wise, W. C. Endotoxin-induced procoagulant activity, eicosanoid synthesis, and tumor necrosis factor production by rat peritoneal macrophages Effect of endotoxin tolerance and glucan. Circ. Shock 31, 281-295 (1990). 

Adib-Conquy, M., and Cavaillon, J. M. Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression. J Biol Chem 277 (2002) 27927-27934. 

Li, L., Cousart, S., Hu, J., and McCall, C. E. Characterization of Interleukin-1 Receptor-associated Kinase in Normal and Endotoxin-tolerant Cells. J Biol Chem 275 (2000) 23340-23345. 

Tolerance to endotoxin develops after repeated administration of small doses to animals and is characterized by the attenuation of the cardiovascular effects and mortality caused by a subsequent challenge with high-dose endotoxin (Johnson and Greisman, 1985). Two distinct phases of endotoxin tolerance have been reported an early-phase tolerance, which is poorly understood, beginning within 24-96 hr after endotoxin exposure, and a late-phase tolerance, developing several weeks after the initial exposure to endotoxin, which is associated with the production of antiendotoxin antibodies (Johnson and Greisman, 1985). 

Several different mechanisms may contribute to the development of endotoxin tolerance in vivo. The early-phase tolerance to endotoxin is associated with a reduced release of TNF, colony-stimulating factor, and IFN-y (Beutler etal., 1986 Sanchez-Cantu etal., 1989 Evans etal, 1991 Zucker-man et al., 1989b). These cytokines are key mediators of the cardiovascular dysfunction elicited by endotoxin (see above). 

Thus, we have investigated the relationship between the early-phase tolerance to endotoxin and the induction of iNOS in vivo. In particular, we have studied (1) whether the early-phase tolerance to endotoxin is associated with a reduced ability of endotoxin to induce iNOS, (2) whether this is associated with increased circulating levels of endogenous glucocorticoids, and (3) whether any rise in plasma glucocorticoids is responsible for suppressing the induction of iNOS and the blunted cardiovascular response to endotoxin in endotoxin-tolerant animals. 

Thus, the development of cardiovascular tolerance to endotoxin in the rat is associated with a reduced ability of endotoxin to induce iNOS, In addition, endotoxin tolerance is associated with a marked rise in plasma glucocorticoid levels. The attenuation of the induction of iNOS by endogenous glucocorticoids is likely to account for endotoxin-induced cardiovascular tolerance. Elevated glucocorticoids play a key role in the development of endotoxin tolerance and may serve to protect individuals with chronic inflammatory disorders from the deleterious consequences of excessive NO production. 

Sanchez-Cantu, L., Rode, H. N., and Cristou, N. V. (1989). Endotoxin tolerance is associated with reduced secretion of tumor necrosis factor. Arch. Surg. 124, 1432-1436. 

Szab6, C., Thiemermann, C., Wu, C. C., Perretti, M., and Vane, J. R. (1994a). Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc. Natl. Acad. Set. U.S.A. 91, nX-TlS. 

Wang, J, F., and Spitzer, J. J. Hepatic NO release during endotoxin tolerance. Proc. IBC Int. Symp. Nitric Oxide, 3rd p. 31. 

Zuckerman, S. H., Evans, G. F., and Butler, L. D. (1989b). Endotoxin tolerance Independent regulation of interleukin-1 and tumor necrosis factor expression. Infect. Immun. 59, 2774-2780. 

D. Charon, M. Mondange, J. F. Pons, K. L. Blay, and R. Chaby, Synthesis and in vitro activities of a spacer-containing glycophospholipid ligand of a lipopolysaccharide receptor involved in endotoxin tolerance, Bioorg. Med. Chem., 6 (1998) 755-765. 

Endotoxin tolerance also results in altered eicosanoid metabolism. Plasma levels of iTxB2 and i6-keto-PGFio were measured after administration of endotoxin at normally lethal (15 mg kgand supralethal (50 mg kg doses In contrast to marked elevations of plasma iTxB2 and id-keto-PGFjgj after endotoxin administration in non-tolerant control rats, levels in tolerant rats were significantly reduced. Tolerant rats also demonstrated enhanced... 

Greisman, S.E. (1983). Induction of endotoxin tolerance. In Nowotny, A. (ed.) Beneficial Effects of Endotoxin, pp. 149-178. (New York Plenum Press)... 

Rogers, T.S., Halushka, P.V., Wise, W.C. and Cook, J.A. (1986). Differential alterations of lipoxygenase and cyclo-oxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance. Prostaglandins, 31(4), 639-650... 

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