Endotoxin in Human Disease and its Endogenous Control

Shnyra, Alexander; Luchi, Michael; Gao, Jiangjun; Papasian, Christopher J.; Horn, David L.; Silverstein, Richard; Morrison, David C.

doi:10.1007/978-1-4612-1222-5_13

Cited by 2 publications

(3 citation statements)

References 142 publications

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“…36,164 An early and critical finding in that development was the discovery that dexamethasone down-regulates LPS-stimulated TNF production at the level of the macrophage. 3,75 Nevertheless, dexamethasone is unable to protect against the lethal actions of exogenous TNF, even within the D-galN lethality model (see above).…”

Section: Protecting Agentsmentioning

confidence: 99%

D-Galactosamine lethality model: scope and limitations

Silverstein¹

2004

J. Endotoxin Res.

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106

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D-Galactosamine (D-galN) is well established as sensitizing mice and other animals to the lethal effects of TNF, specifically, and by several orders of magnitude. Protection by anti-TNF neutralizing antibody is complete, as is (metabolically-based) protection by uridine. Sensitization occurs regardless of the origin of the released TNF, whether it is released from macrophages and/or T-cells. The same is true for the challenging agent which leads to the release of TNF, whether it is endotoxin, a superantigen, lipoprotein, bacterial DNA, or bacteria, either killed or proliferating. Most studies have utilized endotoxin as the challenging agent, and more than 70 agents have been reported to confer protection against LPS and/or TNF challenge in the model. The model has provided new insight regarding modes of protection, including from dexamethasone, which protects against challenge from LPS but not from challenge by TNF. The D-galN lethality model has also been used to test for synergistic behavior between different bacterial components, and to test for lethality when only small amounts of the challenging agent are available (lipid A chemistry).

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Section: Protecting Agentsmentioning

confidence: 99%

D-Galactosamine lethality model: scope and limitations

Silverstein¹

2004

J. Endotoxin Res.

Self Cite

106

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show abstract

“…36, 164 An early and critical finding in that development was the discovery that dexamethasone down-regulates LPS-stimulated TNF production at the level of the macrophage. 3,75 Nevertheless, dexamethasone is unable to protect against the lethal actions of exogenous TNF, even within the D-galN lethality model (see above).…”

Section: Implications Of Tnf-mediated Lethality Toward Varied Routes mentioning

confidence: 99%

“…Glucocorticoids can be considered as potentially beneficial within such a context, although glucocorticoids have long remained controversial in terms of effectiveness against bacterial sepsis. 36,164 An early and critical finding in that development was the discovery that dexamethasone down-regulates LPS-stimulated TNF production at the level of the macrophage. 3,75 Nevertheless, dexamethasone is unable to protect against the lethal actions of exogenous TNF, even within the D-galN lethality model (see above).…”

Section: Protecting Agentsmentioning

confidence: 99%

Review: D-Galactosamine lethality model: scope and limitations

Silverstein

2004

Journal of Endotoxin Research

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INTRODUCTIONGalanos and coworkers published two reports, one in 1979 and the other in 1987, that together provided the framework for more than 250 papers from a variety of laboratories using D-galactosamine (D-galN) as a sensitizing agent to TNF-mediated lethality. 1,2 Included in those initial reports, it was established that administration of D-galN in sufficient dose and at the same time as either LPS or TNF was able to reduce the LD 50 value for LPS and for TNF by several orders of magnitude (see below). Complete protection was afforded by anti-TNF neutralizing antibody establishing that lethality from LPS in this model resulted exclusively from sensitization to the lethal effects of TNF, a particularly seminal finding. 3 Administration of uridine at the time of challenge also completely protected against lethality. It was further established, most definitively from adoptive transfer experiments, that in the D-galN model of LPS lethality, endotoxin responsive macrophages were essential, 1,2,4-6 as is also recognized to be the case for LPS lethality in unsensitized mice. 7 While it is otherwise conceivable that D-galN might sensitize to lethality not only by increasing sensitivity to TNF but also by increasing TNF levels, D-galN does not, of itself, appreciably change circulating levels of TNF following challenge with LPS. 8 Dramatic sensitization to LPS lethality brought on by a simple amino sugar is unique to D-galN. Other chemical agents, such as lead acetate, actinomycin D, among others, are also potent at sensitizing to LPS lethality. 9-12 D-galN is, nevertheless, unique among these in that it is naturally occurring in the host, and sensitizes in a welldefined time period after its administration, by a welldefined metabolic mechanism, and by a well-defined cytokine mechanism, namely via TNF. With respect to the metabolic mechanism, it has been established that the same enzyme machinery that converts glucose to UDP-glucose and galactose to UDP-galactose also con- (D-galN) is well established as sensitizing mice and other animals to the lethal effects of TNF, specifically, and by several orders of magnitude. Protection by anti-TNF neutralizing antibody is complete, as is (metabolically-based) protection by uridine. Sensitization occurs regardless of the origin of the released TNF, whether it is released from macrophages and/or T-cells. The same is true for the challenging agent which leads to the release of TNF, whether it is endotoxin, a superantigen, lipoprotein, bacterial DNA, or bacteria, either killed or proliferating. Most studies have utilized endotoxin as the challenging agent, and more than 70 agents have been reported to confer protection against LPS and/or TNF challenge in the model. The model has provided new insight regarding modes of protection, including from dexamethasone, which protects against challenge from LPS but not from challenge by TNF. The D-galN lethality model has also been used to test for synergistic behavior between different bacterial components, and to test for lethality wh...

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Endotoxin in Human Disease and its Endogenous Control

Cited by 2 publications

References 142 publications

D-Galactosamine lethality model: scope and limitations

D-Galactosamine lethality model: scope and limitations

Review: D-Galactosamine lethality model: scope and limitations

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