Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

Papasian, Christopher J.; Silverstein, Richard; Gao, Jian; Bamberger, David M.; Morrison, David C.

doi:10.1128/iai.70.12.6628-6637.2002

Cited by 18 publications

(26 citation statements)

References 48 publications

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“…3 The ability of dexamethasone to protect D-galN-sensitized (and unsensitized) mice against endotoxin lethality extends to proliferating Gram-negative bacteria, both as seen from dexamethasone protection against each of several Gramnegative bacteria in outbred (CF-1) mice and by the corresponding lack of protection against these same bacteria in endotoxin hyporesponsive (C3H/HeJ) mice. 34,38 D-GalN-sensitization, as discussed above, is not unique to endotoxin nor, by extension, to Gram-negative bacteria; nor is this also true of dexamethasone protection against corresponding lethal challenge. D-GalN sensitizes to the lethal effects of proliferating enterococcal strains (Grampositive), and dexamethasone correspondingly protects.…”

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

confidence: 99%

“…D-GalN sensitizes to the lethal effects of proliferating enterococcal strains (Grampositive), and dexamethasone correspondingly protects. 38 These properties appear, however, to be exceptional to enterococcal strains (E. faecalis, E. faecium) upon comparison with other Gram-positive bacterial proliferating bacteria. Tests with several proliferating staphylococcal and streptococcal isolates demonstrate that D-galN neither sensitizes to lethality, nor does dexamethasone protect.…”

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

confidence: 99%

“…Tests with several proliferating staphylococcal and streptococcal isolates demonstrate that D-galN neither sensitizes to lethality, nor does dexamethasone protect. 38 This whole picture, importantly, changes upon bacterial killing. 33 Dexamethasone does, in fact, protect against imipenem-killed Staph.…”

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

confidence: 99%

“…Similar comparisons with several additional Gram-negative clinical or laboratory isolates led to the same conclusion. 38 The ability of D-galN to increase lethality from live Staph. aureus was only marginal, notwithstanding the D-galNsensitized lethality seen with heat-killed Staph.…”

Section: Mechanisms Of Lps Lethality In Normal Versus D-galnsensitizementioning

confidence: 99%

“…2 Indeed, in the years that have followed, D-galN has been found to sensitize mice, among other animal species, to the lethal effects of superantigens, [14][15][16][17][18][19][20][21][22][23][24][25] bacterial lipoprotein and lipopeptides, [26][27][28] bacterial (CpG) DNA, [29][30][31][32] as well as to the Gram-negative and Gram-positive bacteria from which they are derived. [33][34][35][36][37][38] …”

Section: Introductionmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

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

confidence: 99%

Section: Mechanisms Of Lps Lethality In Normal Versus D-galnsensitizementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Review: D-Galactosamine lethality model: scope and limitations

Silverstein

2004

Journal of Endotoxin Research

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Experimental pathogenesis and host immune responses of Enterococcus faecalis infection in Nile tilapia (Oreochromis niloticus)

et al. 2019

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Neutralization of Tumor Necrosis Factor in Preclinical Models of Sepsis

Lorente

Marshall

2005

Shock

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Tumor necrosis factor (TNFalpha), a cardinal early mediator of the innate host inflammatory response, has been an attractive target for therapeutic intervention in human sepsis. However, pooled data from 12 completed randomized controlled trials show only a very modest impact on mortality in a highly heterogeneous population of patients. To gain insight into the preclinical in vivo biology of TNFalpha that might aid in better identifying appropriate patient populations for therapeutic intervention, we undertook a systematic review of published reports of preclinical studies assessing the consequences of neutralization of TNFalpha in models of acute infection or inflammation. We identified 143 reports incorporating 484 unique experimental comparisons in seven different animal species. The effects of neutralization of TNFalpha in these were quite variable. Neutralization of TNFalpha was beneficial in endotoxemia, or after systemic challenge with gram-negative organisms, Staphylococcus aureus, or Group B streptococci. On the other hand, neutralization was detrimental in infections caused by Streptococcus pneumoniae, Candida spp., or intracellular pathogens such as Listeria and Mycobacterium tuberculosis, and in models of pneumonia. Treatment was more efficacious when delivered before infectious challenge, and the therapeutic signal increased as the baseline mortality in the placebo group increased. Evidence of neutralization of TNFalpha bioactivity, and of attenuation of inflammation, was typically accompanied by evidence of impairment of antimicrobial defenses. Multiple specific and nonspecific therapeutic strategies were identified. We conclude that the beneficial effects of TNF in systemic inflammation occur at the cost of impaired antimicrobial defenses, and that a better understanding of the consequences of neutralization of TNFalpha in vivo could aid in better defining optimal patient populations for therapeutic intervention.

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Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

Cited by 18 publications

References 48 publications

Review: D-Galactosamine lethality model: scope and limitations

Review: D-Galactosamine lethality model: scope and limitations

Experimental pathogenesis and host immune responses of Enterococcus faecalis infection in Nile tilapia (Oreochromis niloticus)

Neutralization of Tumor Necrosis Factor in Preclinical Models of Sepsis

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