Blockade of Tumor Necrosis Factor Reduces Lipopolysaccharide Lethality, but Not the Lethality of Cecal Ligation and Puncture

Remick, Daniel G.; Manohar, Prerana; Bolgos, G.; Rodriguez, Jorge Luis; Moldawer, Lyle L.; Wollenberg, Gordon K.

doi:10.1097/00024382-199508000-00002

Cited by 149 publications

(84 citation statements)

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“…As the purified LPS used in these experiments is a selective TLR4 agonist, the present results indicate that primed TLR4 reactivity is indeed involved in mediating the lethal LPS response. We acknowledge that the discovery that TNF-␣ plays an important role in LPS lethality is clearly not, by itself, a novel finding, as it has already been shown that blocking TNF-␣ activity in vivo protects normal mice from LPS lethality [36,37]. However, this is the first report showing the importance of TNF-␣ in mediating the lethal second hit response to an otherwise nonlethal dose of LPS following injury.…”

Section: Discussionmentioning

confidence: 81%

Linking the “two-hit” response following injury to enhanced TLR4 reactivity

Murphy

Paterson

Kriynovich

et al. 2004

Journal of Leukocyte Biology

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Severe injury can initiate an exaggerated systemic inflammatory response and multiple organ failure (MOF) if a subsequent immune stimulus, "second hit", occurs. Using a mouse thermal injury model, we tested whether changes in innate immune cell reactivity following injury can contribute to the development of heightened inflammation and MOF. Using high-purity Escherichia coli lipopolysaccharide (LPS) to selectively stimulate Tolllike receptor 4 (TLR4), we demonstrate augmented interleukin (IL)-1␤, tumor necrosis factor ␣ (TNF-␣), and IL-6 production by 1 day but particularly, at 7 days after injury. The in vivo significance of enhanced TLR4 responsiveness was explored by challenging sham or burn mice with LPS at 1 or 7 days after injury and determining mortality along with in vivo cytokine and chemokine levels. Mortality was high (75%) in LPS-challenged burn but not sham mice at 7 days, although not at 1 day, after injury. Death was associated with leukocyte sequestration in the lungs and livers along with increased proinflammatory cytokine and chemokine levels in these organs. Blocking TNF-␣ activity prevented this mortality, suggesting that excessive TNF-␣ production contributes to this lethal response. These findings demonstrate the potential lethality of excessive TLR4 reactivity after injury and provide an explanation for the exaggerated inflammatory response to a second hit, which can occur following severe injury. J. Leukoc. Biol. 77: 16 -23; 2005.

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Section: Discussionmentioning

confidence: 81%

Linking the “two-hit” response following injury to enhanced TLR4 reactivity

Murphy

Paterson

Kriynovich

et al. 2004

Journal of Leukocyte Biology

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“…Our data extend those observations by demonstrating that in response to sepsis, PI3K serves as a negative regulatory mechanism for several important immunoregulatory and proinflammatory cytokines. It should also be noted that the precise role of circulating cytokines in the pathophysiology of sepsis/septic shock is controversial, and there is no definitive cause-and-effect relationship between systemic cytokine levels and survival outcome in sepsis (35). Nevertheless, it is clear that inhibition of PI3K results in increased serum cytokine levels during sepsis and increased susceptibility to septic mortality, but it is not clear that these two events are causally related.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Phosphoinositide 3-Kinase Pathway Alters Innate Resistance to Polymicrobial Sepsis

Williams¹,

Li²,

Ha³

et al. 2004

The Journal of Immunology

154

162

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We examined the effect of modulating phosphoinositide 3-kinase (PI3K) activity in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Inhibition of PI3K activity with wortmannin increased serum cytokine levels and decreased survival time in septic mice. We have reported that an immunomodulator, glucan phosphate, induces protection in murine polymicrobial sepsis. We observed that glucan stimulated tissue PI3K activity, which positively correlated with increased survival in septic mice. We investigated the effect of PI3K inhibition on survival in septic mice treated with glucan. Treatment of mice with the PI3K inhibitors, wortmannin and LY294002, completely eliminated the protective effect of glucan, indicating that protection against septic mortality was mediated through PI3K. Inhibition of PI3K resulted in increased serum levels of IL1-β, IL-2, IL-6, IL-10, IL-12, and TNF-α in septic mice. Apoptosis is thought to play a central role in the response to septic injury. We observed that inhibition of PI3K activity in septic mice resulted in increased splenocyte apoptosis and a change in the anatomic distribution of splenocyte apoptosis. We conclude that PI3K is a compensatory mechanism that suppresses proinflammatory and apoptotic processes in response to sepsis and/or inflammatory injury. Thus, PI3K may play a pivotal role in the maintenance of homeostasis and the integrity of the immune response during sepsis. We also observed that glucan phosphate decreased septic morbidity and mortality through a PI3K-dependent mechanism. This suggests that stimulation of the PI3K pathway may be an effective approach for preventing or treating sepsis and/or septic shock.

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“…To date, no other pathogenic mediators of sepsis have been specifically targeted this late in the course of sepsis to rescue animals from lethality. By comparison, administration of anti-TNF antibodies can actually increase mortality in cecal perforation, and anti-macrophage migration inhibitory factor antibodies are ineffective if administered Ͼ8 h after cecal perforation (23,25). Widening the therapeutic window to 24 h is a critical necessity.…”

Section: Materials and Methods)mentioning

confidence: 99%

Reversing established sepsis with antagonists of endogenous high-mobility group box 1

Yang

Ochani

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,028

974

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Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1␤] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1␤. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 g per mouse) or the DNAbinding A box (600 g per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls ‫؍‬ 28% vs. anti-HMGB1 antibody group ‫؍‬ 72%, P < 0.03; GST control protein ‫؍‬ 28% vs. A box ‫؍‬ 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

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Blockade of Tumor Necrosis Factor Reduces Lipopolysaccharide Lethality, but Not the Lethality of Cecal Ligation and Puncture

Cited by 149 publications

References 0 publications

Linking the “two-hit” response following injury to enhanced TLR4 reactivity

Linking the “two-hit” response following injury to enhanced TLR4 reactivity

Modulation of the Phosphoinositide 3-Kinase Pathway Alters Innate Resistance to Polymicrobial Sepsis

Reversing established sepsis with antagonists of endogenous high-mobility group box 1

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