Endotoxemia in Human Septic Shock

Danner, Robert L.; Elin, Ronald J.; Reilly, Joseph; Hosseini, Jeanette M.; Schlesinger, Terri; Parrillo, Joseph E.

doi:10.1097/00003246-198804000-00077

Cited by 146 publications

(199 citation statements)

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“…The role of superantigens in sepsis is not fully understood, but they are known to have a potentiating effect on the TLR4 ligand endotoxin/LPS (6). Because the vast majority of superantigens are secreted by Gram-positive bacteria, the relevance of this synergy is restricted to cases of polymicrobial sepsis or translocation of Gram-negative bacteria from the gut, with endotoxin release, in patients with Gram-positive sepsis (30).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

Kearney

Wang

Redmond

et al. 2011

The Journal of Immunology

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Bacterial superantigens are Gram-positive exotoxins that induce proinflammatory cytokine release in vitro, cause lethal shock in vivo, and can be detected in the bloodstream of critically ill patients. They also have a powerful priming effect on the TLR4 agonist LPS. The aim of this study was to investigate the relationship between superantigens and the TLR2 agonist bacterial lipoprotein (BLP). Priming of human monocytes or PBMCs with superantigens significantly enhanced proinflammatory cytokine TNF-α and IL-6 release in response to BLP stimulation. The priming effect of superantigens could be blocked by inhibiting p38 MAPK during the priming phase as opposed to NF-κB or ERK inhibition. This was consistent with higher expression of the phosphorylated p38 after superantigen priming and BLP or LPS stimulation. C57BL/6 mice with superantigen priming (10 μg/mouse) when challenged with BLP (600 μg/mouse) exhibited substantially higher mortality (100%) compared with mice without superantigen priming (zero). Mice given superantigen alone did not demonstrate any signs of illness. Mice challenged with both superantigen and BLP had significantly higher levels of serum TNF-α and IL-6 compared with those of mice challenged with either agent alone. Depletion of the monocyte/macrophage subpopulation significantly reduced the mortality rate from 100 to 20% in superantigen-primed, BLP-challenged C57BL/6 mice, with a 5- to 10-fold decrease in serum TNF-α and IL-6. Our results demonstrate that bacterial superantigens enhance the in vitro proinflammatory cytokine release and in vivo lethality of BLP. This novel finding may help to explain the massive proinflammatory cytokine release seen in superantigen-mediated septic shock.

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Section: Discussionmentioning

confidence: 99%

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

Kearney

Wang

Redmond

et al. 2011

The Journal of Immunology

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“…The latter finding contrasts with data from other groups. 13,20,21 There could be two explanations for this. First, only one septic patient had a blood culture positive for Gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

Procalcitonin, C-reactive protein, and endotoxin after bone marrow transplantation: identification of children at high risk of morbidity and mortality from sepsis

Sauer

Tiede

Fuchs

et al. 2003

Bone Marrow Transplant

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Summary:We prospectively evaluated the capacity of serum procalcitonin (PCT), compared with serum levels of Creactive protein (CRP) and endotoxin, to identify children at high risk for mortality from sepsis after BMT. Of 47 pediatric bone marrow transplantation patients studied, 22 had an uneventful course post-transplant (Group 1), 17 survived at least one septic event (Group 2), and eight died from multiorgan failure (MOF) following septic shock (Group 3). Median concentrations of PCT over the course of the study were 1.3, 15.2, and 102.8 ng/ml, respectively, in each of the three groups (Po0.002 for each comparison). Median concentrations of CRP were 91, 213, and 260 mg/l, respectively (Po0.001 for Group 1 vs Group 2 and Group 3; P ¼ NS for Group 2 vs Group 3). Median concentrations of endotoxin were 0.21, 0.30, and 0.93 U/l, respectively (P ¼ NS for each comparison). Median concentrations of PCT, in contrast to serum CRP and endotoxin, correlated with the severity of sepsis (8.2 ng/ml in 'sepsis' and 22.3 ng/ml in 'severe sepsis', P ¼ 0.028) and provided useful prognostic information during septic episodes.

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“…However, excessive innate immune activation of proinflammatory cytokines can be harmful, leading to microcirculatory dysfunction, tissue damage, shock, or even death of the host (3)(4)(5)(6). Our recent finding suggests that conventional T cells play a critical role in tempering such unleashed inflammatory responses by innate cells in adult mice (7).…”

mentioning

confidence: 99%

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

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

146

129

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Neonates suffer high morbidity and mortality in infection, presumably because of the lack of a fully developed adaptive and innate immune system. Evidence of poor innate responses in neonates has been shown by using a model that sensitizes the host to Toll-like receptor (TLR)-mediated inflammation with D-galactosamine (DGalN). However, we show that neonatal mice demonstrate much stronger inflammatory responses than adult mice in response to LPS stimulation, and such hypersensitivity extends to other TLR agonists including actual viral infection. Our study reveals that the ensuing inflammatory reaction after D-GalN sensitization reflects preferential toxicity of D-GalN to adult liver cells, rather than accurately reflecting the TLR response to LPS. We show further that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection. Remarkably, through transfer of T cells into neonates or depletion of T cells in adult mice, we show that T cells are sufficient and necessary to control the early inflammatory response to LPS. Therefore, neonates might suffer from the unleashed innate responses caused by an insufficient number of T cells, which leads to increased morbidity and mortality.

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Endotoxemia in Human Septic Shock

Cited by 146 publications

References 0 publications

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

Bacterial Superantigens Enhance the In Vitro Proinflammatory Response and In Vivo Lethality of the TLR2 Agonist Bacterial Lipoprotein

Procalcitonin, C-reactive protein, and endotoxin after bone marrow transplantation: identification of children at high risk of morbidity and mortality from sepsis

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

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