Monophosphoryl Lipid a Protects Against Gram-Positive Sepsis and Tumor Necrosis Factor

Astiz, Mark E.; Galera, Angel; Saha, Dhanonjoy C.; Carpati, Charles; Rackow, Eric C.

doi:10.1097/00024382-199410000-00007

Cited by 24 publications

(30 citation statements)

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“…16,2003 BACTERIAL SEPSIS 393 plasminogen activator on macrophages, and up regulation of adhesion molecules on endothelial cells (185,222,247,410,411). In addition, Kobayashi et al observed reduced IL-1 production in SR-A knockout mice after an LPS challenge and proposed that binding of LPS to SR-A induces the release of IL-1 (271).…”

Section: Scavenger Receptorsmentioning

confidence: 99%

“…In healthy human volunteers, LPS tolerance could be induced by the infusion of monophosphoryl lipid A, but no clinical trials with septic patients have been performed (18). Interestingly, cross-tolerance to gram-positive infection could be induced in mice, indicating that this therapy might be effective in gram-negative and gram-positive sepsis (16).…”

Section: Immunosuppression and Neutralization Of Proinflammatory Cytomentioning

confidence: 99%

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Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

2003

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Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins

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Section: Scavenger Receptorsmentioning

confidence: 99%

Section: Immunosuppression and Neutralization Of Proinflammatory Cytomentioning

confidence: 99%

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

2003

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“…In addition, endotoxin tolerant mice are partially protected from the lethality induced by septic peritonitis (38,39). Because the biological responses triggered by CpG-ODN are similar to those induced by LPS, we investigated whether treatment with CpG-ODN would alter cytokine production by mononuclear phagocytes.…”

Section: Effects Of Cpg-odn Treatment On Cytokine Production By Mononmentioning

confidence: 99%

Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

Weighardt

Feterowski

Veit

et al. 2000

The Journal of Immunology

121

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Recent reports support the concept that the major defect in polymicrobial sepsis is an impaired immunologic response to infection. Oligodeoxynucleotides containing CpG sequence motifs (CpG-ODN) were previously shown to induce immune protection in models of chronic infection with intracellular bacteria, parasites, and viruses due to their ability to augment IFN-γ-dependent Th1 responses. Here, we demonstrate that challenging mice with CpG-ODN substantially increases the resistance against acute polymicrobial sepsis. Systemic levels of IL-12, IL-18, and IL-10 were not altered in CpG-ODN-treated mice as compared with controls. In contrast, administration of CpG-ODN resulted in a strongly enhanced accumulation of neutrophils at the primary site of infection. Neutrophils of CpG-ODN-treated mice exhibited an up-regulation of phagocytic receptors, an increased phagocytic activity, and an elevated production of reactive oxygen metabolites. These results suggest that the protective effects of CpG-ODNs in acute polymicrobial sepsis are related to an enhanced effector cell response of innate immunity. CpG-ODN may therefore represent potent agents for the treatment of sepsis-associated immunoparalysis.

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“…The attenuated toxicity of MPLA is associated with reduced induction of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and gamma interferon (IFN-␥) during initial exposure (13,29). MPLA retains significant immunomodulatory activity and prior treatment with MPLA increases survival after otherwise lethal exposure to LPS in animal models (2,16,39). However, the effect of MPLA on the innate response to clinically relevant models of bacterial infection has not been determined.…”

mentioning

confidence: 99%

The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

et al. 2011

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Monophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model of Pseudomonas aeruginosa burn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G؉ neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.

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Monophosphoryl Lipid a Protects Against Gram-Positive Sepsis and Tumor Necrosis Factor

Cited by 24 publications

References 0 publications

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

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