Therapeutic approach to regulate innate immune response by Toll‐like receptor 4 antagonist E5564 in rats with D‐galactosamine‐induced acute severe liver injury

Kitazawa, Toshiyuki; Tsujimoto, Tatsuhiro; Kawaratani, Hideto; Fukui, Hiroshi

doi:10.1111/j.1440-1746.2008.05770.x

Cited by 29 publications

(25 citation statements)

References 28 publications

(30 reference statements)

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“…In previous studies we found that Kupffer cells, part of innate immune system, produce a variety of cytokines known to be involved in the pathogenesis of cirrhotic liver [2], and Kupffer cells trigger the innate immune response through TLR4 in acute liver failure [15]. We also demonstrated that Kupffer cell phagocytic activity is reduced, but the innate immune response is enhanced, mediated by TLR4, in NASH [16].…”

Section: Discussionmentioning

confidence: 56%

Innate Immune Reactivity of the Ileum–Liver Axis in Nonalcoholic Steatohepatitis

et al. 2012

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Section: Discussionmentioning

confidence: 56%

Innate Immune Reactivity of the Ileum–Liver Axis in Nonalcoholic Steatohepatitis

et al. 2012

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“…(1) Lipid A mimetics (for example, E5564 and CRX-526 [150,151]) which bind to the TLR4-MD2 complex but lack intrinsic activity and thus prevent binding of the lipid A portion of LPS and subsequent TLR4 activation…”

Section: Future Prospectsmentioning

confidence: 99%

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Guo

Friedman

2010

Fibrogenesis Tissue Repair

259

235

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Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

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“…A phase II study in septic patients showed possible survival benefits in subgroups. Other investigators are studying its use for treating various other potentially TLR4 mediated conditions, e.g ., chronic LPS-mediated airway disease,17 liver disease,18, 19 contact lens-associated corneal inflammation,20 myocardial and renal ischemia-reperfusion injury21, 22.…”

Section: Eritoran Tetrasodiummentioning

confidence: 99%

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies

Barochia

Solomon²,

Cui³

et al. 2011

Expert Opinion on Drug Metabolism & Toxicology

143

105

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Introduction-Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4 (TLR4).Areas covered-This review focuses on the rationale for the use of eritoran tetrasodium in sepsis, as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Pre-clinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms "eritoran" and "E5564" are discussed.Expert opinion-Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS, and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis is currently under investigation. Even if the ongoing phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies will be necessary to define its clinical usage.

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Therapeutic approach to regulate innate immune response by Toll‐like receptor 4 antagonist E5564 in rats with D‐galactosamine‐induced acute severe liver injury

Abstract: TLR4 antagonist E5564 reduced GalN-induced ALI in rats. It may contribute to the treatment of acute liver failure through blocking endotoxin-induced TNF-alpha overproduction of macrophages.

Cited by 29 publications

References 28 publications

Innate Immune Reactivity of the Ileum–Liver Axis in Nonalcoholic Steatohepatitis

Innate Immune Reactivity of the Ileum–Liver Axis in Nonalcoholic Steatohepatitis

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies

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