Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

Su, Grace L.; Gong, Ke; Fan, Min; Kelley, William M.; Hsieh, Jason K.; Sun, Jian; Hemmila, Mark R.; Arbabi, Saman; Remick, Daniel G.; Wang, Stewart C.

doi:10.1002/hep.20533

Cited by 51 publications

(36 citation statements)

References 47 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present findings are also consistent with recent observations in patients with advanced cirrhosis and ascites where elevated LBP levels have been found to correlate with marked immune and hemodynamic derangement (2) and increased susceptibility to severe infectious complications (1). In addition, previous work by our group has demonstrated that LBP also contributes to increased hepatic injury and death following acetaminophen-induced liver injury (34). Taken together, this suggests that the presence of underlying liver pathology may alter the effect of LBP on LPS signaling, leading to a predominantly stimulatory rather than inhibitory immune response with acute-phase levels of LBP.…”

Section: Discussionsupporting

confidence: 93%

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Minter¹,

Bi²,

Ben-Josef³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

GL. LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction. Am J Physiol Gastrointest Liver Physiol 296: G45-G54, 2009. First published October 23, 2008 doi:10.1152/ajpgi.00041.2008.-It is generally accepted that low levels of lipopolysaccharide (LPS)-binding protein (LBP) augment the cell's response to LPS, whereas high levels of LBP have been shown to inhibit cell responses to LPS. Clinical studies and in vitro work by our group have demonstrated that, in the setting of liver disease, increased or acute-phase levels of LBP may actually potentiate rather than inhibit an overwhelming proinflammatory response. Therefore, in the present studies we sought to determine the role of acute-phase LBP in mediating morbidity and mortality in animals challenged with LPS in the setting of biliary obstruction. Using LBP-deficient mice and LBP blockade in wild-type mice, we demonstrate that high levels of LBP are deleterious in the setting of cholestasis. Following biliary obstruction and intraperitoneal LPS challenge, hepatic injury, hepatic neutrophil infiltration, and mortality were significantly increased in animals with an intact LBP acute-phase response. Kupffer cell responses from these animals demonstrated a significant increase in several inflammatory mediators, and Kupffer cell-associated LBP appears to be responsible for these differences, at least in part. Our results indicate that the role of LBP signaling in inflammatory conditions is complex and heterogeneous, and elevated levels of LBP are not always protective. Increased LBP production in the setting of cholestatic liver disease appears to be deleterious and may represent a potential therapeutic target for preventing overwhelming inflammatory responses to LPS in this setting.

show abstract

Section: Discussionsupporting

confidence: 93%

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Minter¹,

Bi²,

Ben-Josef³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…Blind analysis was performed on all samples to determine the degree of lesion as previously described [15]. The percentage of necrosis was estimated by evaluating the number of microscopic fields with necrosis compared with the entire cross section.…”

Section: Methodsmentioning

confidence: 99%

High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

et al. 2012

View full text Add to dashboard Cite

BackgroundAcetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose.MethodsMale C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses.Results24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.ConclusionHMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

show abstract

“…Furthermore, different innate immune system knockout or mutant mice have been shown to have altered susceptibility to APAP hepatotoxicity. Knockout or mutant mice that lack IFN-g, lipopolysaccharide-binding protein, Fas or FasL, or CXC chemokine receptor 2 (CXCR2) are less susceptible to APAP hepatotoxicity [69,[74][75][76]. Knockout mice that lack IL-10, IL-6, or C-C chemokine receptor 2, however, are more susceptible [77][78][79].…”

Section: Role Of Innate Immune System In Acetaminophen Hepatotoxicitymentioning

confidence: 97%

Mechanisms of Drug-Induced Liver Disease

Gunawan

Kaplowitz

2007

Clinics in Liver Disease

145

View full text Add to dashboard Cite

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

Cited by 51 publications

References 47 publications

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

Mechanisms of Drug-Induced Liver Disease

Contact Info

Product

Resources

About