Lipopolysaccharide-neutralizing antibody reduces hepatocyte injury from acute hepatotoxin administration

Abstract

Endogenous lipopolysaccharide has been implicated as a cofactor in the hepatocellular injury and death resulting from toxic liver injury. To prevent this lipopolysaccharide-induced injury and to further understand the mechanism of this effect, an anti-lipopolysaccharide antibody was administered to rats in which toxic hepatocellular injury was induced. Rats were given the hepatotoxin galactosamine together with an isotypic control antibody B55 or the anti-lipopolysaccharide antibody E5. E5 treatment resulted in reductions of serum AST levels of 43% at 36 hr (p < 0.02) and 60% at 48 hr (NS) after galactosamine administration. These decreases in AST values were accompanied by diminished histological evidence of injury and inflammation. In carbon tetrachloride-induced liver injury, E5 similarly reduced serum AST levels at 36 and 48 hr by 47% (p < 0.04) and 54% (p < 0.03), respectively. E5 treatment was equally effective in reducing AST levels 48 hr after administration of carbon tetrachloride, whether the initial dose of antibody was given 1 hr before or 3 or 6 hr after the administration of this toxin. To understand the mechanism of this E5 effect, the activation of the toxic cytokine tumor necrosis factor-alpha and the chemotactic cytokine monocyte chemoattractant protein 1 was examined by Northern-blot analysis of RNA from rat livers after galactosamine-induced injury and treatment with B55 or E5. Despite E5's efficacy in reducing hepatocellular damage, E5 treatment did not affect the timing or magnitude of tumor necrosis factor-alpha or monocyte chemoattractant protein 1 activation during galactosamine-induced injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of low molecular fraction of MGN-3, a modified arabinoxylan from rice bran, on acute liver injury by inhibition of NF-κB and JNK/MAPK expression

“…Endogenously produced endotoxin has been implicated as a cofactor in GalN-induced hepatocellular injury, death [29,30] and TNF hypersensitivity [31]. GalN is known to sensitize animals both to the lethal effects of LPS and to a principal LPS-induced mediator, TNF-α [32].…”

Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β

“…In the liver, autophagy in hepatocytes limits liver injury [29], including that from the hepatotoxin GalN [12]. Our recent finding that macrophage autophagy down regulates LPS-induced inflammation in hepatic steatosis [16], suggested that macrophage autophagy may similarly block injurious inflammation in LPS dependent toxin-induced liver injury [30, 31]. The present findings demonstrate that macrophage autophagy limits GalN/LPS injury by modulating cytokine production, but by the mechanism of inhibiting inflammasome-mediated IL-1β cleavage which is distinct from the anti-inflammatory effect of macrophage autophagy in steatotic liver injury.…”

Downregulation effects of beta-elemene on the levels of plasma endotoxin, serum TNF-alpha, and hepatic CD14 expression in rats with liver fibrosis

“…In contrast, adding LPS aggravates liver injuries caused by these hepatotoxins [15]. In CaCl 4 -and galactosamine-induced liver injuries, adding anti-LPS antibody E-5 significantly reduces the hepatotoxicity caused by these agents [16]. These studies demonstrate the role of endogenous LPS in toxin-induced liver injuries.…”

“…The inhibition of TNF-α activity can decrease liver injuries. Adding soluble TNF receptors that diminish the biologic effects of TNF-α decreases liver enzymes significantly, improves liver histology, and decreases mortality after acute CaCl 4 administration [16].…”