Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-ĸ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IĸB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-ĸB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.

Prognostication of disease relapse and survival is essential for cancer patients and genetic variations in cancer patients may serve as important indicators. A single-nucleotide polymorphism (SNP) mapping to the tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene at position 138241110 displays three genotypes (AA, AC and CC). The aim of this study was to evaluate the potential prognostic value of the TNFAIP3-SNP in esophageal cancer (EC). Genomic DNA was extracted from peripheral blood leukocytes of 173 patients who underwent complete surgical resection for EC and did not receive any neoadjuvant or adjuvant therapy. For SNP detection, a 260- bp fragment was PCR amplified, purified and sequenced with tested primers. The product was analyzed by automatic DNA sequencer.The TNFAIP3 genotypes were correlated with clinico-pathological parameters, tumor cell dissemination in bone marrow and clinical outcome. The C-allele carrier presented with higher disease stage (P<0.001). This was predominantly because of the presence of lymph node metastasis (P<0.001). The recurrence rate was higher in C-allele carriers (AC and CC genotype; P=0.004). Kaplan-Meier plots for disease-free (P=0.017) and overall survival (P<0.001) displayed a gene dosage-associated outcome with AA genotype patients presenting the longest and CC genotype patients the poorest survival. In disease stage-adjusted multivariate analysis the TNFAIP3-SNP was identified as an independent prognostic factor for survival (hazard ratio 1.9; P=0.008). The TNFAIP3-SNP allows risk stratification of EC patients and may be a useful tool to identify patients eligible for multimodal therapy concepts.

The administration of rhEPO brought about increased survival and attenuation of the hepatic injury. This was associated with decreased hepatic NF-κB and JNK activation and thus TNF-α and IL-1β levels. These findings have important implications for the potential use of rhEPO in FHF.

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