Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure

Background & Aims: The tumor necrosis factor (TNF)-alpha/TNF receptor syste m is critical for liver development because hepatocytes undergo apoptosis i f the antiapoptotic cascades resulting in RelA NF-kappa B activation are no t effective. Therefore, we studied the role of TNF-alpha in fulminant hepat ic failure (FHF) and developed a new therapeutic strategy, Methods: Serum l evels and hepatic expression of TNF-alpha and both TNF receptors were deter mined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenov iral vectors were constructed expressing dominant-negative proteins interfe ring with intracellular TNF-alpha-dependent pathways. The relevance of thes e constructs was studied in primary mouse hepatocytes and in a murine model of FHF, Results: Serum levels of TNF-alpha and TNF receptors are significa ntly increased in FHF; this increase correlates with patient prognosis, In livers of patients with FHF, infiltrating mononuclear cells express high am ounts of TNF-alpha and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apo ptotic hepatocytes are significantly increased in FHF, and there is a stron g correlation with TNF-alpha expression, which is even more pronounced in a reas of mononuclear infiltrates, In an in vivo FHF model, the Fas-associate d death domain (FADD), adenovirus selectively blocked the intracellular pat hway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes, Conclusions: The results show that the TNF-alpha/TNF-R1 system is involved in the pathogenesis of FHF in humans. Studies in this animal model indicate that FADD may serve as a molecular ta rget to prevent liver cell death in vivo.