Gastroenterology

Gastroenterology

Volume 119, Issue 2, August 2000, Pages 446-460
Gastroenterology

Liver, Pancreas, and Biliary Tract
Tumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure,☆☆,

https://doi.org/10.1053/gast.2000.9364Get rights and content

Abstract

Background & Aims: The tumor necrosis factor (TNF)-α/TNF receptor system is critical for liver development because hepatocytes undergo apoptosis if the antiapoptotic cascades resulting in RelA NF-κB activation are not effective. Therefore, we studied the role of TNF-α in fulminant hepatic failure (FHF) and developed a new therapeutic strategy. Methods: Serum levels and hepatic expression of TNF-α and both TNF receptors were determined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenoviral vectors were constructed expressing dominant-negative proteins interfering with intracellular TNF-α–dependent pathways. The relevance of these constructs was studied in primary mouse hepatocytes and in a murine model of FHF. Results: Serum levels of TNF-α and TNF receptors are significantly increased in FHF; this increase correlates with patient prognosis. In livers of patients with FHF, infiltrating mononuclear cells express high amounts of TNF-α and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apoptotic hepatocytes are significantly increased in FHF, and there is a strong correlation with TNF-α expression, which is even more pronounced in areas of mononuclear infiltrates. In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes. Conclusions: The results show that the TNF-α/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 target to prevent liver cell death in vivo.

GASTROENTEROLOGY 2000;119:446-460

Section snippets

Patient sera and controls

Twenty-two patients with FHF admitted to our intensive care unit were included in the study. FHF was defined as deterioration of liver function (<14 days) without signs of CLD resulting in jaundice, decrease in coagulation factors (factors V and II <50%), and encephalopathy.22, 23 International normalized ratio, serum transaminase, and bilirubin values were determined as biochemical markers of liver function. Blood was taken from each patient immediately after admission and daily thereafter

Increased serum TNF-α, TNF-R1, and TNF-R2 levels are evident in patients with FHF

Serum samples of patients with FHF showed that levels of TNF-α, sTNF-R1, and sTNF-R2 were significantly increased at all time points compared with controls (P < 0.001 for TNF-α, sTNF-R1, and sTNF-R2; Figure 1.

. (A) TNF-α, (B) sTNF-R1, and (C) sTNF-R2 receptor levels are increased in serum from patients with FHF. Serum was obtained fom controls (C) and FHF patients. Specific time points are shown for patients with FHF: directly at admission (A), time point of decision when the patients recovered

Discussion

FHF is characterized by the sudden onset of liver deterioration associated with symptoms such as jaundice, encephalopathy, and increased aminotransferase levels. Since the introduction of liver transplantation, the prognosis of patients with FHF has improved.32 However, currently no therapy is available to block liver cell destruction and thus save the organ. Earlier studies indicated that TNF-α production is increased in the serum of FHF patients, but it was unclear how this cytokine might

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    Address requests for reprints to: Christian Trautwein, M.D., Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. e-mail: [email protected]; fax: (49) 511-55-71-03.

    ☆☆

    Supported by Deutsche Forschungsgemeinschaft Tr 285 3-4 and the Bonfor program of the University of Bonn.

    This work is dedicated on the occasion of the 70th birthday of Prof. Dr. K.-H. Meyer zum Büschenfelde.

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