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American Journal of Pathology, Vol 146, 1220-1234, Copyright © 1995 by American Society for Investigative Pathology

REGULAR ARTICLES

Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models

M Leist, F Gantner, I Bohlinger, G Tiegs, PG Germann and A Wendel
Department of Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.

We investigated the role of hepatocyte apoptosis in four different murine models of acute inflammatory liver failure. Liver damage induced in D-galactosamine-sensitized mice by endotoxin infection was initiated by processes typical of apoptosis, ie, chromatin condensation, DNA fragmentation, and formation of intracellular apoptotic bodies. DNA was cleaved into oligonucleosomal fragments in the liver before a significant rise of alanine aminotransferase in plasma occurred. Passive immunization against tumor necrosis factor (TNF) completely inhibited the injury caused by endotoxin. Direct injection of recombinant TNF-alpha also caused DNA fragmentation followed by alanine aminotransferase release into the plasma. Pretreatment of mice with interleukin-1 beta, which is known to suppress TNF-induced lethality, completely prevented apoptosis and liver failure in this model. These results demonstrate the causal role of TNF in endotoxin-induced hepatic apoptosis. TNF-inducible hepatocyte apoptosis in vivo was not only observed in D-galactosamine-sensitized mice, but also when the alternative transcriptional inhibitor actinomycin D was used. In mice injected with the TNF-inducing T cell mitogen concanavalin A, hepatic apoptosis was even noticed without requirement of additional sensitizers. We conclude that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.


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S. Angermüller, G. Künstle, and G. Tiegs
Pre-apoptotic Alterations in Hepatocytes of TNF{alpha}-treated Galactosamine-sensitized Mice
J. Histochem. Cytochem., October 1, 1998; 46(10): 1175 - 1184.
[Abstract] [Full Text]

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 Am. J. Pathol.Home page
J. Shi, K. Aisaki, Y. Ikawa, and K. Wake
Evidence of Hepatocyte Apoptosis in Rat Liver after the Administration of Carbon Tetrachloride
Am. J. Pathol., August 1, 1998; 153(2): 515 - 525.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
K. B. Seydel and S. L. Stanley Jr.
Entamoeba histolytica Induces Host Cell Death in Amebic Liver Abscess by a Non-Fas-Dependent, Non-Tumor Necrosis Factor Alpha-Dependent Pathway of Apoptosis
Infect. Immun., June 1, 1998; 66(6): 2980 - 2983.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. Jaeschke, M. A. Fisher, J. A. Lawson, C. A. Simmons, A. Farhood, and D. A. Jones
Activation of Caspase 3 (CPP32)-Like Proteases Is Essential for TNF-{alpha}-Induced Hepatic Parenchymal Cell Apoptosis and Neutrophil-Mediated Necrosis in a Murine Endotoxin Shock Model
J. Immunol., April 1, 1998; 160(7): 3480 - 3486.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Y.-M. Kim, R. V. Talanian, and T. R. Billiar
Nitric Oxide Inhibits Apoptosis by Preventing Increases in Caspase-3-like Activity via Two Distinct Mechanisms
J. Biol. Chem., December 5, 1997; 272(49): 31138 - 31148.
[Abstract] [Full Text] [PDF]

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 JEMHome page
M. Leist, B. Single, A. F. Castoldi, S. Kuhnle, and P. Nicotera
Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis
J. Exp. Med., April 21, 1997; 185(8): 1481 - 1486.
[Abstract] [Full Text] [PDF]

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 Arch OphthalmolHome page
T. M. Nork, G. L. Poulsen, L. L. Millecchia, R. G. Jantz, and R. W. Nickells
p53 Regulates Apoptosis in Human Retinoblastoma
Arch Ophthalmol, February 1, 1997; 115(2): 213 - 219.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
Y.-M. Kim, M. E. de Vera, S. C. Watkins, and T. R. Billiar
Nitric Oxide Protects Cultured Rat Hepatocytes from Tumor Necrosis Factor-alpha -induced Apoptosis by Inducing Heat Shock Protein 70Expression
J. Biol. Chem., January 10, 1997; 272(2): 1402 - 1411.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. P. Beigneux, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
The Acute Phase Response Is Associated with Retinoid X Receptor Repression in Rodent Liver
J. Biol. Chem., May 19, 2000; 275(21): 16390 - 16399.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Y. Zhao, S. Li, E. E. Childs, D. K. Kuharsky, and X.-M. Yin
Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-alpha -induced Liver Injury
J. Biol. Chem., July 13, 2001; 276(29): 27432 - 27440.
[Abstract] [Full Text] [PDF]


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