BACKGROUND & AIMS: Apoptosis of hepatocytes is a central feature of ischemic injury in the liver. The aim of this study was to identify extracellular inducers of apoptosis in the murine ischemic liver. METHODS: Involvement of tumor necrosis factor (TNF)-alpha and Fas signaling was evaluated using various knockout mice (TNF-receptor 1 [TNF-R1]-/-, Fas[lpr]-/-, and Fas ligand[gld]-/-) and wild-type mice pretreated with pentoxifylline, an inhibitor of TNF-alpha synthesis. RESULTS: Expression of TNF-alpha was increased after ischemia and reperfusion in wild-type mice and TNF-R1-deficient mice when compared with sham-operated animals. Pentoxifylline prevented up-regulation of TNF-alpha expression. Inhibition of TNF-alpha resulted in significant decrease of serum aspartate aminotransferase levels and prolonged animal survival. Markers of apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, cytochrome C release, and caspase 3 activity) were consistently decreased, and animal survival was prolonged after blocking TNF-alpha. In contrast, inhibition of Fas signaling did not alter parameters of tissue injury or apoptosis, and animal survival remained unchanged. CONCLUSIONS: We identify TNF-alpha as a crucial inducer of apoptotic cell death in the ischemic liver. A role for Fas could not be identified. These findings may lead to novel strategies to prevent ischemic injury of the liver.
BACKGROUND & AIMS: Apoptosis of hepatocytes is a central feature of ischemic injury in the liver. The aim of this study was to identify extracellular inducers of apoptosis in the murineischemic liver. METHODS: Involvement of tumor necrosis factor (TNF)-alpha and Fas signaling was evaluated using various knockout mice (TNF-receptor 1 [TNF-R1]-/-, Fas[lpr]-/-, and Fas ligand[gld]-/-) and wild-type mice pretreated with pentoxifylline, an inhibitor of TNF-alpha synthesis. RESULTS: Expression of TNF-alpha was increased after ischemia and reperfusion in wild-type mice and TNF-R1-deficientmice when compared with sham-operated animals. Pentoxifylline prevented up-regulation of TNF-alpha expression. Inhibition of TNF-alpha resulted in significant decrease of serum aspartate aminotransferase levels and prolonged animal survival. Markers of apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, cytochrome C release, and caspase 3 activity) were consistently decreased, and animal survival was prolonged after blocking TNF-alpha. In contrast, inhibition of Fas signaling did not alter parameters of tissue injury or apoptosis, and animal survival remained unchanged. CONCLUSIONS: We identify TNF-alpha as a crucial inducer of apoptotic cell death in the ischemic liver. A role for Fas could not be identified. These findings may lead to novel strategies to prevent ischemic injury of the liver.
Authors: Pierre-Alain Clavien; Jean Emond; Jean Nicolas Vauthey; Jacques Belghiti; Ravi S Chari; Steven M Strasberg Journal: J Gastrointest Surg Date: 2004 Mar-Apr Impact factor: 3.452
Authors: Sabarinathan Ramachandran; Jane M Liaw; Jianluo Jia; Sean C Glasgow; Wei Liu; Krista Csontos; G A Upadhya; T Mohanakumar; William C Chapman Journal: Transpl Immunol Date: 2012-01-21 Impact factor: 1.708
Authors: Mahmoud Abu-Amara; Kurinchi Selvan Gurusamy; George Glantzounis; Barry Fuller; Brian R Davidson Journal: Cochrane Database Syst Rev Date: 2009-10-07
Authors: Thomas A Moore; Michelle L Perry; Andrew G Getsoian; Christine L Monteleon; Anna L Cogen; Theodore J Standiford Journal: Infect Immun Date: 2003-09 Impact factor: 3.441