no direct relevance, that I know of, to anything ongoing at GLFD. Just parking (AASLD abstract).......
Presentation Title: INHIBITION OF POLY(ADP-RIBOSE) POLYMERASE (PARP) PROTECTS MICE FROM CHOLESTATIC LIVER INJURY.
Reviewing Code: DO1 Cell Death (Necrosis and Apoptosis)
Author Block: Peter Fickert, Michael Trauner, Andrea Fuchsbichler, Gernot Zollner, Martin Wagner, Karl-Franzens University, Graz, Austria; Rainer Zenz, Research Insitute of Molecular Pathology, Vienna, Austria; Zsuzsanna Zsengeller, Csaba Szabo, Inotek Pharmaceuticals Corporation, Beverly, MA; Helmut Denk, Karl-Franzens University, Graz, Austria.
Background & Aims: Cholestatic liver injury results from intrahepatic accumulation of toxic bile acids. The mechanisms leading to hepatocyte cell death in cholestasis are poorly defined. This study was designed to elucidate these mechanisms. Methods: Studies were performed in common-bile-duct-ligated (CBDL) and cholic-acid-fed (CA) mice as well as mice injected with the Fas agonist Jo2. In addition, PARP-/- mice and mice treated with the PARP inhibitor PJ34 (20 mg/kg i.p. 2/d) were fed CA. Cell death was determined using H & E staining, double immunofluorescence microscopy for terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assay, activated caspase-3 and cytokeratin (CK) 18, and electron microscopy (ELMI). Serum alanine aminotransferase (ALT), bilirubin and bile acid and hepatic ATP levels were investigated. Results: Jo2-challenged mice showed activation of caspase-3, breakdown of the CK intermediate filament network (characteristic of hepatocyte apoptosis), and classical morphologic features of apoptotic cell death in H & E stained sections and ELMI. In contrast, cholestatic mice lacked significant activation of caspase-3 and typical CK alterations were rarely seen despite a frequently positive TUNEL assay. Thus, oncosis was the primary type of cell death in cholestatic mouse models as determined by H & E staining and ELMI. Liver injury was significantly reduced in PARP-/- and PJ34-treated mice. Summary & Conclusions: Oncosis represents the main type of hepatocyte death in cholestatic mice. The relative contribution of apoptosis to cholestatic liver injury may be overestimated by the use of non-specific detection systems. Inhibition of PARP may represent a therapeutic target in cholestatic liver diseases. |
