Oncosis represents the main type of cell death in mouse models of cholestasis.
OBJECTIVE
Since the mechanisms leading to hepatocyte death in cholestasis are not well defined, we aimed to obtain closer insights into the related pathogenetic principles.


METHODS
Cell death was assessed in common bile duct ligated (CBDL) and cholic acid (CA)-fed mice, and compared to Fas agonist Jo2-injected mice by studying H and E-stained tissue sections, DNA ladder analysis, caspase-3-like activity assay, immunohistochemistry, double immunofluorescence microscopy for activated caspase-3 and cytokeratin (CK) 18, the TUNEL method, and electron microscopy.


RESULTS
Jo2-treated mice showed activation of caspase-3, breakdown of the CK intermediate filament network, and classical morphological features of apoptosis. In contrast, in CA-fed and CBDL mice, oncosis characterized by cell swelling and ruptured cell membranes was the predominant type of cell death, whereas in both experimental conditions significant activation of caspase-3 was absent and typical CK alterations were rare despite frequent positivity of the TUNEL assay.


CONCLUSIONS
(i) Oncosis represents the main type of hepatocyte death in acute cholestasis in mice. (ii) The importance of apoptosis in cholestasis may be overestimated if non-specific detection systems (e.g. TUNEL assay) are used.
Fickert
Peter
P
Laboratory of Experimental Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University, Auenbruggerplatz 15, A-8036 Graz, Austria. peter.fickert@klinikum-graz.at
Trauner
Michael
M
Fuchsbichler
Andrea
A
Zollner
Gernot
G
Wagner
Martin
M
Marschall
Hanns-Ulrich
HU
Zatloukal
Kurt
K
Denk
Helmut
H
D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D001652:Bile Ducts / Q000502:physiology; D016923:Cell Death; D002462:Cell Membrane / Q000473:pathology; D002779:Cholestasis / Q000473:pathology*; D019826:Cholic Acid / Q000633:toxicity; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice
D001647:Bile Acids and Salts; D001219:Aspartate Aminotransferases; D019826:Cholic Acid