Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis.
There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.
Salunga
Thucydides L
TL
Department of Pathology I, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Cui
Zheng-Guo
ZG
Shimoda
Shinji
S
Zheng
Hua-Chuan
HC
Nomoto
Kazuhiro
K
Kondo
Takashi
T
Takano
Yasuo
Y
Selmi
Carlo
C
Alpini
Gianfranco
G
Gershwin
M Eric
ME
Tsuneyama
Koichi
K
D017209:Apoptosis; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D047209:Eosinophil Peroxidase / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D018384:Oxidative Stress; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D006997:Hypochlorous Acid; D047209:Eosinophil Peroxidase; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D005978:Glutathione