Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats.
OBJECTIVE
To investigate the effects of heme oxygenase-1 (HO-1) against oxidant-induced injury caused by bile duct ligation (BDL).


METHODS
Either cobalt protoporphyrin (CoPP), a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis. Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and cytokine and collagen-Ialpha (Col-Ialpha) mRNA expression was detected using RNase protection assays.


RESULTS
Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly, enzyme release was not reduced in rats receiving CoPP. Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius red-positive areas were increased to about 11.7% after BDL. Collagen-Ialpha and TGF-beta mRNA increased significantly by BDL. Again, this effect was increased by HO-1 overexpression.


CONCLUSIONS
Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1 overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.
Department of Internal Medicine, University of Regensburg, Regensburg 93042, Germany. matthias.froh@klinik.uni-regensburg.de
Matthias
M
Froh
Lars
L
Conzelmann
Peter
P
Walbrun
Susanne
S
Netter
Reiner
R
Wiest
Michael-D
MD
Wheeler
Mark
M
Lehnert
Takehiko
T
Uesugi
Jurgen
J
Scholmerich
Ronald G
RG
Thurman
D000199:Actins / Q000032:analysis; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001652:Bile Ducts; D002779:Cholestasis / Q000150:complications* / Q000201:enzymology*; D002908:Chronic Disease; D051547:Heme Oxygenase-1 / Q000502:physiology*; D007150:Immunohistochemistry; D008026:Ligation; D008099:Liver / Q000201:enzymology; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000199:Actins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase