Lack of therapeutic improvement of liver fibrosis in rats by dexamethasone in spite of ascites amelioration.
Pathophysiology of liver fibrosis (LF) includes hepatic parenchymal cell destruction and connective tissue formation. Although dexamethasone has been used in the liver diseases, there is controversy over the beneficial effects of dexamethasone on LF. Previous studies showed that CCAAT/enhancer binding protein-beta (C/EBPbeta) activation contributes to hepatocyte regeneration and dissolution of fibrosis and that dexamethasone activates C/EBPbeta whereas C/EBPbeta-mediated gene induction by dexamethasone is antagonized by a corepressor. The present study investigated the possible therapeutic effect of dexamethasone for the treatment of LF in rats. We injected rats with multiple doses of dimethylnitrosamine (DMN) for 4 weeks and then used the LF rats to determine whether dexamethasone treatment therapeutically improved liver functions and resolved fibers accumulated in the liver. Dexamethasone (100 microg/kg, po, three times per week for 4 weeks) failed to restore the body weight gain and liver weight decreased by LF. The body weight gain reduced during LF was further decreased by dexamethasone treatment. Animals were subjected to blood biochemical, liver histopathological and immunochemical analyses. Although dexamethasone treatment significantly reduced ascites in LF rats, the plasma albumin and total protein levels decreased in fibrotic rats were not restored. Impaired liver functions during LF including elevated plasma aminotransferases and bilirubin levels along with GSTA2 repression were not recovered by dexamethasone. Dexamethasone failed to decrease the fibrosis score and to eliminate the extracellular matrix and alpha-smooth muscle actin accumulated in the fibrotic liver. The results of the present study showed that dexamethasone ameliorated ascites in LF rats but failed to improve the liver functions and fiber accumulation, and that the possible beneficial effect of dexamethasone might result from anti-inflammatory effect but not from liver improvement.
Ki
Sung Hwan
SH
National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.
Choi
Dal Woong
DW
Kim
Choon Won
CW
Kim
Sang Geon
SG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001201:Ascites / Q000188:drug therapy*; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000378:metabolism; D005982:Glutathione Transferase / Q000097:blood / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000097:blood / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D008115:Liver Regeneration; D009130:Muscle, Smooth / Q000378:metabolism; D051381:Rats; D000637:Transaminases / Q000097:blood / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D003907:Dexamethasone; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D000637:Transaminases; D001663:Bilirubin