Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis.
BACKGROUND
The trisubstituted methylxanthine derivative pentoxifylline inhibits hepatic stellate cell proliferation and collagen synthesis in vitro. The antifibrotic effect of pentoxifylline in a suitable in vivo model of chronic liver fibrogenesis remains to be tested.


METHODS
Groups of adult rats (n=20-23) received oral pentoxifylline at a dose of 8 mg/kg/day from week 1 to week 6, and 16 mg/kg/day from week 1 to week 6 or week 4 to week 6 after complete bile duct occlusion. Animals who underwent sham operation that received 16 mg/kg/day pentoxifylline and untreated rats with bile duct occlusion alone served as controls. After six weeks, animals were sacrificed and parameters of fibrogenesis determined.


RESULTS
Bile duct occlusion caused portal cirrhosis with a 10-fold increased hepatic collagen content in the absence of inflammation or necrosis. This was accompanied by an 11-fold elevated serum aminoterminal procollagen III peptide (PIIINP). The drug induced a dramatic eightfold downregulation of procollagen I mRNA, and suppression of the fibrogenic factors transforming growth factor beta1 and connective tissue growth factor by 60-70%. However, profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased twofold, resulting in only a moderate decrease in liver collagen, fibrosis score, and PIIINP.


CONCLUSIONS
We conclude that targeting pentoxifylline to the fibrogenic cells, thereby avoiding upregulation of TIMP-1, could become a potent antifibrogenic tool in chronic liver disease.
Raetsch
C
C
Department of Gastroenterology, University Hospital Benjamin Franklin, Free University of Berlin, Germany.
Jia
J D
JD
Boigk
G
G
Bauer
M
M
Hahn
E G
EG
Riecken
E-O
EO
Schuppan
D
D
D000284:Administration, Oral; D000818:Animals; D002779:Cholestasis / Q000150:complications / Q000378:metabolism; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D015342:DNA Probes / Q000032:analysis; D018076:DNA, Complementary / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006909:Hydroxyproline / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism; D010431:Pentoxifylline / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D016207:Cytokines; D015342:DNA Probes; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C041876:procollagen Type III-N-terminal peptide; D003094:Collagen; D006909:Hydroxyproline; D010431:Pentoxifylline