rate hepatic collagen accumulation even in advanced (biliary) Silymarin (SIL), a standardized plant extract containing fibrosis; and 3) PIIINP appears to be a suitable serum marker about 60% polyphenole silibinin, is used as a hepatoprotective to monitor the inhibition of hepatic fibrogenesis in this model agent. Its antifibrotic potential in chronic liver diseases has of biliary fibrosis. (HEPATOLOGY 1997;26:643-649.) not been explored. Therefore, we applied SIL to adult Wistar rats that were subjected to complete bile duct occlusion (BDO) by injection of sodium amidotrizoate (Ethibloc). ThisProven therapy that halts the progression of liver fibrosis treatment induces progressive portal fibrosis without signifior induces regression of established cirrhosis is urgently cant inflammation. Rats with sham-operation that received needed. For several reasons, such therapy is not available: SIL at 50 mg/kg/d (n Å 10) and rats with BDO alone (n Å 1) the evolution of fibrosis in man is usually slow; 2) fibrosis 20) served as controls, whereas groups of 20 animals were is difficult to quantify from needle biopsies; 3) sampling error fed SIL at a dose of 25 and 50 mg/kg/d during weeks 1 through poses a severe problem in small tissue specimens; and 4) 6 or doses of 50 mg/kg/d during weeks 4 through 6 of BDO.suitable animal models that mirror at least a subgroup of Animals were sacrificed after 6 weeks for determination of human chronic liver diseases are lacking. Serum markers blood chemistries, total and relative liver collagen (as hyof liver fibrosis that could be used as suitable noninvasive droxyproline [HYP]), and the serum aminoterminal propeppredictors of the enhanced synthesis and deposition of hetide of procollagen type III (PIIINP). BDO in untreated rats patic collagen, i.e., fibrogenesis, or its removal, i.e., fibrolysis, caused an almost ninefold increase in total liver collagen (16.1 would be an attractive alternative for monitoring patients { 3.1 vs. 1.8 { 0.4 mg HYP, P õ .001). SIL at 50 mg/kg/d under therapy with a potential antifibrotic agent. However, reduced total HYP by 30% to 35%, either when given from final proof that such parameters are clinically useful, alweek 1 through 6 or from week 4 through 6 after BDO (10. 6 though suggested in several recent reports, is still needed.1,2 { 2.7 and 10.2 { 3.9 mg HYP, both P õ .01 vs. BDO alone), For these reasons, we selected and improved the rat model whereas 25 mg/kg/d were ineffective. Because SIL at 50 mg/ of biliary fibrosis secondary to bile duct obstruction (BDO). kg/d also reduced the collagen content per gram of liver tissue, This model can induce progressive portal fibrosis and finally it acted as a true antifibrotic agent. The single value of PIIINP cirrhosis, being almost devoid of the generation of toxic radiat killing paralleled the antifibrotic activity of SIL with 11.6 cals, massive hepatocyte necrosis, or major inflammation. It { 3.8 and 9.9 { 3.7 vs. 15.3 { 5.2 mg/L in both high-dose therefore resembles human (biliary) liver fibrosis and allo...

No abstract

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 β1 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.

rate hepatic collagen accumulation even in advanced (biliary) Silymarin (SIL), a standardized plant extract containing fibrosis; and 3) PIIINP appears to be a suitable serum marker about 60% polyphenole silibinin, is used as a hepatoprotective to monitor the inhibition of hepatic fibrogenesis in this model agent. Its antifibrotic potential in chronic liver diseases has of biliary fibrosis. (HEPATOLOGY 1997;26:643-649.) not been explored. Therefore, we applied SIL to adult Wistar rats that were subjected to complete bile duct occlusion (BDO) by injection of sodium amidotrizoate (Ethibloc). ThisProven therapy that halts the progression of liver fibrosis treatment induces progressive portal fibrosis without signifior induces regression of established cirrhosis is urgently cant inflammation. Rats with sham-operation that received needed. For several reasons, such therapy is not available: SIL at 50 mg/kg/d (n Å 10) and rats with BDO alone (n Å 1) the evolution of fibrosis in man is usually slow; 2) fibrosis 20) served as controls, whereas groups of 20 animals were is difficult to quantify from needle biopsies; 3) sampling error fed SIL at a dose of 25 and 50 mg/kg/d during weeks 1 through poses a severe problem in small tissue specimens; and 4) 6 or doses of 50 mg/kg/d during weeks 4 through 6 of BDO.suitable animal models that mirror at least a subgroup of Animals were sacrificed after 6 weeks for determination of human chronic liver diseases are lacking. Serum markers blood chemistries, total and relative liver collagen (as hyof liver fibrosis that could be used as suitable noninvasive droxyproline [HYP]), and the serum aminoterminal propeppredictors of the enhanced synthesis and deposition of hetide of procollagen type III (PIIINP). BDO in untreated rats patic collagen, i.e., fibrogenesis, or its removal, i.e., fibrolysis, caused an almost ninefold increase in total liver collagen (16.1 would be an attractive alternative for monitoring patients { 3.1 vs. 1.8 { 0.4 mg HYP, P õ .001). SIL at 50 mg/kg/d under therapy with a potential antifibrotic agent. However, reduced total HYP by 30% to 35%, either when given from final proof that such parameters are clinically useful, alweek 1 through 6 or from week 4 through 6 after BDO (10. 6 though suggested in several recent reports, is still needed.1,2 { 2.7 and 10.2 { 3.9 mg HYP, both P õ .01 vs. BDO alone), For these reasons, we selected and improved the rat model whereas 25 mg/kg/d were ineffective. Because SIL at 50 mg/ of biliary fibrosis secondary to bile duct obstruction (BDO). kg/d also reduced the collagen content per gram of liver tissue, This model can induce progressive portal fibrosis and finally it acted as a true antifibrotic agent. The single value of PIIINP cirrhosis, being almost devoid of the generation of toxic radiat killing paralleled the antifibrotic activity of SIL with 11.6 cals, massive hepatocyte necrosis, or major inflammation. It { 3.8 and 9.9 { 3.7 vs. 15.3 { 5.2 mg/L in both high-dose therefore resembles human (biliary) liver fibrosis and allo...

No abstract