Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells.
During the course of liver fibrogenesis, myofibroblast-like cells (MFLC), mostly derived from hepatic stellate cells, proliferate and synthesize excessive amounts of extracellular matrix components. Pentoxifylline (PTX) elicits antiproliferative and antifibrogenic effects in human dermal fibroblasts. The aim of this study was to test the effects of PTX on the proliferation and the synthesis of collagen and gelatinase A in cultured human hepatic MFLC. MFLC were obtained by outgrowth from human liver explants. PTX markedly reduced serum-driven cell proliferation, as assessed by nuclear autoradiography experiments and measurement of actual cell growth. Growth inhibition was totally reversed after removal of the drug. PTX also affected collagen synthesis, as measured by [3H]hydroxyproline incorporation into proteins. Synthesis of secreted collagen was reduced by 24% and 67% at concentrations of 100 microg/mL and 500 microg/mL, respectively. This was associated with a decrease in type I and III procollagen messenger RNA (mRNA), indicating an effect at a pretranslational level. In contrast, PTX did not affect either gelatinase A activity released in culture medium or the expression of its specific mRNA. In conclusion, PTX exhibits potent antiproliferative and antifibrogenic effects toward hepatic MFLC. These results suggest that PTX might have therapeutic implications in chronic liver disease.
Préaux
A M
AM
Unité INSERM 99 and Département de Pathologie Tissulaire et Cellulaire, Hôpital Henri Mondor, Créteil, France.
Mallat
A
A
Rosenbaum
J
J
Zafrani
E S
ES
Mavier
P
P
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D018093:Gelatinases / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000096:biosynthesis; D010431:Pentoxifylline / Q000494:pharmacology*
D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D010431:Pentoxifylline