Pentoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting interleukin-6 production.
OBJECTIVE
Pig serum-induced rat liver fibrosis is a model of liver fibrosis in the absence of obvious hepatocyte injury. Penoxifylline (PTX), a xanthine derivative, which is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production from inflammatory cells, has also been shown to inhibit the growth of hepatic stellate cells and to inhibit collagen synthesis in these cells in vitro. We investigated the effect of PTX on pig serum-induced liver fibrosis in vivo, and assessed the mechanisms of prevention of fibrogenesis by this drug.


METHODS
Male Wistar rats were given intraperitoneal injections of 0.5 ml normal pig serum twice a week for 10 weeks with or without concomitant oral administration of PTX (20 mg/kg).


RESULTS
Rats that received pig serum showed significant liver fibrosis, and their serum interleukin-6 (IL-6) and hyaluronic acid levels were significantly increased. The serum levels of IL-6 were well correlated with the serum levels of hyaluronic acid, and increased as the liver fibrosis progressed. Penoxifylline prevented the development of fibrosis in this animal model and reduced the serum levels of IL-6 in a dose-dependent manner. In vitro, by the addition of PTX to the culture medium of the rat hepatic stellate cells (HSCs), the proliferation of the HSCs was significantly inhibited and IL-6 in the culture supernatant was also reduced significantly. Exogenous addition of IL-6 partially restored the proliferation.


CONCLUSIONS
Penoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting the proliferation of HSCs and by inhibiting the production of IL-6 from HSCs.
Toda
Kyoko
K
Division of Basic Research, Bio Medical Laboratory, Kitasato University, Tokyo, Japan.
Kumagai
Naoki
N
Kaneko
Fumihiko
F
Tsunematsu
Satoshi
S
Tsuchimoto
Kanji
K
Saito
Hidetsugu
H
Hibi
Toshifumi
T
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006820:Hyaluronic Acid / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology*; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D044967:Serum; D012720:Severity of Illness Index; D013552:Swine
D015850:Interleukin-6; D020011:Protective Agents; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D010431:Pentoxifylline