Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats.
1. In the present study, we investigated the preventive effects of pirfenidone (PFD), an antifibrotic agent, on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. 2. Treatment with DMN caused a significant decrease in bodyweight and liver weight. Oral PFD (500 mg/kg daily for 4 weeks) essentially prevented this DMN-induced loss in bodyweight and tended to suppress the loss in liver weight. There were no significant differences in liver weight and serum L-alanine aminotransferase levels between PFD-treated and -untreated groups. Pirfenidone has no major side effects in vivo. 3. Pirfenidone suppressed the induction of hepatic fibrosis determined by histological evaluation and reduced hepatic hydroxyproline levels. Expression of mRNA for type I collagen and transforming growth factor-beta in the liver was also suppressed by PFD treatment. 4. Because hepatic stellate cells (HSC) are the major cellular source of extracellular matrix in hepatic fibrosis, we examined the effects of PFD on type I collagen production in vitro using rat primary HSC cultures. Pirfenidone inhibited collagen production in HSC culture in a dose-dependent manner. 5. These results demonstrate that the inhibitory effects of PFD against hepatic fibrosis may be due, at least in part, to blockade of collagen production by HSC and suggest that PFD may be potentially useful in the prevention of the development of hepatic fibrosis.
Tada
S
S
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-12 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nakamuta
M
M
Enjoji
M
M
Sugimoto
R
R
Iwamoto
H
H
Kato
M
M
Nakashima
Y
Y
Nawata
H
H
D000818:Animals; D015152:Blotting, Northern; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004128:Dimethylnitrosamine; D006909:Hydroxyproline / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D011728:Pyridones; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen; C093844:pirfenidone; D004128:Dimethylnitrosamine; D006909:Hydroxyproline