Dimethyl sulfoxide inhibits dimethylnitrosamine-induced hepatic fibrosis in rats.
We studied the preventive effects of dimethyl sulfoxide (DMSO) on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral DMSO (2 ml/kg daily for 4 weeks) essentially prevented this DMN-induced body and liver weight loss with no major side effects. DMSO suppressed the induction of hepatic fibrosis, as determined by histological evaluation, and reduced hepatic hydroxyproline. It also suppressed the expression of mRNA for type I collagen in the liver. Because hepatic stellate cells (HSC) are the major cellular source of the collagen in hepatic fibrosis, we examined the effects of DMSO on collagen production in vitro using rat primary HSC culture. However, it was found that DMSO did not inhibit the collagen production in vitro. We next evaluated the effects of DMSO on tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) production by Kupffer cells, because these factors represent major activator of HSC, and because monocyte-macrophage infiltration has been implicated as being pathogenetically important for hepatic fibrosis induced by DMN. DMSO inhibited lipopolysaccharide (LPS)-induced TNFalpha and NO production, and reduced TNFalpha mRNA levels. DMSO also suppressed the LPS-induced nuclear factor kappa B activation in a murine macrophage-like cell line. These results suggest that the inhibitory effects of DMSO on hepatic fibrosis may be primarily exerted via blocking of DMN-induced inflammation. These results also implied that DMSO may be potentially useful for preventing the development of hepatic fibrosis.
Nakamuta
M
M
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. nakamuta@intmed3.med.kyushu-u.ac.jp
Ohta
S
S
Tada
S
S
Tsuruta
S
S
Sugimoto
R
R
Kotoh
K
K
Kato
M
M
Nakashima
Y
Y
Enjoji
M
M
Nawata
H
H
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004128:Dimethylnitrosamine / Q000008:administration & dosage*; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D024042:Collagen Type I; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008156:Luciferases; D004128:Dimethylnitrosamine; D006909:Hydroxyproline; D004121:Dimethyl Sulfoxide