Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells.
The aim of this study was to investigate whether matrix metalloproteinases (MMP-13, 9) of Kupffer cells induced by gadolinium chloride (GdCl(3)) treatment can reverse dimethylnitrosamine (DMN)-induced liver fibrosis (in vivo) and the effect of GdCl(3) on MAP kinase activity (in vitro). Male Wistar rats 6 weeks of age received DMN (10 mg/kg) three successive days a week for 4 weeks. Then two groups of rats (n = 6 each) were treated twice weekly with either GdCl(3) (7 mg/kg) or saline solution intravenously for the next 4 weeks. Animals were sacrificed to estimate the degree of liver fibrosis. Isolated Kuppfer cells were treated with GdCl(3) and the expressions of MMPs, MAP kinase activity (ERK, SAPK/JNK, P38) as well as apoptosis were also examined. Rats that received DMN for 4 weeks followed by GdCl(3) injection for 4 weeks showed an reduced liver hydroxyproline content compared to rats treated with DEN followed by saline (277 +/- 22 VS 348 +/- 34 microg/g, n = 6 each, P < 0.01). There were significantly increased MMP-13 mRNA levels in GdCl(3)-treated rats. However, no significant change was observed in procollagen type I mRNA levels. Isolated Kuppfer cells treated with GdCl(3) showed increased MAP kinase activity, especially P38 pathway as well as MMP-13, 9 mRNA and type I collagen-degrading activity leading to apoptosis. SB203580, inhibitor of P38 pathway diminished these activation and prevented apoptosis. These results suggest that Kuppfer cells can reverse liver fibrosis via the expression of MMPs mainly through P38 pathway.
Sakaida
Isao
I
Department of Gastroenterology and Hepatology School of Medicine, Yamaguchi University, Yamaguchi-Pref. 755-8505, Ube, Japan. sakaida@po.cc.yamaguchi-u.ac.jp
Hironaka
Koji
K
Terai
Shyuji
S
Okita
Kiwamu
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002452:Cell Count; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004123:Dimethylamines / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006909:Hydroxyproline / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D004123:Dimethylamines; D012333:RNA, Messenger; D005682:Gadolinium; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020780:Matrix Metalloproteinase 9; C013962:dimethylnitramine; C038958:gadolinium chloride; D006909:Hydroxyproline