Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice.
Plasma fibronectin (FN) has a broad range of biological functions involved in cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, reticuloendothelial system function, and ischemic injury. In this study, we examined the effects of FN on D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant liver failure in mice. Female Balb/c mice received intraperitoneal injection of 50 mug/kg of LPS and 400 mg/kg of GalN simultaneously. Thirty minutes before GalN/LPS administration, human plasma FN (FN group) or the same dose of human serum albumin (control group) was given intravenously. GalN/LPS induced a marked decrease in plasma FN, which was reversed by FN pretreatment. The survival rate of the FN group was markedly improved in a dose-dependent manner compared with that of the control group (survival rate 0%). FN prevented increases in the concentrations of serum enzymes and total bilirubin related to liver injury. FN pretreatment significantly suppressed tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 levels, and enhanced IL-10 levels in serum and liver tissue compared with the control group. Moreover, TUNEL staining, caspase 3 and 8 activities, and necrosis in the remnant liver were significantly decreased in the FN-treated rats compared with the controls. Furthermore, FN pretreatment inhibited the activation of nuclear factor (NF)-kappaB and increased the expression of Bcl-xL protein in liver tissue. These results suggest that FN protected against GalN/LPS-induced liver failure by a mechanism involving inhibition of NF-kappaB activation, which caused down-regulation of TNF-alpha and involved up-regulation of IL-10, and elevation of Bcl-xL induced a blockage of apoptotic signals, by which apoptosis of hepatocytes caused by GalN/LPS was suppressed.
Qiu
Zeyu
Z
Department of Surgery, Kansai Medical University, Osaka 570-8507, Japan.
Kwon
A-Hon
AH
Tsuji
Katsushige
K
Kamiyama
Yasuo
Y
Okumura
Tadayoshi
T
Hirao
Yutaka
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D005260:Female; D005353:Fibronectins / Q000008:administration & dosage*; D005688:Galactosamine / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000096:biosynthesis; D009336:Necrosis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000096:biosynthesis
C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D005353:Fibronectins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051020:bcl-X Protein; D005688:Galactosamine