ABSTRACT
Tissue inhibitor of matrix metalloproteinases type 1, inhibiting the majority of matrix metalloproteinases, can both suppress and stimulate tumor growth. The concentrations and activities of tissue matrix metalloproteinase inhibitor-1 were measured in C57Bl/6 mice during progression and metastasizing of Lewis lung adenocarcinoma. Activities of matrix metalloproteinases in tumor tissue of mice were lower than in liver and lung tissues of intact animals. Serum concentration of tissue inhibitor increased significantly during the development of Lewis lung adenocarcinoma. Macrophage depression (injection of gadolinium chloride associated with a decrease in metastasis number) decreased serum concentration of tissue inhibitor, but it did not attain the control level observed in intact mice. These findings attest to a pleiotropic antitumor effect of tissue matrix metalloproteinase inhibitor-1 reflecting disorders in matrix metalloproteinase regulation during the progress of Lewis lung adenocarcinoma in mice.
Subject(s)
Carcinoma, Lewis Lung/physiopathology , Gene Expression Regulation, Neoplastic/physiology , Matrix Metalloproteinase Inhibitors , Neoplasm Metastasis/physiopathology , Tissue Inhibitor of Metalloproteinase-1/metabolism , Animals , Carcinoma, Lewis Lung/metabolism , Gadolinium , Liver/metabolism , Lung/metabolism , Mice , Mice, Inbred C57BL , Tissue Inhibitor of Metalloproteinase-1/bloodABSTRACT
We studied the role of selective suppression of liver Kupffer cells (gadolinium chloride, 14 mg/kg intravenously) in the development of intrahepatic cholestasis in CBA/C57B1/6 mice after intraperitoneal injection of alpha-naphthylisothiocyanate in a single dose of 200 mg/kg. Pretreatment with gadolinium chloride increased the severity of cholestasis and signs of liver damage. Gadolinium accumulation in the liver peaked after 24 h and was accompanied by a decrease in activities of cathepsin D and cathepsin B and concentration of matrix metalloprotease-2. Our results confirm the hypothesis that normal function of Kupffer cells and extracellular matrix plays an important role in cholestasis. Administration of gadolinium chloride serves as a convenient model to study the side effects, toxicity, and safety of lanthanides as nanoparticles.
Subject(s)
Cholestasis, Intrahepatic/chemically induced , Cholestasis, Intrahepatic/metabolism , Liver/cytology , Macrophages/physiology , 1-Naphthylisothiocyanate/pharmacology , Animals , Cathepsin B/metabolism , Cathepsin D/metabolism , Gadolinium/pharmacology , Kupffer Cells/drug effects , Kupffer Cells/physiology , Liver/drug effects , Liver/ultrastructure , Macrophages/drug effects , Male , Matrix Metalloproteinase 2/metabolism , Mice , Mice, Inbred C57BL , Microscopy, Electron, TransmissionABSTRACT
Lysosomal enzyme activity in the bile and blood serum was compared in mice with experimental intrahepatic cholestasis induced by alpha-naphthyl isothiocyanate and Triton WR 1339. Triton WR 1339 increases the synthesis of cholesterol (fatty acid precursor) in liver cells. The development of intrahepatic cholestasis was confirmed by the increase in activities of alkaline phosphatase and gamma-glutamyltransferase in blood serum. Administration of Triton WR 1339 in a dose of 100 mg/100 g was followed by a 10-fold increase in beta-galactosidase activity (hepatocyte lysosomal enzyme) in the bile, but not in the serum of mice. beta-Galactosidase activity significantly increased in the bile, but decreased in the serum of mice after treatment with a-naphthyl isothiocyanate in a dose of 200 mg/kg. Our results indicate that intrahepatic cholestasis is manifested in increased secretion of lysosomal glycosidases into the bile. Bile components can aggravate damage to liver cells by affecting the processes of hepatocyte apoptosis and necrosis.
Subject(s)
Bile/enzymology , Cholestasis, Intrahepatic/enzymology , Lysosomes/enzymology , 1-Naphthylisothiocyanate/toxicity , Alkaline Phosphatase/blood , Alkaline Phosphatase/metabolism , Animals , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/chemically induced , Cholesterol/biosynthesis , Cholesterol/blood , Hexosaminidases/blood , Hexosaminidases/metabolism , Male , Mice , Mice, Inbred CBA , Polyethylene Glycols/toxicity , beta-Galactosidase/blood , beta-Galactosidase/metabolism , beta-N-Acetylhexosaminidases/blood , beta-N-Acetylhexosaminidases/metabolism , gamma-Glutamyltransferase/blood , gamma-Glutamyltransferase/metabolismABSTRACT
The concentration of tissue inhibitor of type 1 metalloproteinases in blood serum from intact CBA mice measured by enzyme immunoassay is similar to that in healthy humans. The concentration of tissue inhibitor of type 1 metalloproteinases in mouse bile was higher than in blood serum, while its concentration in liver homogenate more than 1000-fold exceeded that in the serum, which attests to its primarily intracellular localization in the liver. Loading of liver cell lysosomes with Triton WR-1339 and development of intrahepatic cholestasis did not affect the concentration of tissue inhibitor of type 1 metalloproteinases in liver homogenate and bile. Administration of CCl4 to mice for 4.5 weeks was accompanied by an increase in the concentration of tissue inhibitor of type 1 metalloproteinases in blood serum, but not in liver homogenate. These changes reflect dysregulation of metalloproteinases, development of inflammation, and progression of the initial stage of connective tissue formation in mouse liver.
