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1.
Eur J Clin Invest ; 37(9): 731-6, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17696963

ABSTRACT

BACKGROUND: Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. MATERIAL AND METHODS: We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non-nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non-nucleating gallbladder biles, as well as 1-5 micromol L(-1) malondialdehyde on cultured gallbladder epithelial cells, was determined. RESULTS: Our data show an increased malondialdehyde (7.2 +/- 1.8 vs. 3.8 +/- 0.5 micromol L(-1), P = 0.01) and mucin concentration (0.9 +/- 0.09 vs. 0.41 +/- 0.03 mg mL(-1), P = 0.01) and an increased mucin secretagogue activity (2.0 +/- 0.5 vs. 1.1 +/- 0.3 mucin secretion/control, P = 0.04) and cholesterol saturation index (1.2 +/- 0.1 vs. 08 +/- 0.1, P = 0.04) in rapid as compared to non-nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. CONCLUSIONS: Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease.


Subject(s)
Bile/metabolism , Cholelithiasis/etiology , Lipid Peroxidation/physiology , Mucins/metabolism , Adult , Cholelithiasis/complications , Female , Humans , Male , Middle Aged
2.
Brain Res Mol Brain Res ; 100(1-2): 103-17, 2002 Apr 30.
Article in English | MEDLINE | ID: mdl-12008026

ABSTRACT

Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) are involved in many cell migration phenomena and produced by many cell types, including neurons and glia. To assess their possible roles in brain injury and regeneration, we investigate their production by glial cells, after brain injury and in tissue culture, and we investigate whether they are capable of digesting known axon-inhibitory proteoglycans. To determine the action of MMPs, we incubated astrocyte conditioned medium with activated MMPs, then did western blots for several chondroitin sulphate proteoglycans. MMP-3 digested all five proteoglycans tested, whereas MMP-2 digested only two and MMP-9 none. To determine whether MMPs or TIMPs are produced by astrocytes in vitro, we tested both primary cultures and astrocyte cell lines by western blotting, and compared them with Schwann cells. All cultures produced at least some MMPs and TIMPs, with no obvious correlation with the ability of axons to grow on those cells. Both MMP-9 and TIMP-3 were regulated by various cytokines. To determine which cells produce MMPs and TIMPs after brain injury, we made lesions of adult rat cortex, and did immunohistochemistry. MMP-2 was seen to be induced in activated astrocytes through the whole thickness of the cortex but not deeper, but MMP-3 was not seen in the injured brain. TIMP-2 and TIMP-3 immunoreactivities were induced in activated astrocytes in deep cortex and the underlying white matter. In situ hybridisation confirmed induction of TIMP-2 in glia as well as neurons, but showed no expression of TIMP-4. These results show that both MMPs and TIMPs are produced by some astrocytes, but TIMP production is particularly strong, especially in deep cortex and white matter which is more inhibitory for axon regeneration. Conversely the MMPs produced may not be adequate to promote migration of cells and axons within the glial scar.


Subject(s)
Astrocytes/enzymology , Brain Injuries/enzymology , Brain/enzymology , Gliosis/enzymology , Matrix Metalloproteinases/metabolism , Nerve Regeneration/physiology , Tissue Inhibitor of Metalloproteinases/metabolism , Animals , Animals, Newborn , Antibody Specificity , Astrocytes/cytology , Brain/pathology , Brain/physiopathology , Brain Injuries/pathology , Brain Injuries/physiopathology , Cells, Cultured , Cerebral Cortex/enzymology , Cerebral Cortex/injuries , Cerebral Cortex/physiopathology , Chondroitin Sulfate Proteoglycans/metabolism , Cytokines/metabolism , Cytokines/pharmacology , Gliosis/pathology , Gliosis/physiopathology , Growth Cones/enzymology , In Situ Hybridization , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 3/genetics , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinases/genetics , RNA, Messenger/metabolism , Rats , Tissue Inhibitor of Metalloproteinase-2/genetics , Tissue Inhibitor of Metalloproteinase-2/metabolism , Tissue Inhibitor of Metalloproteinase-3/drug effects , Tissue Inhibitor of Metalloproteinase-3/metabolism , Tissue Inhibitor of Metalloproteinases/genetics , Up-Regulation/physiology , Tissue Inhibitor of Metalloproteinase-4
3.
Am J Physiol Gastrointest Liver Physiol ; 280(5): G1043-8, 2001 May.
Article in English | MEDLINE | ID: mdl-11292614

ABSTRACT

E-selectin, expressed on endothelial cells, mediates adhesion of leukocytes and tumor cells to endothelium. CA19-9 (sialyl-Lewis(a)) and sialyl-Lewis(x) are specific ligands for E-selectin. We have recently shown that mucin-rich culture media from human gallbladder epithelial cells contains CA19-9. In this study, we have tested whether human biliary mucin binds to E-selectin. The ability of mucins to inhibit the adhesion of HL-60 cells to immobilized E-selectin was taken as an index for E-selectin binding. Gallbladder bile, hepatic bile, and culture medium from human gallbladder epithelial cells completely inhibited the adhesion of HL-60 cells to E-selectin. The mucin-rich fractions of human bile exhibited strong inhibition, whereas mucin-free fractions had little effect. In contrast to human bile samples, CA19-9-free medium from cultured dog gallbladder epithelial cells failed to inhibit HL-60 binding. Furthermore, after CA19-9 immunoaffinity chromatography, which selectively extracted CA19-9 from bile, bile samples showed poor inhibition of HL-60 adhesion to immobilized E-selectin. A good correlation was observed between E-selectin binding and CA 19-9 concentrations in bile. Our results show that human bile has E-selectin binding activity that is mediated by the CA19-9 side chain of biliary mucin.


Subject(s)
Bile/physiology , CA-19-9 Antigen/metabolism , E-Selectin/metabolism , Inflammation/physiopathology , Mucins/physiology , Animals , Cell Adhesion , Cells, Cultured , Chromatography, Affinity , Culture Media, Conditioned , Dogs , Epithelial Cells/cytology , Epithelial Cells/physiology , Gallbladder/cytology , Gallbladder/physiology , HL-60 Cells , Humans , Ligands , Recombinant Fusion Proteins/metabolism
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