Indomethacin and retinoic acid modify mouse intestinal inflammation and fibrosis: a role for SPARC.
ABSTRACT The mouse model of 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced intestinal fibrosis allows for detailed study of the extracellular matrix changes that complicate Crohn's disease. Indomethacin induces intestinal fibrosis, while retinoic acid (RA) reduces liver fibrosis. Secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix-modifying agent, may potentially link these opposing effects. Our aim was to determine the effects of indomethacin and RA and to evaluate their correlation to SPARC expression in the TNBS mouse model. CD-1 mice were randomised to TNBS enemas weekly for 2 or 8 weeks with or without indomethacin (0.2 mg/kg per day) or RA (100 microg/kg per day). At 2 weeks, indomethacin/TNBS enhanced and RA reduced inflammation, tissue destruction and fibrosis. The expression of SPARC was inversely related to fibrosis, but not to inflammation, in the TNBS-alone groups at 2 weeks; these differences were lost by 8 weeks. The results demonstrate that indomethacin increases TNBS-induced fibrosis in mice, while RA reduces it, and that SPARC may link these opposing effects.
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ABSTRACT: Sinusoidal Ito cells (stellate or fat-storing cells) undergo excessive cellular proliferation before the establishment and progression of hepatic fibrosis and cirrhosis. Retinoic acid and transforming growth factor beta (TGF beta) both inhibit Ito-cell [3H]thymidine incorporation in serum-containing media. Serum-induced mitogenicity was dependent on platelet-derived growth factor (PDGF). Additionally, pre-treatment of Ito cells with retinoic acid and TGF beta blocked PDGF-induced cell proliferation. TGF beta, but not retinoic acid, diminished PDGF-receptor and smooth-muscle alpha-actin abundance.Biochemical Journal 09/1991; 278 ( Pt 1):43-7. · 4.65 Impact Factor
- Journal of Clinical Investigation 06/2001; 107(9):1049-54. · 12.81 Impact Factor
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ABSTRACT: SPARC (secreted protein, acidic and rich in cysteine) is a Ca(2+)-binding glycoprotein that has recently been identified as a member of a group of proteins that exert antispreading effects on various cultured cells. In addition, SPARC is induced during the later stages of F9 stem cell differentiation to parietal endoderm (PE). When treated with retinoic acid and dibutyryl cAMP, F9 cells differentiate into PE and SPARC mRNA is increased approximately 20-fold. To determine whether the chronic overexpression or inhibition of expression of SPARC would affect the morphology, attachment, or differentiation of F9 cells, we transfected undifferentiated F9 cells with cDNA encoding SPARC or anti-sense SPARC and cloned lines that expressed either elevated or reduced levels of SPARC protein. The transfected F9 cells displayed altered morphologies in culture: cells of four overexpressing lines appeared clumped and rounded, whereas those of three underexpressing lines were spread and flat, in comparison to controls. Moreover, the morphological differences persisted during differentiation of the lines to PE. The altered morphology was not due to an increased expression of collagenases and did not affect the ability of the cells to attach and adhere to tissue culture plastic. The altered phenotype of the transfected F9 cells appeared to be directly related to the level of extracellular SPARC. Since overexpression of SPARC induced rounding and aggregation of F9 cells in culture, we propose that SPARC facilitates modulation of cell-cell or cell-substrate interactions in vivo.Experimental Cell Research 04/1992; 199(1):134-46. · 3.56 Impact Factor