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  • Title: Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease.
    Author: Punekar S, Zak S, Kalter VG, Dobransky L, Punekar I, Lawler JW, Gutierrez LS.
    Journal: Pathobiology; 2008; 75(1):9-21. PubMed ID: 18334835.
    Abstract:
    OBJECTIVE: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. METHODS: TSP-1-deficient mice (TSP-1-/-) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-beta(1), basic FGF, VEGF, TNF-alpha and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. RESULTS: TSP-1(-/-) mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1-/- mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1-/- mice. TSP-1-/- mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. CONCLUSIONS: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.
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