Thrombospondin 1 and Its Mimetic Peptide ABT-510 Decrease Angiogenesis and Inflammation in a Murine Model of Inflammatory Bowel DiseasePunekar S.a · Zak S.a · Kalter V.G.a · Dobransky L.a · Punekar I.a · Lawler J.W.b · Gutierrez L.S.a
aWilkes University, Wilkes-Barre, Pa., and bBeth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass., USA
Dr. Linda S. Gutierrez
Department of Biology, 354 Stark Learning Center
Wilkes University, 84 W. South St.
Wilkes-Barre, PA 18766 (USA)
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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-β1, basic FGF, VEGF, TNF-α 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.
© 2008 S. Karger AG, Basel
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