Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease.
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.
Punekar
Salman
S
Wilkes University, Wilkes-Barre, PA 18766, USA.
Zak
Samantha
S
Kalter
Valerie G
VG
Dobransky
Larissa
L
Punekar
Imran
I
Lawler
Jack W
JW
Gutierrez
Linda S
LS
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000098:blood supply / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D020868:Gene Silencing; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1