Angiogenesis blockade as a new therapeutic approach to experimental colitis

Silvio Danese*, Miquel Sans, David M. Spencer, Ivy Beck, Fernando Doñate, Marian L. Plunkett, Carol De La Motte, Raymond Redline, David E. Shaw, Alan D. Levine, Andrew P. Mazar, Claudio Fiocchi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Background: Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective treatment in animal models of inflammation, but has not been tested in experimental colitis. Aim: To investigate the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis. Method: Interleukin 10-deficient (IL10 -/-) mice and wild-type mice were kept in ultra-barrier facilities (UBF) or conventional housing, and used for experimental conditions. Dextran sodium sulphate (DSS)-treated mice were used as a model of acute colitis. Mice were treated with ATN-161 or its scrambled peptide ATN-163. Mucosal neoangiogenesis and mean vascular density (MVD) were assessed by CD31 staining. A Disease Activity Index (DAI) was determined, and the severity of colitis was determined by a histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell proliferation by thymidine incorporation. Result: MVD increased in parallel with disease progression in IL10-/- mice kept in conventional housing, but not in IL10 -/- mice kept in UBF. Angiogenesis also occurred in DSS-treated animals. IL10-/- mice with established disease treated with ATN-161, but not with ATN-163, showed a significant and progressive decrease in DAI. The histological colitis score was significantly lower in ATN-161-treated mice than in scrambled peptide-treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN-161-treated mice than in ATN-163-treated mice. No therapeutic effects were observed in the DSS model of colitis. ATN-161 showed no direct immunomodulatory activity in vitro. Conclusion: Active angiogenesis occurs in the gut of IL10-/- and DSS-treated colitic mice and parallels disease progression. ATN-161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in IL10-/- mice but not in the DDS model of inflammatory bowel disease (IBD). The results provide the rational basis for considering anti-angiogenic strategies in the treatment of IBD in humans.

Original languageEnglish (US)
Pages (from-to)855-862
Number of pages8
JournalGut
Volume56
Issue number6
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Gastroenterology

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