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

Research output: Contribution to journalArticlepeer-review

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
Pages (from-to)855-862
Number of pages8
JournalGut
Volume56
Issue number6
DOIs
Publication statusPublished - Jun 2007

ASJC Scopus subject areas

  • Gastroenterology

Fingerprint Dive into the research topics of 'Angiogenesis blockade as a new therapeutic approach to experimental colitis'. Together they form a unique fingerprint.

Cite this