Angiogenesis blockade as a new therapeutic approach to experimental colitis

Silvio Danese ^1*, Miquel Sans ², David Spencer ³, Ivy Beck ⁴, Fernando Donate ⁴, Marian Plunkett ⁴, Carol de la Motte ⁵, Raymond Redline ⁴, David Shaw ⁶, Alan Levine ³, Andrew Mazar ⁴ and Claudio Fiocchi ⁵

¹ Istituto Clinico Humanitas, Italy
² Case Western Reserve University, Spain
³ Case Western Reserve University, United States
⁴ Attenuon, United States
⁵ Cleveland Clinic, United States
⁶ Shaw Research and Development, United States

^* To whom correspondence should be addressed. E-mail: sdanese{at}hotmail.com.

Accepted 8 December 2006

Abstract

Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective therapy in animal models of inflammation, but has not been tested in experimental colitis. We investigated the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis. IL-10-/- mice and wild type (WT) 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 severity of colitis by a blinded histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell (LPMC) proliferation by thymidine incorporation. MVD increased in parallel with disease progression in IL-10-/- mice kept in conventional housing, but not in IL-10-/- mice kept in UBF. Angiogenesis also occurred in DSS-treated animals. IL-10-/- mice with established disease treated with ATN-161, but not ATN-163, showed a significant and progressive drop of the DAI. The histological colitis score was significantly lower in ATN-161-treated compared to scrambled peptide-treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN-161- compared to ATN-163-treated animals. No therapeutic effects were observed in the DSS model of colitis. ATN-161 showed no direct immunomodulatory activity in vitro. Active angiogenesis occurs in the gut of IL-10-/- and DSS-treated colitic mice and parallels disease progression. ATN-161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in the IL-10-/- but not the DDS model of IBD. Our results provide the rational basis for considering anti-angiogenic strategies in the treatment of human IBD.

Keywords: ANGIOGENESIS, CROHN, ULCERATIVE COLITIS

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