Angiogenesis blockade as a new therapeutic approach to experimental colitis
- Silvio Danese1,
- Miquel Sans2,
- David M Spencer3,
- Ivy Beck4,
- Fernando Doñate4,
- Marian L Plunkett4,
- Carol de la Motte5,
- Raymond Redline6,
- David E Shaw7,
- Alan D Levine3,
- Andrew P Mazar4,
- Claudio Fiocchi5
- 1Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
- 2Department of Gastroenterology, Hospital Clinic i Provincial/ IDIBAPS, CIBER-EHD, Barcelona, Spain
- 3Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- 4Attenuon, LLC, San Diego, California, USA
- 5Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
- 6Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- 7DE Shaw Research and Development, New York, New York, USA
- Correspondence to:
Dr S Danese
Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy; sdanese{at}hotmail.com
- Accepted 8 December 2006
- Revised 31 October 2006
- Published Online First 14 December 2006
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.
- DAI, Disease Activity Index
- DSS, dextran sodium sulphate
- IBD, inflammatory bowel disease
- IL, interleukin
- IP, intraperitoneal
- LPMC, lamina propria mononuclear cells
- LPS, lipopolysaccharide
- MVD, mean vascular density
- PBS, phosphate-buffered saline
- UBF, ultra-barrier facility
- VEGF, vascular endothelial growth factor
- WT, wild type
Footnotes
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Published Online First 14 December 2006
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Competing interests: None.
