Angiogenesis blockade as a new therapeutic approach to experimental colitis

• Published in: Gut Vol. 56; no. 6; pp. 855 - 862
• Main Authors: Danese, Silvio, Sans, Miquel, Spencer, David M, Beck, Ivy, Doñate, Fernando, Plunkett, Marian L, de la Motte, Carol, Redline, Raymond, Shaw, David E, Levine, Alan D, Mazar, Andrew P, Fiocchi, Claudio
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.06.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Acute Disease; Alzheimer's disease; Angiogenesis; Angiogenesis Inhibitors - therapeutic use; Animals; Atherosclerosis; Biological and medical sciences; Cancer; Cell Proliferation; Cells, Cultured; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colitis - pathology; Colon; Colon - blood supply; Cytokines; Cytokines - biosynthesis; DAI; dextran sodium sulphate; Dextran Sulfate; Diabetic retinopathy; Disease Activity Index; Disease Models, Animal; Disease Progression; DSS; Gastroenterology. Liver. Pancreas. Abdomen; IBD; Inflammation; Inflammatory bowel disease; interleukin; Interleukin-10 - deficiency; Intestinal Mucosa - blood supply; intraperitoneal; lamina propria mononuclear cells; lipopolysaccharide; LPMC; LPS; mean vascular density; Medical sciences; Mice; Mice, Inbred C57BL; MVD; Neovascularization, Pathologic - drug therapy; Oligopeptides - therapeutic use; Other diseases. Semiology; PBS; Peptides; phosphate-buffered saline; Psoriasis; Rheumatoid arthritis; Rodents; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; UBF; ultra-barrier facility; vascular endothelial growth factor; VEGF; wild type; United States > US; California; Mucosa; Thymidine; Inflammatory disease; Dextran; Angiogenesis; Crohn disease; Chronic; Treatment; Blood substitute; Blood vessel; Digestive diseases; Intestinal disease; Colitis; Colon; Pyrimidine nucleoside; Ulcerative colitis
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2006.114314

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.