title: Angiogenesis blockade as a new therapeutic approach to experimental colitis.
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.
  
  
  OBJECTIVE
  To investigate the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy. sdanese@hotmail.com
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.forename: Ivy
authors.initials: I
authors.lastname: Beck
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.forename: Marian L
authors.initials: ML
authors.lastname: Plunkett
authors.forename: Carol
authors.initials: C
authors.lastname: de la Motte
authors.forename: Raymond
authors.initials: R
authors.lastname: Redline
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
mesh_terms: D000208:Acute Disease; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000098:blood supply; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D016753:Interleukin-10 / Q000172:deficiency; D007413:Intestinal Mucosa / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D009842:Oligopeptides; D016753:Interleukin-10; D016264:Dextran Sulfate; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide