title: Thrombospondin peptide ABT-898 inhibits inflammation and angiogenesis in a colitis model.
abstract: OBJECTIVE
  To evaluate the efficacy of the improved thrombospondin mimetic peptide ABT-898 in a murine model of ulcerative colitis.
  
  
  METHODS
  The dextran sodium sulfate (DSS) was used for the induction of colitis in both TSP-1 deficient (TSP-1(-/-)) and wild type (WT) mice during 7 d. While mice were receiving the DSS dissolved in the drinking water, the ABT-898 peptide was dissolved in sterile 5% glucose solution and delivered using mini pumps subcutaneously implanted. Plasma samples were analyzed for interleukin (IL)-6 by ELISA assay and colonic tissues were harvested, fixed and processed for histological evaluation. Immunohistochemistry using antibodies for the detection of CD31 and MECA in endothelial cells was performed. Inflammation was graded in colonic sections and the number of microvessels in each lesion was assessed. Activation of signal transducer and activator of transcription 3 (STAT3) in colonic samples was quantified by immunohistochemistry and Western blotting using antibodies against total STAT3 and phosphorylated STAT3 (pSTAT3) (Ser727).
  
  
  RESULTS
  Treatment with ABT-898 considerably diminished the inflammatory response in WT and TSP-1(-/-) mice (P < 0.0001 in both groups vs control). Identification of blood vessels highlighted by CD31/MECA immunohistochemistry, showed significantly reduced vessel counts in colitic lesions of WT and TSP-1(-/-) mice treated with ABT898 (TSP-1(-/-) controls/TSP-1(-/-) treated, P = 0.0002; WT controls/WT treated, P = 0.0005). Consistently, IL-6 was significantly diminished in plasma samples of TSP-1(-/-) and WT treated with the peptide when compared to the control mice (P = 0.0002 and P = 0.0148, respectively). pSTAT3 positive cells were quantified in WT and TSP-1(-/-) treated with ABT-898. A significant decrease in positive cells for pSTAT3 was observed in treated mice (TSP-1(-/-) controls/TSP-1(-/-) treated, P = 0.0089; WT/WT treated, P = 0.0110). These results were confirmed by Western blotting analyses showing lower levels of pSTAT3 in colitic lesions from mice treated with the peptide ABT-898.
  
  
  CONCLUSIONS
  These findings indicate that the new peptide ABT-898 ameliorates inflammation and angiogenesis and might be a therapeutic alternative in IBD and inflammatory diseases.
authors.affiliation: Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Gutierrez
authors.affiliation: Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Ling
authors.affiliation: Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Nye
authors.affiliation: Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Papathomas
authors.affiliation: Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dickinson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D003093:Colitis, Ulcerative / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D018952:Antigens, CD34; D015415:Biomarkers; C448783:HIAF-1 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019700:Thrombospondin 1; C554676:acetyl-glycyl-valyl-allo-isoleucyl-seryl-glutaminyl-isoleucyl-arginyl-prolyl-cysteinamide; C577686:interleukin-6, mouse; C585483:Thbs1 protein, mouse; D016264:Dextran Sulfate
keywords: ABT-510; ABT-898; Angiogenesis; Dextran sodium sulfate model; Inflammatory bowel disease; Interleukin-6; STAT-3; Thrombospondin 1