title: Infliximab therapy inhibits inflammation-induced angiogenesis in the mucosa of patients with Crohn's disease.
abstract: OBJECTIVE
  Inflammation-driven angiogenesis contributes to the pathogenesis of inflammatory bowel disease (IBD). In line with this, the efficacy of inhibitors of angiogenesis has been demonstrated in experimental models of colitis. Currently, the ability of infliximab, an anti-tumor necrosis factor-α (TNF-α) agent that is highly beneficial in patients with IBD, to affect mucosal angiogenesis in patients with Crohn's disease (CD) and ulcerative colitis (UC) is unknown.
  
  
  METHODS
  Patients with active CD (n=14) were treated with infliximab for 1 year, and peripheral blood and intestinal mucosa samples were collected before and after treatment. Mucosal angiogenesis was evaluated by CD31 and Ki-67 staining in endoscopic biopsies at baseline (week 0) and at week 54. The release of vascular endothelial growth factor-A (VEGF-A) by cultured mucosal extracts was measured by enzyme-linked immunosorbent assay (ELISA), before and after administration of infliximab, as well as in cultures of human intestinal fibroblasts (HIFs) stimulated with TNF-α in the presence or absence of infliximab. Migration of human intestinal microvascular endothelial cells (HIMECs) was investigated by migration assays.
  
  
  RESULTS
  Microvessel density was significantly higher in the mucosa from patients with CD compared with tissue from healthy control individuals. Of the 14 patients, 8 (57%) showed a clinical remission in response to infliximab, which was associated with a significant reduction of microvascular density. Morphometric vessel analysis further confirmed the significant reduction of the area of vascular section after administration of infliximab. Furthermore, the expression levels of the proliferation marker Ki-67 in endothelial cells were significantly reduced after treatment. The mucosal concentration of VEGF-A was also significantly decreased, whereas in vitro exposure of HIF to infliximab virtually abolished TNF-α-induced VEGF-A production. These phenomena did not occur in patients who showed no clinical response to infliximab.
  
  
  CONCLUSIONS
  Administration of infliximab downregulates mucosal angiogenesis in patients with CD and restrains production of VEGF-A by mucosal fibroblasts. It is proposed that this ameliorates inflammation-driven angiogenesis in the gut mucosa and contributes to the therapeutic efficacy of blockade of TNF-α.
authors.affiliation: Department of Hematology, Catholic University Medical School, Rome, Italy. srutella@rm.unicatt.it
authors.forename: Sergio
authors.initials: S
authors.lastname: Rutella
authors.forename: Gionata
authors.initials: G
authors.lastname: Fiorino
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Carmen
authors.initials: C
authors.lastname: Correale
authors.forename: Antonino
authors.initials: A
authors.lastname: Spinelli
authors.forename: Nico
authors.initials: N
authors.lastname: Pagano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggiano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Repici
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001808:Blood Vessels / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003424:Crohn Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D019394:Ki-67 Antigen; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000069285:Infliximab