title: GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization.
abstract: BACKGROUND
  Emergency operations performed on an obstructed colon are accompanied by an increased risk of anastomotic insufficiency. Tissue-destructive matrix metalloproteinase (MMP) activity is elevated in the obstructed colon and contributes to a loss of suture-holding submucosal collagen, which may be mediated by tumor necrosis factor (TNF)-α. Our aim was to study the effect of the non-selective MMP and TNF-α converting enzyme (TACE) inhibitor GM6001 (30 mg/kg) on anastomosis repair in obstructed left colon. GM6001 has been proved to be highly efficacious in elective anastomosis rodent models.
  
  
  METHODS
  A partial obstruction of the distal colon was induced in male Sprague-Dawley rats. After 4 d the obstructed colonic segment was resected, and an end-to-end anastomosis was constructed. Seven days later, the anastomoses were evaluated for clinical leakage. Histopathological and immunohistochemical assessments were also performed. Finally, the direct effect of GM6001 on epithelialization was studied in cultured colonic epithelial cells.
  
  
  RESULTS
  Unlike the robust beneficial effect on anastomosis under uncomplicated conditions, here GM6001 had a negative impact on anastomotic wound healing following colonic obstruction and substantially (p=0.004) more rats in the GM6001 group (75%) than in the control group (11%) had developed anastomotic leakage. In the anastomotic wounds, the myofibroblast abundance and cell proliferation were similar in the two groups. Histologically, GM6001 treatment resulted in wider and minimally epithelialized wounds that were commonly necrotic on the luminal side and infiltrated with numerous granulocytes. In vitro, GM6001 also delayed (p=0.026) epithelialization of denuded intestinal epithelium grown on type I collagen.
  
  
  CONCLUSIONS
  Non-selective MMP/TACE inhibition with GM6001 increased the anastomotic complications following colon obstruction. Inhibition of epithelialization is one possible mechanism responsible for the increased leakage following GM6001 treatment.
authors.affiliation: 1 Department of Surgery, Skåne University Hospital , Malmö, Sweden .
authors.forename: Martin
authors.initials: M
authors.lastname: Rehn
authors.affiliation: 2 Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen , Copenhagen, Denmark .
authors.forename: Peter-Martin
authors.initials: PM
authors.lastname: Krarup
authors.affiliation: 3 Department of Pathology, Bispebjerg Hospital, University of Copenhagen , Copenhagen, Denmark .
authors.forename: Lise H
authors.initials: LH
authors.lastname: Christensen
authors.affiliation: 2 Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen , Copenhagen, Denmark .
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Seidelin
authors.affiliation: 2 Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen , Copenhagen, Denmark .|4 Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen , Copenhagen, Denmark .|5 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark .
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Ågren
authors.affiliation: 1 Department of Surgery, Skåne University Hospital , Malmö, Sweden .
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
mesh_terms: D057868:Anastomotic Leak / Q000175:diagnosis*; D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000601:surgery*; D004151:Dipeptides / Q000008:administration & dosage* / Q000009:adverse effects*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D007415:Intestinal Obstruction / Q000601:surgery*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D017207:Rats, Sprague-Dawley
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide