title: Nonselective matrix metalloproteinase but not tumor necrosis factor-α inhibition effectively preserves the early critical colon anastomotic integrity.
abstract: BACKGROUND
  Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-α (TNF-α) induces MMPs and may influence anastomosis repair.
  
  
  METHODS
  We assessed the efficacies of the nonselective hydroxamate MMP inhibitor GM6001, the selective hydroxamate MMP inhibitor AG3340 and a TNF-α antagonist with respect to anastomotic breaking strength of left-sided colon anastomoses in male Sprague-Dawley rats.
  
  
  RESULTS
  Systemic GM6001 treatment effectively blocked MMP activity and maintained the initial breaking strength day 0 of the anastomoses when administered subcutaneously as daily depositions (100 mg/kg) or continuously (10 mg/kg/day). In contrast, the anastomotic biomechanic strength was lowered by 55% (p < 0.001) in vehicle-treated rats on postoperative day 3. GM6001 treatment increased breaking strength by 88% (p < 0.0005) compared with vehicle-treated rats day 3 and reduced (p = 0.003) the occurrence of spontaneous anastomotic dehiscence. Histologically, the anastomotic wound was narrower (p < 0.05) in the longitudinal direction in GM6001-treated animals whereas GM6001 had no significant effect on inflammatory cell infiltration or epithelialization. AG3340 (10 mg/kg) increased (p < 0.012) breaking strength by 47% compared with vehicle on day 3 but did not significantly prevent the reduction of the initial breaking strength on day 0. Although the increased TNF-α levels in the wound were attenuated, the anastomotic breaking strength was not improved (p = 0.62) by the TNF-α (10 mg/kg) inhibitor given systemically.
  
  
  CONCLUSIONS
  Pharmacological nonselective MMP inhibition ought to be explored as a prophylactic regimen to reduce anastomotic complications following colorectal resection. The involvement of TNF-α was insignificant in anastomotic wound healing in an experimental model.
authors.affiliation: Department of Surgery K, Bispebjerg Hospital, Copenhagen, Denmark. magnus.agren@mail.dk
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Ågren
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andersen
authors.forename: Line
authors.initials: L
authors.lastname: Andersen
authors.forename: Christine Bruun
authors.initials: CB
authors.lastname: Schiødt
authors.forename: Vikas
authors.initials: V
authors.lastname: Surve
authors.forename: Troels T
authors.initials: TT
authors.lastname: Andreassen
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Lennart E
authors.initials: LE
authors.lastname: Franzén
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaissé
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heegaard
authors.forename: Lars N
authors.initials: LN
authors.lastname: Jorgensen
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000473:pathology / Q000601:surgery*; D004151:Dipeptides / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009930:Organic Chemicals; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C113282:prinomastat; D020782:Matrix Metalloproteinases