PMID- 21193914
OWN - NLM
STAT- MEDLINE
DCOM- 20110606
LR  - 20211020
IS  - 1432-1262 (Electronic)
IS  - 0179-1958 (Linking)
VI  - 26
IP  - 3
DP  - 2011 Mar
TI  - Nonselective matrix metalloproteinase but not tumor necrosis factor-alpha inhibition 
      effectively preserves the early critical colon anastomotic integrity.
PG  - 329-37
LID - 10.1007/s00384-010-1106-3 [doi]
AB  - BACKGROUND: Increased matrix metalloproteinase (MMP) activity has been implicated 
      in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-alpha 
      (TNF-alpha) 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-alpha 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-alpha levels in the wound were 
      attenuated, the anastomotic breaking strength was not improved (p = 0.62) by the 
      TNF-alpha (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-alpha was insignificant in anastomotic wound healing in an experimental model.
FAU - Agren, Magnus S
AU  - Agren MS
AD  - Department of Surgery K, Bispebjerg Hospital, Copenhagen, Denmark. 
      magnus.agren@mail.dk
FAU - Andersen, Thomas L
AU  - Andersen TL
FAU - Andersen, Line
AU  - Andersen L
FAU - Schiodt, Christine Bruun
AU  - Schiodt CB
FAU - Surve, Vikas
AU  - Surve V
FAU - Andreassen, Troels T
AU  - Andreassen TT
FAU - Risteli, Juha
AU  - Risteli J
FAU - Franzen, Lennart E
AU  - Franzen LE
FAU - Delaisse, Jean-Marie
AU  - Delaisse JM
FAU - Heegaard, Anne-Marie
AU  - Heegaard AM
FAU - Jorgensen, Lars N
AU  - Jorgensen LN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101231
PL  - Germany
TA  - Int J Colorectal Dis
JT  - International journal of colorectal disease
JID - 8607899
RN  - 0 (Dipeptides)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan 
      methylamide)
RN  - 0 (Organic Chemicals)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 10T6626FRK (prinomastat)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Anastomosis, Surgical
MH  - Animals
MH  - Colon/*drug effects/pathology/*surgery
MH  - Dipeptides/pharmacology
MH  - Extracellular Space/drug effects/enzymology
MH  - Male
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Matrix Metalloproteinases/metabolism
MH  - Organic Chemicals/pharmacology
MH  - Protease Inhibitors/*pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/metabolism
EDAT- 2011/01/05 06:00
MHDA- 2011/06/07 06:00
CRDT- 2011/01/04 06:00
PHST- 2010/12/03 00:00 [accepted]
PHST- 2011/01/04 06:00 [entrez]
PHST- 2011/01/05 06:00 [pubmed]
PHST- 2011/06/07 06:00 [medline]
AID - 10.1007/s00384-010-1106-3 [doi]
PST - ppublish
SO  - Int J Colorectal Dis. 2011 Mar;26(3):329-37. doi: 10.1007/s00384-010-1106-3. Epub 
      2010 Dec 31.