Nonselective matrix metalloproteinase but not tumor necrosis factor-alpha inhibition effectively preserves the early critical colon anastomotic integrity

作者：Agren Magnus S^*; Andersen Thomas L; Andersen Line; Schiodt Christine Bruun; Surve Vikas; Andreassen Troels T; Risteli Juha; Franzen Lennart E; Delaisse Jean Marie; Heegaard Anne Marie; Jorgensen Lars N

来源：International Journal of Colorectal Disease, Clinical and Molecular Gastroenterology and Surgery, 2011, 26(3): 329-337.

DOI：10.1007/s00384-010-1106-3

• Colon
• Wound repair
• Collagen
• Proteinases
• Cytokine

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.
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.
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.
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.

• 出版日期2011-3