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

Magnus S. Ågren; Thomas L. Andersen; Line Andersen; Christine Bruun Schiødt; Vikas Surve; Troels T. Andreassen; Juha  Risteli; Lennart E. Franzén; Jean-Marie Delaissé; Anne-Marie Heegaard; Lars Nannestad Jørgensen

doi:10.1007/s00384-010-1106-3

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

Magnus S. Ågren, Thomas L. Andersen, Line Andersen, Christine Bruun Schiødt, Vikas Surve, Troels T. Andreassen, Juha Risteli, Lennart E. Franzén, Jean-Marie Delaissé, Anne-Marie Heegaard, Lars Nannestad Jørgensen

20 Citations (Scopus)

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.

Original language	English
Journal	International Journal of Colorectal Disease
Volume	26
Issue number	3
Pages (from-to)	329-337
Number of pages	9
ISSN	0179-1958
DOIs	https://doi.org/10.1007/s00384-010-1106-3
Publication status	Published - Mar 2011

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Former Faculty of Pharmaceutical Sciences

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10.1007/s00384-010-1106-3

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Ågren, M. S., Andersen, T. L., Andersen, L., Schiødt, C. B., Surve, V., Andreassen, T. T., Risteli, J., Franzén, L. E., Delaissé, J-M., Heegaard, A-M., & Jørgensen, L. N. (2011). Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity. International Journal of Colorectal Disease, 26(3), 329-337. https://doi.org/10.1007/s00384-010-1106-3

Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity. / Ågren, Magnus S.; Andersen, Thomas L.; Andersen, Line et al.

In: International Journal of Colorectal Disease, Vol. 26, No. 3, 03.2011, p. 329-337.

Research output: Contribution to journal › Journal article › Research › peer-review

Ågren, MS, Andersen, TL, Andersen, L, Schiødt, CB, Surve, V, Andreassen, TT, Risteli, J, Franzén, LE, Delaissé, J-M, Heegaard, A-M & Jørgensen, LN 2011, 'Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity', International Journal of Colorectal Disease, vol. 26, no. 3, pp. 329-337. https://doi.org/10.1007/s00384-010-1106-3

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title = "Nonselective matrix metalloproteinase but not tumor necrosis factor-a 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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "{\AA}gren, {Magnus S.} and Andersen, {Thomas L.} and Line Andersen and Schi{\o}dt, {Christine Bruun} and Vikas Surve and Andreassen, {Troels T.} and Juha Risteli and Franz{\'e}n, {Lennart E.} and Jean-Marie Delaiss{\'e} and Anne-Marie Heegaard and J{\o}rgensen, {Lars Nannestad}",

year = "2011",

month = mar,

doi = "10.1007/s00384-010-1106-3",

language = "English",

volume = "26",

pages = "329--337",

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TY - JOUR

T1 - Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity

AU - Ågren, Magnus S.

AU - Andersen, Thomas L.

AU - Andersen, Line

AU - Schiødt, Christine Bruun

AU - Surve, Vikas

AU - Andreassen, Troels T.

AU - Risteli, Juha

AU - Franzén, Lennart E.

AU - Delaissé, Jean-Marie

AU - Heegaard, Anne-Marie

AU - Jørgensen, Lars Nannestad

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1007/s00384-010-1106-3

DO - 10.1007/s00384-010-1106-3

M3 - Journal article

SN - 0179-1958

VL - 26

SP - 329

EP - 337

JO - International Journal of Colorectal Disease

JF - International Journal of Colorectal Disease

IS - 3

ER -

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

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