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

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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.

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References

  1. Frye J, Bokey EL, Chapuis PH, Sinclair G, Dent OF (2009) Anastomotic leakage after resection of colorectal cancer generates prodigious use of hospital resources. Colorectal Dis 11:917–920

    Article  CAS  PubMed  Google Scholar 

  2. Bertelsen CA, Andreasen AH, Jorgensen T, Harling H (2010) Anastomotic leakage after anterior resection for rectal cancer: risk factors. Colorectal Dis 12:37–43

    Article  CAS  PubMed  Google Scholar 

  3. Walker KG, Bell SW, Rickard MJ, Mehanna D, Dent OF, Chapuis PH, Bokey EL (2004) Anastomotic leakage is predictive of diminished survival after potentially curative resection for colorectal cancer. Ann Surg 240:255–259

    Article  PubMed  Google Scholar 

  4. Hendriks T, Mastboom WJ (1990) Healing of experimental intestinal anastomoses. Parameters for repair. Dis Colon Rectum 33:891–901

    Article  CAS  PubMed  Google Scholar 

  5. Syk I, Ågren MS, Adawi D, Jeppsson B (2001) Inhibition of matrix metalloproteinases enhances breaking strength of colonic anastomoses in an experimental model. Br J Surg 88:228–234

    Article  CAS  PubMed  Google Scholar 

  6. Ågren MS, Andersen TL, Mirastschijski U, Syk I, Schiødt CB, Surve V, Lindebjerg J, Delaissé JM (2006) Action of matrix metalloproteinases at restricted sites in colon anastomosis repair: an immunohistochemical and biochemical study. Surgery 140:72–82

    Article  PubMed  Google Scholar 

  7. Ågren MS, Andersen L, Heegaard AM, Jorgensen LN (2008) Effect of parenteral zinc sulfate on colon anastomosis repair in the rat. Int J Colorectal Dis 23:857–861

    Article  PubMed  Google Scholar 

  8. Stumpf M, Klinge U, Wilms A, Zabrocki R, Rosch R, Junge K, Krones C, Schumpelick V (2005) Changes of the extracellular matrix as a risk factor for anastomotic leakage after large bowel surgery. Surgery 137:229–234

    Article  PubMed  Google Scholar 

  9. Pasternak B, Matthiessen P, Jansson K, Andersson M, Aspenberg P (2010) Elevated intraperitoneal matrix metalloproteinases-8 and -9 in patients who develop anastomotic leakage after rectal cancer surgery: a pilot study. Colorectal Dis 12:e93–e98

    CAS  PubMed  Google Scholar 

  10. Kiyama T, Onda M, Tokunaga A, Efron DT, Barbul A (2001) Effect of matrix metalloproteinase inhibition on colonic anastomotic healing in rats. J Gastrointest Surg 5:303–311

    Article  CAS  PubMed  Google Scholar 

  11. Ågren MS, Jorgensen LN, Delaissé JM (2004) Matrix metalloproteinases and colon anastomosis repair: a new indication for pharmacological inhibition? Mini Rev Med Chem 4:769–778

    PubMed  Google Scholar 

  12. de Hingh IH, Siemonsma MA, de Man BM, Lomme RM, Hendriks T (2002) The matrix metalloproteinase inhibitor BB-94 improves the strength of intestinal anastomoses in the rat. Int J Colorectal Dis 17:348–354

    Article  PubMed  Google Scholar 

  13. Renkiewicz R, Qiu L, Lesch C, Sun X, Devalaraja R, Cody T, Kaldjian E, Welgus H, Baragi V (2003) Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Arthritis Rheum 48:1742–1749

    Article  CAS  PubMed  Google Scholar 

  14. Ishimura K, Moroguchi A, Okano K, Maeba T, Maeta H (2002) Local expression of tumor necrosis factor-alpha and interleukin-10 on wound healing of intestinal anastomosis during endotoxemia in mice. J Surg Res 108:91–97

    Article  CAS  PubMed  Google Scholar 

  15. Mirastschijski U, Johannesson K, Jeppsson B, Ågren MS (2005) Effect of a matrix metalloproteinase activity and TNF-alpha converting enzyme inhibitor on intra-abdominal adhesions. Eur Surg Res 37:68–75

    Article  CAS  PubMed  Google Scholar 

  16. Matsumoto H, Koga H, Iida M, Tarumi K, Fujita M, Haruma K (2006) Blockade of tumor necrosis factor-alpha-converting enzyme improves experimental small intestinal damage by decreasing matrix metalloproteinase-3 production in rats. Scand J Gastroenterol 41:1320–1329

    Article  CAS  PubMed  Google Scholar 

  17. de Meijer VE, Sverdlov DY, Popov Y, Le HD, Meisel JA, Nose V, Schuppan D, Puder M (2010) Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice. PLoS One 5:e11256

    Article  PubMed  Google Scholar 

  18. Shalinsky DR, Brekken J, Zou H, McDermott CD, Forsyth P, Edwards D, Margosiak S, Bender S, Truitt G, Wood A, Varki NM, Appelt K (1999) Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann NY Acad Sci 878:236–270

    Article  CAS  PubMed  Google Scholar 

  19. Hande KR, Collier M, Paradiso L, Stuart-Smith J, Dixon M, Clendeninn N, Yeun G, Alberti D, Binger K, Wilding G (2004) Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor. Clin Cancer Res 10:909–915

    Article  CAS  PubMed  Google Scholar 

  20. Witte MB, Thornton FJ, Kiyama T, Efron DT, Schulz GS, Moldawer LL, Barbul A (1998) Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength. Surgery 124:464–470

    Article  CAS  PubMed  Google Scholar 

  21. Mirastschijski U, Haaksma CJ, Tomasek JJ, Ågren MS (2004) Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp Cell Res 299:465–475

    Article  CAS  PubMed  Google Scholar 

  22. Christensen H, Andreassen TT, Oxlund H (1992) Age-related alterations in the strength and collagen content of left colon in rats. Int J Colorectal Dis 7:85–88

    Article  CAS  PubMed  Google Scholar 

  23. Sassi ML, Eriksen H, Risteli L, Niemi S, Mansell J, Gowen M, Risteli J (2000) Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 26:367–373

    Article  CAS  PubMed  Google Scholar 

  24. Garnero P, Ferreras M, Karsdal MA, Nicamhlaoibh R, Risteli J, Borel O, Qvist P, Delmas PD, Foged NT, Delaissé JM (2003) The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. J Bone Miner Res 18:859–867

    Article  CAS  PubMed  Google Scholar 

  25. Verhofstad MH, Lange WP, van der Laak JA, Verhofstad AA, Hendriks T (2001) Microscopic analysis of anastomotic healing in the intestine of normal and diabetic rats. Dis Colon Rectum 44:423–431

    Article  CAS  PubMed  Google Scholar 

  26. Seifert WF, Wobbes T, Hendriks T (1996) Divergent patterns of matrix metalloproteinase activity during wound healing in ileum and colon of rats. Gut 39:114–119

    Article  CAS  PubMed  Google Scholar 

  27. Shaper KR, Savage FJ, Hembry RM, Boulos PB (2001) Regulation of matrix metalloproteinases in a model of colonic wound healing in a rabbit. Dis Colon Rectum 44:1857–1866

    Article  CAS  PubMed  Google Scholar 

  28. Vaalamo M, Karjalainen-Lindsberg ML, Puolakkainen P, Kere J, Saarialho-Kere U (1998) Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol 152:1005–1014

    CAS  PubMed  Google Scholar 

  29. Lokuta MA, Huttenlocher A (2005) TNF-alpha promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway. J Leukoc Biol 78:210–219

    Article  CAS  PubMed  Google Scholar 

  30. Reunanen N, Li SP, Ahonen M, Foschi M, Han J, Kähäri VM (2002) Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. J Biol Chem 277:32360–32368

    Article  CAS  PubMed  Google Scholar 

  31. Ipaktchi K, Mattar A, Niederbichler AD, Hoesel LM, Hemmila MR, Su GL, Remick DG, Wang SC, Arbabi S (2006) Topical p38 MAPK inhibition reduces dermal inflammation and epithelial apoptosis in burn wounds. Shock 26:201–209

    Article  CAS  PubMed  Google Scholar 

  32. Zubaidi A, Buie WD, Hart DA, Sigalet D (2010) Temporal expression of cytokines in rat cutaneous, fascial, and intestinal wounds: a comparative study. Dig Dis Sci 55:1581–1588

    Article  CAS  PubMed  Google Scholar 

  33. Salmela MT, Pender SL, Karjalainen-Lindsberg ML, Puolakkainen P, Macdonald TT, Saarialho-Kere U (2004) Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing. Scand J Gastroenterol 39:1095–1104

    Article  CAS  PubMed  Google Scholar 

  34. Sachsenberg-Studer EM, Runne U, Wehrmann T, Wolter M, Kriener S, Engels K, Elshorst-Schmidt T, Kaufmann R, Borradori L (2001) Bullous colon lesions in a patient with bullous pemphigoid. Gastrointest Endosc 54:104–108

    Article  CAS  PubMed  Google Scholar 

  35. Lund LR, Rømer J, Bugge TH, Nielsen BS, Frandsen TL, Degen JL, Stephens RW, Danø K (1999) Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J 18:4645–4656

    Article  CAS  PubMed  Google Scholar 

  36. Sinnamon MJ, Carter KJ, Fingleton B, Matrisian LM (2008) Matrix metalloproteinase-9 contributes to intestinal tumourigenesis in the adenomatous polyposis coli multiple intestinal neoplasia mouse. Int J Exp Pathol 89:466–475

    Article  PubMed  Google Scholar 

  37. Jensen SA, Vainer B, Bartels A, Brünner N, Sørensen JB (2010) Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells—associations with histopathology and patients outcome. Eur J Cancer 46:3233–3242

    Article  CAS  PubMed  Google Scholar 

  38. Wagenaar-Miller RA, Gorden L, Matrisian LM (2004) Matrix metalloproteinases in colorectal cancer: is it worth talking about? Cancer Metastasis Rev 23:119–135

    Article  CAS  PubMed  Google Scholar 

  39. Balcom JH, Keck T, Warshaw AL, Antoniu B, Lauwers GY, Fernandez-del Castillo C (2002) Perioperative matrix metalloproteinase inhibition therapy does not impair wound or anastomotic healing. J Gastrointest Surg 6:488–495

    Article  PubMed  Google Scholar 

  40. Mirastschijski U, Impola U, Karsdal MA, Saarialho-Kere U, Ågren MS (2002) Matrix metalloproteinase inhibitor BB-3103 unlike the serine proteinase inhibitor aprotinin abrogates epidermal healing of human skin wounds ex vivo. J Invest Dermatol 118:55–64

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Michael Engsig was helpful in initiating this project. This research has been supported by a Marie Curie Fellowship of the European Community program Human Potential under contract number HPMF-CT-2001-01429, the Danish Medical Research Council (22-02-0287), and LEO Pharma.

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Authors and Affiliations

  1. Department of Surgery K, Bispebjerg Hospital, Copenhagen, Denmark

    Magnus S. Ågren, Line Andersen & Lars N. Jorgensen

  2. Nordic Bioscience A/S, Herlev, Denmark

    Magnus S. Ågren, Thomas L. Andersen, Christine Bruun Schiødt, Vikas Surve, Jean-Marie Delaissé & Anne-Marie Heegaard

  3. Clinical Cell Biology, Vejle Hospital, Vejle, Denmark

    Thomas L. Andersen & Jean-Marie Delaissé

  4. Institute of Anatomy, University of Aarhus, Aarhus, Denmark

    Troels T. Andreassen

  5. Department of Clinical Chemistry, University of Oulu, Oulu, Finland

    Juha Risteli

  6. Department of Pathology and Cytology, Aleris Medilab, Taby, Sweden

    Lennart E. Franzén

  7. Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark

    Line Andersen & Anne-Marie Heegaard

  8. Department of Surgery K, Bispebjerg Hospital, Bispebjerg Bakke 23, DK, 2400, Copenhagen, Denmark

    Magnus S. Ågren

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  1. Magnus S. Ågren
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Correspondence to Magnus S. Ågren.

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Ågren, M.S., Andersen, T.L., Andersen, L. et al. Nonselective matrix metalloproteinase but not tumor necrosis factor-α inhibition effectively preserves the early critical colon anastomotic integrity. Int J Colorectal Dis 26, 329–337 (2011). https://doi.org/10.1007/s00384-010-1106-3

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