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Selective matrix metalloproteinase inhibition increases breaking strength and reduces anastomotic leakage in experimentally obstructed colon

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Colonic obstruction causes loss of collagen and impairment of anastomotic integrity by matrix metalloproteinases (MMPs). Unexpectedly, pharmacological MMP inhibition increased anastomotic leakage (AL) in obstructed colon possibly due to the non-selective nature of these compounds and the experimental model applied. We therefore studied the effects of selective MMP inhibition on the healing of anastomoses in colon obstructed by a novel laparoscopic technique.

Methods

Left colon was obstructed in 38 male Sprague-Dawley rats (226–284 g). After 12 h, stenoses were resected and end-to-end anastomoses constructed. Baseline breaking strength was determined in 6 animals on day 0. The remaining 32 rats were randomized to daily treatment with the selective MMP-8, MMP-9, and MMP-12 inhibitor AZD3342 (n = 16) or vehicle (n = 16). On day 3, anastomoses were evaluated for AL and breaking strength. Isolated anastomotic wound tissue was analyzed on total collagen and pepsin-insoluble and pepsin-soluble collagen by hydroxyproline. The soluble collagens were further differentiated into native, measured by Sircol, and fragmented forms.

Results

Baseline breaking strength was maintained with AZD3342 but decreased by 25% (P = 0.023) in the vehicle group. The anastomotic breaking strength of AZD3342-treated rats was 44% higher (P = 0.008) than the vehicle-treated rats. Furthermore, the AL rate was reduced (P = 0.037) with AZD3342 compared with vehicle treatment. AZD3342 treatment influenced neither the total or insoluble collagen concentrations nor the degree of fragmentation of the soluble collagen triple helices.

Conclusion

Selective MMP inhibition increased anastomotic breaking strength and reduced AL after resection of colonic obstruction.

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Authors and Affiliations

  1. Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

    Peter-Martin Krarup, Lars Nannestad Jorgensen, Mark Berner Hansen & Magnus S. Ågren

  2. Department of Pathology, Aalborg Hospital, Aalborg, Denmark

    Mikkel Eld

  3. AstraZeneca Research and Development, Mölndal, Sweden

    Mark Berner Hansen

  4. Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

    Magnus S. Ågren

  5. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Magnus S. Ågren

Authors
  1. Peter-Martin Krarup
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  2. Mikkel Eld
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  3. Lars Nannestad Jorgensen
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  4. Mark Berner Hansen
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  5. Magnus S. Ågren
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Corresponding author

Correspondence to Peter-Martin Krarup.

Ethics declarations

The experiments were approved by the Animal Ethics Committee of the Danish Ministry of Justice (2010/561-1775).

Financial support

The study was supported by AstraZeneca Global R&D, the I.M. Dæhnfeldt Foundation, the A.P. Møller Foundation, and the Danish Medical Association.

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Krarup, PM., Eld, M., Jorgensen, L.N. et al. Selective matrix metalloproteinase inhibition increases breaking strength and reduces anastomotic leakage in experimentally obstructed colon. Int J Colorectal Dis 32, 1277–1284 (2017). https://doi.org/10.1007/s00384-017-2857-x

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  • DOI: https://doi.org/10.1007/s00384-017-2857-x

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