GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization

Rehn, Matilda; Krarup, Peter‐Martin; Christensen, Lise; Seidelin, Jakob Benedict; Ågren, Magnus S.; Syk, Ingvar

doi:10.1089/sur.2014.248

Cited by 7 publications

(9 citation statements)

References 43 publications

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“…The noninjured colon segment was snap-frozen in liquid nitrogen and stored at -80°C until analysed for mRNAs. An end-to-end single-layer anastomosis was made using 8 interrupted, inverted polypropylene monofilament 6/0 sutures (Prolene®) placed 2 mm from the resection margins [ 18 , 19 ]. Saline (37°C) was applied to the abdominal cavity (5 mL) and subcutaneous tissue (2.5 mL).…”

Section: Methodsmentioning

confidence: 99%

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Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

Kjær

Russell

Schjerling

et al. 2020

Gastroenterology Research and Practice

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Background. The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. Methods. Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) β1, and soluble collagen proteins were measured on days 3 and 5. Results. ZP1849 treatment increased Ki67 (P<0.0001) and IGF-1 (P<0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased (P=0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels (P<0.0001) and soluble collagen proteins (P<0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 (P<0.001) in both groups. ZP1849 treatment reduced TGF-β1 protein levels on day 5 (P<0.001) but did not impact MMP-7 transcription. Conclusions. The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.

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Section: Methodsmentioning

confidence: 99%

“…On days 3 or 5, rats were anesthetized with N 2 O/isoflurane. The anastomosis was freed of adhesions, resected in toto, transported to Petri dish with saline, and evaluated macroscopically for AL [ 18 ]. The animals were killed by cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

Kjær

Russell

Schjerling

et al. 2020

Gastroenterology Research and Practice

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“…35 There is some evidence in rats that a general tissue protease inhibitor has a beneficial effect during uncomplicated anastomotic healing, yet a detrimental effect after colonic obstruction. 36 The process of creating an anastomosis significantly alters the local microbiota at the site of the anastomosis. 37 There is new evidence that the presence of specific bacterial families and low microbial diversity correlates with anastomotic leakage.…”

Section: The Biology Of Anastomotic Healingmentioning

confidence: 99%

Prevention of Perioperative Anastomotic Healing Complications

Guyton

Hyman

Alverdy

2016

Advances in Surgery

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Synopsis The anastomotic healing complications of postoperative leak and stricture continue to plague surgeons despite many broadly targeted interventions. Evaluation of preventive measure efficacy is difficult due to inconsistent definitions and reporting of these complications. Few interventions have been shown to impact rates of leakage or stricture. However, new evidence is emerging that the intestinal microbiota can play an important role in the development of anastomotic complications. A more holistic approach to understanding the mechanisms of anastomotic complications is needed in order to develop tailored interventions to reduce their frequency. Such an approach may require a more complete definition of the role of the microbiota in anastomotic healing.

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“…Another clinical example is the regeneration of the mucosal epithelium of anastomotic wounds after resection of diseased colorectal tissue. While they are beneficial for normal anastomotic wound healing [9,48], broad-spectrum MMPI therapies are detrimental to anastomotic wound repair under complicated conditions [49]. Under these conditions, nonselective MMPIs severely delay epithelial coverage resulting in increased invasion by pathogenic microorganisms, abscess formation, and anastomosis insufficiencies [49].…”

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confidence: 99%

“…While they are beneficial for normal anastomotic wound healing [9,48], broad-spectrum MMPI therapies are detrimental to anastomotic wound repair under complicated conditions [49]. Under these conditions, nonselective MMPIs severely delay epithelial coverage resulting in increased invasion by pathogenic microorganisms, abscess formation, and anastomosis insufficiencies [49]. Additionally, inhibition of the antimicrobial MMP-12 may contribute to weakening of the host defense [50].…”

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confidence: 99%

Matrix Metalloproteinases: How Much Can They Do?

Ågren

Keller

2020

IJMS

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Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a disintegrin and metalloproteinase domain) and 19 secreted ADAMTSs (a disintegrin and metalloproteinase thrombospondin domain). The many setbacks from the clinical trials of broad-spectrum MMP inhibitors for cancer indications in the late 1990s emphasized the extreme complexity of the participation of these proteolytic enzymes in biology. This editorial mini-review summarizes the Special Issue, which includes four review articles and 10 original articles that highlight the versatile roles of MMPs, ADAMs, and ADAMTSs, in normal physiology as well as in neoplastic and destructive processes in tissue. In addition, we briefly discuss the unambiguous involvement of MMPs in wound healing.

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GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization

Abstract: Non-selective MMP/TACE inhibition with GM6001 increased the anastomotic complications following colon obstruction. Inhibition of epithelialization is one possible mechanism responsible for the increased leakage following GM6001 treatment.

Cited by 7 publications

References 43 publications

Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

Prevention of Perioperative Anastomotic Healing Complications

Matrix Metalloproteinases: How Much Can They Do?

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