Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing

Kostan W. Reisinger*, Dirk H. S. M. Schellekens, Joanna W. A. M. Bosmans, Bas Boonen, Karel W. E. Hulsewe, Prapto Sastrowijoto, Joep P. M. Derikx, Joep Grootjans, Martijn Poeze

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

Abstract

Objective: To study the effects of COX-2 on colonic surgical wound healing.

Background: Cyclooxygenase-2 (COX-2) is a key enzyme in gastrointestinal homeostasis. COX-2 inhibitors have been associated with colonic anastomotic leakage.

Methods: Wildtype, COX-2 knockout and COX-2 heterozygous mice were subjected to a model of colonic anastomotic leakage, and were treated with vehicle, diclofenac, or prostaglandin E2 (PGE2), the most important COX-2 product in the intestine. We assessed anastomotic leakage, mortality, angiogenesis, and inflammation. Furthermore, we investigated the association between anastomotic leakage and a human polymorphism of the COX-2 gene resulting in low COX-2 levels.

Results: Diclofenac, a nonsteroidal anti-inflammatory drug inhibiting COX-2, increased anastomotic leakage compared to vehicle-treated mice (100% vs 25%, respectively). Similarly, 92% of COX-2-deficient mice developed anastomotic leakage (P = 0.003) compared to WT. PGE2 partly rescued this severe phenotype because only 46% of PGE2-administered COX-2 knockout mice developed anastomotic leakage (P = 0.02). This may be related to decreased neovascularization, because decreased CD31 staining, indicating less blood vessels, was observed in COX-2(-/-) mice (2 vessels/mm(2) vs 6 vessels/mm(2) in controls (P = 0.03)). This effect could partly be reversed by administration of PGE2 to COX-2(-/-) mice. No significant differences in inflammation were found. PTGS2-765G>C polymorphism in humans, associated with reduced COX-2 expression, was associated with higher anastomotic leakage rates.

Conclusions: COX-2-induced PGE2 production is essential for intestinal wound healing after colonic surgery, possibly via its effects on angiogenesis. These data emphasize that COX-2 inhibitors should be avoided after colonic surgery, and administration of PGE2 might be favorable for a selection of patients.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalAnnals of Surgery
Volume265
Issue number3
DOIs
Publication statusPublished - Mar 2017

Keywords

  • anastomotic leakage
  • colorectal surgery
  • cyclooxygenase-2
  • diclofenac
  • prostaglandin E2
  • ptgs2
  • PTGS2-765G > C
  • NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • ERAS(R) SOCIETY RECOMMENDATIONS
  • SURGERY ENHANCED RECOVERY
  • MESENCHYMAL STEM-CELLS
  • PERIOPERATIVE CARE
  • PROMOTER VARIANT
  • COLONIC SURGERY
  • LEAKAGE
  • RISK
  • CANCER

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