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 Hulsewé, Prapto Sastrowijoto, Joep P M Derikx, Joep Grootjans, Martijn Poeze

Research output: Contribution to journalArticleAcademicpeer-review

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 vs 6 vessels/mm 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

Cite this

Reisinger, K. W., Schellekens, D. H. S. M., Bosmans, J. W. A. M., Boonen, B., Hulsewé, K. W. E., Sastrowijoto, P., ... Poeze, M. (2017). Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing. Annals of Surgery, 265(3), 547-554. https://doi.org/10.1097/SLA.0000000000001744
Reisinger, Kostan W ; Schellekens, Dirk H S M ; Bosmans, Joanna W A M ; Boonen, Bas ; Hulsewé, Karel W E ; Sastrowijoto, Prapto ; Derikx, Joep P M ; Grootjans, Joep ; Poeze, Martijn. / Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing. In: Annals of Surgery. 2017 ; Vol. 265, No. 3. pp. 547-554.
@article{f082aa9dfcea42a4b129cfcebb3a5bb4,
title = "Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing",
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 vs 6 vessels/mm 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.",
keywords = "Anastomosis, Surgical, Anastomotic Leak, Angiogenesis Inducing Agents, Animals, Chi-Square Distribution, Colorectal Surgery, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Diclofenac, Disease Models, Animal, Female, Humans, Immunohistochemistry, Male, Mice, Mice, Knockout, Random Allocation, Real-Time Polymerase Chain Reaction, Risk Assessment, Sensitivity and Specificity, Wound Healing, Comparative Study, Journal Article",
author = "Reisinger, {Kostan W} and Schellekens, {Dirk H S M} and Bosmans, {Joanna W A M} and Bas Boonen and Hulsew{\'e}, {Karel W E} and Prapto Sastrowijoto and Derikx, {Joep P M} and Joep Grootjans and Martijn Poeze",
year = "2017",
month = "3",
doi = "10.1097/SLA.0000000000001744",
language = "English",
volume = "265",
pages = "547--554",
journal = "Annals of Surgery",
issn = "0003-4932",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

Reisinger, KW, Schellekens, DHSM, Bosmans, JWAM, Boonen, B, Hulsewé, KWE, Sastrowijoto, P, Derikx, JPM, Grootjans, J & Poeze, M 2017, 'Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing' Annals of Surgery, vol. 265, no. 3, pp. 547-554. https://doi.org/10.1097/SLA.0000000000001744

Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing. / Reisinger, Kostan W; Schellekens, Dirk H S M; Bosmans, Joanna W A M; Boonen, Bas; Hulsewé, Karel W E; Sastrowijoto, Prapto; Derikx, Joep P M; Grootjans, Joep; Poeze, Martijn.

In: Annals of Surgery, Vol. 265, No. 3, 03.2017, p. 547-554.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing

AU - Reisinger, Kostan W

AU - Schellekens, Dirk H S M

AU - Bosmans, Joanna W A M

AU - Boonen, Bas

AU - Hulsewé, Karel W E

AU - Sastrowijoto, Prapto

AU - Derikx, Joep P M

AU - Grootjans, Joep

AU - Poeze, Martijn

PY - 2017/3

Y1 - 2017/3

N2 - 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 vs 6 vessels/mm 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.

AB - 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 vs 6 vessels/mm 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.

KW - Anastomosis, Surgical

KW - Anastomotic Leak

KW - Angiogenesis Inducing Agents

KW - Animals

KW - Chi-Square Distribution

KW - Colorectal Surgery

KW - Cyclooxygenase 2

KW - Cyclooxygenase 2 Inhibitors

KW - Diclofenac

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Random Allocation

KW - Real-Time Polymerase Chain Reaction

KW - Risk Assessment

KW - Sensitivity and Specificity

KW - Wound Healing

KW - Comparative Study

KW - Journal Article

U2 - 10.1097/SLA.0000000000001744

DO - 10.1097/SLA.0000000000001744

M3 - Article

VL - 265

SP - 547

EP - 554

JO - Annals of Surgery

JF - Annals of Surgery

SN - 0003-4932

IS - 3

ER -

Reisinger KW, Schellekens DHSM, Bosmans JWAM, Boonen B, Hulsewé KWE, Sastrowijoto P et al. Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing. Annals of Surgery. 2017 Mar;265(3):547-554. https://doi.org/10.1097/SLA.0000000000001744