title: Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing.
abstract: To study the effects of COX-2 on colonic surgical wound healing.
  
  
  
  Cyclooxygenase-2 (COX-2) is a key enzyme in gastrointestinal homeostasis. COX-2 inhibitors have been associated with colonic anastomotic leakage.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: *Department of Surgery, Maastricht University Medical Center & Nutrim School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands †Department of Surgery, Zuyderland Medical Center, Sittard-Geleen and Heerlen, The Netherlands ‡Department of Pathology, Zuyderland Medical Center, Sittard-Geleen and Heerlen, The Netherlands §Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Kostan W
authors.initials: KW
authors.lastname: Reisinger
authors.forename: Dirk H S M
authors.initials: DH
authors.lastname: Schellekens
authors.forename: Joanna W A M
authors.initials: JW
authors.lastname: Bosmans
authors.forename: Bas
authors.initials: B
authors.lastname: Boonen
authors.forename: Karel W E
authors.initials: KW
authors.lastname: Hulsewé
authors.forename: Prapto
authors.initials: P
authors.lastname: Sastrowijoto
authors.forename: Joep P M
authors.initials: JP
authors.lastname: Derikx
authors.forename: Joep
authors.initials: J
authors.lastname: Grootjans
authors.forename: Martijn
authors.initials: M
authors.lastname: Poeze
mesh_terms: D000714:Anastomosis, Surgical / Q000009:adverse effects* / Q000379:methods; D057868:Anastomotic Leak / Q000517:prevention & control*; D043925:Angiogenesis Inducing Agents; D000818:Animals; D016009:Chi-Square Distribution; D003107:Colorectal Surgery / Q000009:adverse effects / Q000379:methods; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D014945:Wound Healing / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D051546:Cyclooxygenase 2