MYCOPHENOLATE MOFETIL IMPAIRS HEALING OF LEFT-SIDED COLON ANASTOMOSES 1

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Abstract
Introduction. Inadequate healing and consequent leakage from bowelanastomoses are a significant cause of postoperative morbidity and mortality.Immunosuppressive drugs are known to disturb healing processes and to impairthe mechanical stability of bowel anastomosis. Mycophenolate mofetil (MMF) isan immunosuppressive agent that selectively inhibits the proliferation of Tand B lymphocytes and has been shown to be effective in preventing allograftrejection after organ transplantation. Adverse effects are few; however,nothing is known in regard to possible adverse effects of MMF administrationon the healing of bowel anastomosis. The aim of the present study was toevaluate the effect of systemic MMF administration on the healing of colonanastomoses inrats. Methods. Rats underwent laparotomy, division of the left colon, andsigmoidostomy. MMF (25 mg/kg) or vehicle was administered intraperitoneally intwo groups (n=21 per group) 3 days before surgery and then once dailyuntil euthanization (7 animals per group; 2, 4, and 6 days after surgery).Bursting pressure measurements, histologic evaluation, morphometric analysis,mucin and collagen staining, and BrdU immunohistochemistry of the anastomoticsite were performed. Furthermore, matrix protein expression at the anastomoticsite was determined by collagen I and fibronectin Westernblots. Results. Administration of MMF significantly decreased anastomoticbursting pressure postoperatively. Accordingly, histology, mucin staining, andBrdU immunohistochemistry and measurements of the colonic crypt depth showedmore extended inflammation, a significantly lower proliferation rate, and asignificantly thinned mucosal layer in the MMF-treated groups when compared tocontrol animals, whereas matrix synthesis at the anastomotic site was notdifferent. Conclusions. The administration of the immunosuppressive agent MMFsignificantly impairs healing and mechanical stability of colon anastomosis inrats during the early postoperative period. MMF act to disturb host reparativeprocesses mainly by impairment of reparative colonic epithelium proliferationand less by a disturbance of matrixsynthesis.