Mycophenolate mofetil impairs healing of left-sided colon anastomoses.
BACKGROUND
Inadequate healing and consequent leakage from bowel anastomoses are a significant cause of postoperative morbidity and mortality. Immunosuppressive drugs are known to disturb healing processes and to impair the mechanical stability of bowel anastomosis. Mycophenolate mofetil (MMF) is an immunosuppressive agent that selectively inhibits the proliferation of T and B lymphocytes and has been shown to be effective in preventing allograft rejection after organ transplantation. Adverse effects are few; however, nothing is known in regard to possible adverse effects of MMF administration on the healing of bowel anastomosis. The aim of the present study was to evaluate the effect of systemic MMF administration on the healing of colon anastomoses in rats.


METHODS
Rats underwent laparotomy, division of the left colon, and sigmoidostomy. MMF (25 mg/kg) or vehicle was administered intraperitoneally in two groups (n=21 per group) 3 days before surgery and then once daily until 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 anastomotic site were performed. Furthermore, matrix protein expression at the anastomotic site was determined by collagen I and fibronectin Western blots.


RESULTS
Administration of MMF significantly decreased anastomotic bursting pressure postoperatively. Accordingly, histology, mucin staining, and BrdU immunohistochemistry and measurements of the colonic crypt depth showed more extended inflammation, a significantly lower proliferation rate, and a significantly thinned mucosal layer in the MMF-treated groups when compared to control animals, whereas matrix synthesis at the anastomotic site was not different.


CONCLUSIONS
The administration of the immunosuppressive agent MMF significantly impairs healing and mechanical stability of colon anastomosis in rats during the early postoperative period. MMF act to disturb host reparative processes mainly by impairment of reparative colonic epithelium proliferation and less by a disturbance of matrix synthesis.
Zeeh
J
J
Department of Visceral and Transplantation Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland.
Inglin
R
R
Baumann
G
G
Dirsch
O
O
Riley
N E
NE
Gerken
G
G
Büchler
M W
MW
Egger
B
B
D000714:Anastomosis, Surgical; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D005353:Fibronectins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009077:Mucins / Q000378:metabolism; D009173:Mycophenolic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013529:Surgical Wound Dehiscence / Q000209:etiology; D014945:Wound Healing / Q000187:drug effects*
D005353:Fibronectins; D007166:Immunosuppressive Agents; D009077:Mucins; D003094:Collagen; D009173:Mycophenolic Acid