Everolimus interferes with healing of experimental intestinal anastomoses.
BACKGROUND
Although clinical data suggest its existence, little is known about the effect of rapamycin derivatives on wound repair. This study aims to delineate the influence of the mammalian target of rapamycin inhibitor everolimus on wound healing in the rat intestine.


METHODS
Four groups of 26 male Wistar rats received everolimus in daily oral dosages of 0 (controls), 0.5 (group E-0.5), 1.0 (group E-1), and 3.0 (group E-3) mg/kg every 24 hours, respectively, starting four hours before the operation until killing. After resection of 1-cm segments of colon and ileum, intestinal anastomoses were constructed. The animals were killed at days three or seven after operation. Wound healing was assessed by mechanical (bursting pressure, breaking strength), biochemical (collagen content, gelatinase activity), and histologic parameters.


RESULTS
No differences between groups were recorded for any of the parameters on day three. On day seven, a dose-dependent reduction in breaking strength (P<0.05) was measured. The largest effects were found in group E-3 in which the breaking strength was reduced by 56% and 73% in colonic and ileal anastomoses, respectively. A similar pattern was observed with the bursting pressure. Loss of strength was accompanied by a reduction in hydroxyproline content and by a lessened collagen deposition in the wound area but not by an increased gelatinase activity. No further histologic abnormalities were found.


CONCLUSIONS
Everolimus causes a massive reduction in anastomotic strength such as normally observed in the proliferative phase of repair. The data suggest this to be caused by an impaired deposition of collagen in the anastomotic area.
van der Vliet
J Adam
JA
Department of Surgery, Division of Vascular and Transplant Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands. j.vandervliet@chir.umcn.nl
Willems
Martine C M
MC
de Man
Ben M
BM
Lomme
Roger M L M
RM
Hendriks
Thijs
T
D000714:Anastomosis, Surgical; D000818:Animals; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000601:surgery*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D014945:Wound Healing / Q000187:drug effects*
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus