Everolimus interferes with the inflammatory phase of healing in experimental colonic anastomoses.
BACKGROUND
Delayed wound healing is a serious side effect of mTOR inhibitor-based immunosuppression after solid organ transplantation. The aim of this study was to test the hypothesis that the mTOR inhibitor everolimus interferes with the inflammatory phase of healing in experimental colonic anastomoses.


METHODS
Thirty male Sprague-Dawley rats received a colonic anastomosis. Then, animals were randomized to three groups of daily treatment with either vehicle or everolimus in two different dosages (1.0mg/kg or 3.0mg/kg). After 7 d, rats were sacrificed, and mechanical, histologic, and biochemical parameters of intestinal healing were assessed.


RESULTS
Anastomotic bursting pressure was significantly decreased by everolimus in both dosages, whereas hydroxyproline content was reduced only by the high everolimus dosage. Everolimus diminished cellular proliferation and new vessel growth. Furthermore, both quantity as well as quality of newly synthesized collagen fibers in the anastomotic granulation tissue was reduced. On the other hand, myeloperoxidase-positive (MPO) cells and interleukin-6 (IL-6) concentrations were increased, as was the activity of matrix-metalloproteinases MMP-2 and MMP-9.


CONCLUSIONS
Everolimus interferes with the inflammatory phase of healing. However, it remains unclear whether this phenomenon is involved in everolimus impairment of experimental anastomotic repair.
Küper
Markus A
MA
Department of General, Visceral and Transplant Surgery, University of Tübingen, Germany.
Schölzl
Nadja
N
Traub
Frank
F
Mayer
Petra
P
Weinreich
Jürgen
J
Coerper
Stephan
S
Steurer
Wolfgang
W
Königsrainer
Alfred
A
Beckert
Stefan
S
D000714:Anastomosis, Surgical; D000818:Animals; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D000068338:Everolimus; D006909:Hydroxyproline / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D023421:Models, Animal; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D007166:Immunosuppressive Agents; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D000068338:Everolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline; D020123:Sirolimus