title: Everolimus interferes with the inflammatory phase of healing in experimental colonic anastomoses.
abstract: 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.
authors.affiliation: Department of General, Visceral and Transplant Surgery, University of Tübingen, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Küper
authors.forename: Nadja
authors.initials: N
authors.lastname: Schölzl
authors.forename: Frank
authors.initials: F
authors.lastname: Traub
authors.forename: Petra
authors.initials: P
authors.lastname: Mayer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weinreich
authors.forename: Stephan
authors.initials: S
authors.lastname: Coerper
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Steurer
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
mesh_terms: 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
chemical_list: 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