title: Growth hormone abolishes the negative effects of everolimus on intestinal wound healing.
abstract: OBJECTIVE
  To investigate whether the simultaneous treatment with human growth hormone (hGH) abolishes the negative effects of everolimus on anastomotic healing.
  
  
  METHODS
  Forty-eight male Sprague-Dawley-rats were randomized to three groups of 16 animals each (I: vehicle; II: everolimus 3 mg/kg po; III: everolimus 3 mg/kg po + hGH 2.5 mg/kg sc). Animals were pre-treated with hGH and/or everolimus daily for seven days. Then a standard anastomosis was created in the descending colon and treatment was continued for another seven days. The anastomosis was resected in toto and the bursting pressure was assessed as a mechanical parameter of intestinal healing. Moreover, biochemical (Hydroxyproline, PCNA, MPO, MMP-2 and MMP-9) and histological (cell density, angiogenesis, amount of granulation tissue) parameters of intestinal healing were assessed.
  
  
  RESULTS
  Anastomotic bursting pressure was significantly reduced by everolimus and a simultaneous treatment with hGH resulted in considerably higher values (I: 134 ± 19 mmHg, II: 85 ± 25 mmHg, III: 114 ± 25 mmHg; P < 0.05, I vs II; P = 0.09, I vs III and II vs III) Hydroxyproline concentration was significantly increased by hGH compared to everolimus alone (I: 14.9 ± 2.5 μg/mg, II: 8.9 ± 3.6 μg/mg, III: 11.9 ± 2.8 μg/mg; P < 0.05, I vs II/III and II vs III). The number of MPO-positive cells was reduced significantly by hGH compared to everolimus alone (I: 10 ± 1 n/mm², II: 15 ± 3 n/mm², III: 9 ± 2 n/mm²; P < 0.05, I vs II and II vs III), while the number of PCNA-positive cells were increased by hGH (I: 28 ± 3 /mm², II: 12 ± 3 /mm², III: 26 ± 12 /mm²; P < 0.05, I vs II and II vs III). Corresponding to these biochemical findings, HE-histology revealed significantly increased amount of granulation tissue in hGH-treated animals.
  
  
  CONCLUSIONS
  Inhibition of intestinal wound healing by everolimus is partially neutralized by simultaeous treatment with hGH. Both inflammation as well as collagen deposition is influenced by hGH.
authors.affiliation: Markus Alexander Küper, Sebastian Trütschel, Jürgen Weinreich, Alfred Königsrainer, Stefan Beckert, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Markus Alexander
authors.initials: MA
authors.lastname: Küper
authors.affiliation: Markus Alexander Küper, Sebastian Trütschel, Jürgen Weinreich, Alfred Königsrainer, Stefan Beckert, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trütschel
authors.affiliation: Markus Alexander Küper, Sebastian Trütschel, Jürgen Weinreich, Alfred Königsrainer, Stefan Beckert, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weinreich
authors.affiliation: Markus Alexander Küper, Sebastian Trütschel, Jürgen Weinreich, Alfred Königsrainer, Stefan Beckert, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: Markus Alexander Küper, Sebastian Trütschel, Jürgen Weinreich, Alfred Königsrainer, Stefan Beckert, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D000068338:Everolimus / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000494:pharmacology*; D006909:Hydroxyproline / Q000032:analysis; D007422:Intestines / Q000601:surgery*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D019382:Human Growth Hormone; D000068338:Everolimus; D009195:Peroxidase; D058570:TOR Serine-Threonine Kinases; D006909:Hydroxyproline
keywords: Anastomotic healing; Everolimus; Growth hormone; Human growth hormone; Immunosuppression; Wound healing; mTOR-inhibitor