title: Everolimus Improves Microcirculatory Derangements in Experimental Postischemic Pancreatitis Modulating the Expression of Vascular Endothelial Growth Factor, Interleukin 6, and Toll-Like Receptor 4.
abstract: OBJECTIVE
  Ischemia/reperfusion injury (IRI) of the pancreas is a serious complication following pancreatic transplantation and hemorrhagic shock. The present study was designed to investigate the influence of the potent mammalian target of rapamycin inhibitor everolimus interfering via microvascular permeability changing key proteins hypoxia-inducible factor (HIF) and vascular endothelial growth factor on pancreatic IRI-induced microvascular disturbances.
  
  
  METHODS
  Anesthetized male Sprague-Dawley rats were assigned to 3 groups (n = 7/group): (1) sham, (2) 60-minute ischemia/reperfusion of the pancreas (I/R), and (3) I/R and everolimus (10 mg/kg BW orally). Quantification of the effective microvascular permeability (P), functional capillary density (FCD), and leukocyte-endothelial cell interaction (LEI) was performed using digital and analog intravital epifluorescence microscopy. Serum-amylase, lipase, interleukin 6, and vascular endothelial growth factor concentration were quantified using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Sham compared with I/R (P: [×10 cm/s] 0.068 ± 0.079 vs 1.516 ± 0.314; FCD: [cm/cm] 357 ± 14 vs 258 ± 13; LEI: [cells/mm] 148 ± 25 vs 349 ± 75) demonstrates a significant increase in microcirculatory damage and all previously mentioned serum parameters. Except amylase, I/R + everolimus led to a statistically significant improvement of almost all increased parameters (P: 0.434 ± 0.296, FCD: 347 ± 16, LEI: 178 ± 30).
  
  
  CONCLUSIONS
  Everolimus attenuated experimental microvascular and inflammatory IRI of the pancreas. Therefore, these results may warrant further investigation of everolimus as a therapeutic agent following clinical states with pancreatic ischemia/reperfusion.
authors.affiliation: From the *Clinic of General and Visceral Surgery, University of Freiburg, Freiburg; †Section of Endocrine Surgery, Clinic of General, Visceral, and Thoracic Surgery, St Adolf-Stift, Academic Teaching Hospital University of Hamburg, Reinbek; and ‡Clinic for Surgery, University Clinic Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meyer
authors.forename: Hannes
authors.initials: H
authors.lastname: Neeff
authors.forename: Oliver
authors.initials: O
authors.lastname: Thomusch
authors.forename: Tim
authors.initials: T
authors.lastname: Strate
authors.forename: Dietlind
authors.initials: D
authors.lastname: Tittelbach-Helmrich
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hopt
authors.forename: Ernst
authors.initials: E
authors.lastname: von Dobschuetz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000068338:Everolimus / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D010195:Pancreatitis / Q000097:blood / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000097:blood
chemical_list: D007166:Immunosuppressive Agents; D015850:Interleukin-6; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus