title: Suppression of bronchiolitis obliterans in allogeneic rat lung transplantation--effectiveness of everolimus.
abstract: BACKGROUND
  Chronic rejection (CR) after lung transplantation (LTX) manifests pathologically by fibrotic airway remodelling and bronchiolitis obliterans (BO). The role of the mammalian target of rapamycin inhibitor everolimus in preventing this process is poorly understood.
  
  
  METHODS
  A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to analyze the effect of everolimus (2.5 mg/kg/day) on the development of CR. Drug therapy began on postoperative day (POD) 0, 7 and 14 characterizing different grade of acute rejection (AR) of the allograft before drug treatment.
  
  
  RESULTS
  Non-treated recipients developed severe acute rejection (AR) and first signs of CR on POD 20 and a pronounced CR on POD 60. On POD 20, only application of everolimus from POD 0 to 60 significantly reduced acute inflammatory infiltration (p<0.001). Independent of treatment scheme, everolimus suppressed the development of early signs of chronic alterations (POD 20). However, neither early (POD 7-60) nor late (POD 14-60) application of everolimus affected the progression of CR (POD 60). Only its initial treatment (POD 0-60) inhibited the development of BO and vasculopathy (p<0.001). An additional finding was a decrease in body weight after drug application.
  
  
  CONCLUSIONS
  The effectiveness of everolimus after rat LTX depended on the grade of inflammation of the allograft before initiation of drug treatment. Only allografts with no or low grade AR benefit from long-term treatment with everolilmus in the prevention of BO after LTX. It could be speculated that conversion to an everolimus-based immunosuppression after LTX might only be successful in patients free of BO.
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center Regensburg, Germany. marietta.suesskind-von@klinik.uni-regensburg.de
authors.forename: Marietta
authors.initials: M
authors.lastname: von Suesskind-Schwendi
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brunner
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Hirt
authors.forename: Claudius
authors.initials: C
authors.lastname: Diez
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.forename: Thomas
authors.initials: T
authors.lastname: Puehler
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Karla
authors.initials: K
authors.lastname: Lehle
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D000068338:Everolimus; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus