Sirolimus and FK778: a comparison of two anti-proliferative immunosuppressants for prevention of experimental obliterative airway disease.
This study examined the efficacies of sirolimus and the novel immunosuppressive agent FK778 to prevent obliterative airway disease (OAD). Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with sirolimus (0.5 or 2 mg/kg), FK778 (5 or 20 mg/kg), or combination regimens (0.5 + 5 mg/kg, 2 + 20 mg/kg). Tracheal segments were evaluated for degree of luminal obliteration, percentage of luminal epithelial cell coverage, and peritracheal infiltration. In vitro smooth muscle cell (SMC) proliferation and migration assays were performed to assess direct nonimmune-related effects of the drugs. Sirolimus 2 mg/kg and FK778 20 mg/kg effectively reduced graft infiltration and prevented airway obliteration, whereas FK778 5 mg/kg was insufficient. Sirolimus 0.5 mg/kg at least showed moderate inhibitory effects on luminal obliteration and graft infiltration. Combination regimens revealed no significant beneficial effects. Both sirolimus and FK778 barely showed preserved epithelial coverage. Within the range of relevant concentrations, FK778 showed more potent anti-proliferative and anti-migratory effects on SMC in vitro than sirolimus. Both agents proved effective to prevent OAD development without preserving relevant amounts of epithelium. The anti-proliferative potency on SMCs seems to be an especially important mechanism for FK778. De novo combination regimens revealed no beneficial interaction and thus remain doubtful.
Deuse
Tobias
T
Department of Cardiovascular Surgery, University Heart Center, University Hospital Hamburg-Eppendorf, Martinistr, Germany.
Schrepfer
Sonja
S
Koch-Nolte
Friedrich
F
Haddad
Munif
M
Schäfer
Hansjörg
H
Detter
Christian
C
Reichenspurner
Hermann
H
D000480:Alkynes; D000818:Animals; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008173:Lung Diseases, Obstructive / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology; D009570:Nitriles; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D014132:Trachea / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D020123:Sirolimus