Efficacy and safety of inhaled tacrolimus in rat lung transplantation.
OBJECTIVE
Because acute rejection is the most important cause of chronic rejection in lung transplantation, the use of conventional systemic immunosuppression to improve long-term survival needs to be reassessed. The aim of this study was to investigate the efficacy and safety of inhaled tacrolimus for preventing acute rejection of rat lung allografts.


METHODS
Orthotopic left lung transplantation was performed in rats that were divided into 6 groups: control group received no treatment; groups 1.0-IM, 0.5-IM, and 0.3-IM received tacrolimus by intramuscular injection at 1.0, 0.5, and 0.3 mg/(kg.d), respectively; and groups 12-IT and 6-IT received 12 and 6 puffs of inhaled tacrolimus 3 times per day, respectively. Allografts were studied histologically. Whole blood and allograft tacrolimus concentrations were determined.


RESULTS
In groups 1.0-IM and 12-IT, histologic grade of the graft showed significantly less rejection than in the other groups. The blood tacrolimus concentration in group 12-IT (4.87 ng/mL) was significantly lower than that in group 1.0-IM (13.05 ng/mL, P = .0017) on postoperative day 7. Higher allograft tacrolimus concentrations were achieved in group 1.0-IM (478.0 ng/g) than in group 12-IT (270.4 ng/g, P = .009). Weight loss and diarrhea in group 12-IT were less severe than in the groups that received systemic tacrolimus. The proliferating cell nuclear antigen index in bronchus-associated lymphoid tissue cells was significantly lower in group 12-IT than in group 1.0-IM (P = .0209).


CONCLUSIONS
Local immunotherapy with inhaled tacrolimus has great potential for controlling pulmonary allograft rejection in clinical lung transplantation because it has fewer side effects than systemic immunosuppressive agents.
Ide
Noboru
N
Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Nagayasu
Takeshi
T
Matsumoto
Keitarou
K
Tagawa
Tsutomu
T
Tanaka
Kenji
K
Taguchi
Tsunenori
T
Sumida
Yorihisa
Y
Nakashima
Mikiro
M
D000280:Administration, Inhalation; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000379:methods*; D008297:Male; D011336:Probability; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012016:Reference Values; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016559:Tacrolimus / Q000494:pharmacology*; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016559:Tacrolimus