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J Thorac Cardiovasc Surg 2007;133:548-553
© 2007 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Efficacy and safety of inhaled tacrolimus in rat lung transplantation

^a Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
^b Division of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan.

Received for publication March 22, 2006; revisions received July 17, 2006; accepted for publication September 5, 2006.

^_* Address for reprints: Takeshi Nagayasu, MD, Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan (Email: nagayasu{at}net.nagasaki-u.ac.jp).

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).

CONCLUSION: 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.

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