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Effects of inhaled FK 506 on the suppression of acute rejection after lung transplantation: use of a rat orthotopic lung transplantation model.

Ingu A, Komatsu K, Ichimiya S, Sato N, Hirayama Y, Morikawa M, Abe T

Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, Hokkaido, Japan. ashaingu@k6.dion.ne.jp

BACKGROUND: FK 506 inhalant was recently developed for localized administration. We investigated its effects on acute lung allograft rejection and compared its efficacy with that of intramuscular administration of FK 506. METHODS: Rats (n = 123) with orthotopic left lung transplantation were divided into 9 groups. Six groups inhaled FK 506 (5 puffs, 10 puffs or 20 puffs per day), or were given intramuscular administration of FK 506 (0.05, 0.1 or 1.0 mg/kg/day). The other groups included rats receiving an isograft, rats with an untreated allograft, and a placebo group. All groups (n = 6 each) were monitored for 14 days post-operatively as an end-point and graft survival time was determined. The remaining animals were killed 4 days after transplantation. The histologic grade of rejection was determined for all groups (n = 6 each). With both (n = 3 each) inhalation therapy and intramuscular administration of FK 506, which showed similar degrees of effectiveness, both blood FK 506 concentration and cytokine expression in the graft and spleen were evaluated. RESULTS: FK 506 inhalation therapy extended allograft survival time and reduced histologic rejection on Day 4 in all groups. Graft survival time and histologic rejection scores at a dose of 10 puffs/day were comparable to those with 0.1 mg/kg/day of intramuscular FK 506. Trough concentrations of FK 506 in blood were detectable with 0.1 mg/kg/day of intramuscular FK 506, but not with 10 puffs/day. The messenger RNA expression levels of interferon-gamma in the lung allograft was suppressed significantly at a dose of 10 puffs/day. CONCLUSIONS: FK 506 inhalant enhances acute lung allograft survival with lower blood concentrations than when using comparable intramuscular administration.

Published 17 May 2005 in J Heart Lung Transplant, 24(5): 538-43.
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