Effects of inhaled FK 506 on the suppression of acute rejection after lung transplantation: use of a rat orthotopic lung transplantation model.
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.
Ingu
Akira
A
Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, Hokkaido, Japan. ashaingu@k6.dion.ne.jp
Komatsu
Kanshi
K
Ichimiya
Shingo
S
Sato
Noriyuki
N
Hirayama
Yoshitaka
Y
Morikawa
Masayuki
M
Abe
Tomio
T
D000280:Administration, Inhalation; D000818:Animals; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007273:Injections, Intramuscular; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D023421:Models, Animal; D051381:Rats; D016559:Tacrolimus / Q000008:administration & dosage*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016559:Tacrolimus