Ingu Akira, Komatsu Kanshi, Ichimiya Shingo, Sato Noriyuki, Hirayama Yoshitaka, Morikawa Masayuki, Abe Tomio
Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, Hokkaido, Japan.
J Heart Lung Transplant. 2005 May;24(5):538-43. doi: 10.1016/j.healun.2003.12.009.
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.
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.
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.
FK 506 inhalant enhances acute lung allograft survival with lower blood concentrations than when using comparable intramuscular administration.
FK 506吸入剂最近被开发用于局部给药。我们研究了其对急性肺移植排斥反应的影响，并将其疗效与肌肉注射FK 506的疗效进行了比较。
将123只接受原位左肺移植的大鼠分为9组。6组大鼠吸入FK 506（每天5喷、10喷或20喷），或接受肌肉注射FK 506（0.05、0.1或1.0 mg/kg/天）。其他组包括接受同基因移植的大鼠、未治疗的同种异体移植大鼠和安慰剂组。所有组（每组n = 6）术后监测14天作为终点，并确定移植物存活时间。其余动物在移植后4天处死。确定所有组（每组n = 6）的排斥组织学分级。对于吸入疗法和肌肉注射FK 506中显示出相似疗效的两者（每组n = 3），评估了血液中FK 506浓度以及移植物和脾脏中的细胞因子表达。
FK 506吸入疗法延长了所有组的同种异体移植物存活时间，并在第4天降低了组织学排斥反应。每天10喷剂量下的移植物存活时间和组织学排斥评分与肌肉注射0.1 mg/kg/天的FK 506相当。肌肉注射0.1 mg/kg/天的FK 506可检测到血液中FK 506的谷浓度，但每天10喷则检测不到。每天10喷剂量下，肺同种异体移植物中干扰素-γ的信使核糖核酸表达水平显著受到抑制。
与同等剂量的肌肉注射相比，FK 506吸入剂能以更低的血药浓度提高急性肺同种异体移植物的存活率。
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