Intravesical Immune Suppression by Liposomal Tacrolimus in Cyclophosphamide-Induced Inflammatory Cystitis
Intravesical Immune Suppression by Liposomal Tacrolimus in Cyclophosphamide-Induced Inflammatory Cystitis
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DOI：
10.1002/nau.20981
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发表时间：
2011-01-01
影响因子：
2
通讯作者：
Chancellor, Michael B.
中科院分区：
文献类型：
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作者：
Chuang, Yao-Chi;Tyagi, Pradeep;Chancellor, Michael B.
目的：他克莫司具有强有力的免疫抑制作用，促进了其局部应用以达到局部免疫抑制作用。然而，其较差的水溶性在配制生物相容性滴注剂以证明脂质体作为他克莫司载体的研究是合理的方面提出了挑战。研究方法：将成年雌性SD大鼠（N= 52）分为4组，除假手术组（生理盐水注射，ip）外，均注射环磷酰胺（环磷酰胺，200 mg/kg，ip）。其他三组分别滴注生理盐水（1cc，保留1小时）、脂质体（LP-1cc）或脂质体包封的他克莫司（LFK-0.2mg他克莫司/1 ml LP）。除假手术组外，所有组均在第1天和第3天膀胱收获前进行基线膀胱测压，以进行组织学染色（N = 24）。此外，从所有组收集第1天和第3天的4小时基线尿液用于尿液PGE 2测定，并在第3天收集膀胱用于PGE 2和IL 2测定（N= 28）。结果如下：用LFK治疗的大鼠表现出对膀胱炎诱导的炎症反应的抑制，减少了EP 4染色和膀胱过度活动（未治疗的动物中收缩间期减少61.0%），并且使组织和尿液中IL 2和PGE 2水平的数倍升高正常化。在未接受他克莫司治疗的大鼠中，未抑制地塞米松诱导的效应。结论：这是首次报道他克莫司脂质体膀胱内给药的免疫抑制作用。LFK通过调节IL 2、PGE 2和EP 4的功能，显著抑制膀胱炎。这些发现支持了对常规治疗无效的炎性膀胱炎患者进行局部他克莫司治疗的研究。Neurorol。Urodynam。30：421-427，2011. c 2010 Wiley-Liss，Inc.
Aims: Potent immunosuppressive effect of tacrolimus has encouraged its topical application for achieving local antiinflammatory effect. However, its poor aqueous solubility presents challenges in formulating biocompatible instillations to justify the investigation of liposomes as vehicle for tacrolimus. Methods: Adult female Sprague-Dawley rats (N= 52) divided into 4 groups were injected with cyclophosphamide (CYP) (200 mg/kg, ip) except for sham (saline injection, ip). Other three groups were instilled with either saline (1 cc, retained for 1 hr), liposome (LP-1 cc) or liposomal encapsulated tacrolimus (LFK-0.2mg tacrolimus/1 ml LP). Baseline cystometrogram was performed on day 1 and day 3 prior to bladder harvest for histological staining (N = 24) in all groups except sham. In addition, 4-hr baseline urine on day 1 and day 3 was collected from all groups for urine PGE2 assay and bladder harvested for PGE2 and IL2 assay on day 3 (N= 28). Results: Rats treated with LFK demonstrated suppression of CYP induced inflammatory reaction with reduced EP4 staining and bladder overactivity (intercontraction interval 61.0% decrease in untreated animals) as well as normalized the several fold elevation of IL2 and PGE2 levels in tissue and urine. CYP induced effects were not suppressed in rats left untreated with tacrolimus. Conclusions: This is the first report of immunesuppression in bladder by intravesical delivery of tacrolimus using liposomes. LFK significantly inhibited CYP induced inflammatory cystitis through the modulation of IL2, PGE2, and EP4 function. These findings support investigation of local tacrolimus in cases of inflammatory cystitis refractory to conventional therapy. Neurourol. Urodynam. 30: 421-427, 2011. c 2010 Wiley-Liss, Inc.