西罗莫司治疗肝移植术后缺血性胆道损伤

The therapeutic mechanisms of sirolimus treatment for ischemic-type biliary lesions after liver transplantation

目的探讨西罗莫司治疗肝移植术后缺血性胆道损伤（ITBL）的效果及可能机制。方法选取2004年5月至2010年12月临床确诊且具有系列肝脏穿刺活检结果的ITBL患者32例，其中男性25例，女性7例，年龄19—61岁。按是否接受西罗莫司治疗分为治疗组与对照组，在损伤前、损伤期和治疗后3个时段，观察汇管区IL-2、叉头型转录因子（FoxP3）及IL-10的表达、肝功能的变化、胆管损伤程度评分、临床预后。结果发生ITBL时IL-2明显升高（对照组0．138±0．050，治疗组0．141±0．052），而FoxP3和IL-10较前无明显差异；6个月后对照组IL-2、FoxP3及IL-10较治疗前无明显变化，治疗组IL-2（0．107±0．043）较治疗前明显降低（t=2．087，P=0．044），而FoxP3（0．213±0．039）和IL．10（0．187±0．048）较治疗前明显升高（t=-3．822、-4．350，P〈0．01）。发生ITBL时血清ALT、AST、总胆红素、叮-谷氨酰转肽酶、碱性磷酸酶及胆道损伤程度评分较前不同程度地升高；6个月后对照组肝功能指标较治疗前无明显变化，而治疗组肝功能指标较前有不同程度的恢复，胆道损伤程度评分则较治疗前明显降低（4．4±2．4，Z=-2．568，P=0．010）。对照组1年和3年移植物存活率分别为6／13和4／13，治疗组分别为17／19和13／19，两组差异有统计学意义（x2=7．166，P=0．007；妒=5．398，P=0．020）。结论西罗莫司可抑制IL-2的表达，促进FoxP3’调节性T淋巴细胞及IL-10的上调，从而缓解胆道的免疫病理损伤，减少移植物丢失及再次肝移植的可能性。

Objective To investigate the pathogenesis of ischemic-type biliary lesions （ITBLs） in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus. Methods The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years （ranging from 19 to 61 years）. Patients were divided into those who received sirolimus （ sirolimus group） and those who did not （ control group）. The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment. Results Compared with pre-ITBL optical density （OD） values, there was a significantly increase in IL-2 OD（0. 138±0. 050 in control group and 0. 141 ±0. 052 in sirolimus group） , but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-lO OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-20D（O. 107 ± O. 043, t = 2. 087, P = 0. 044 ）, and a significant elevation in FoxP3 （0. 213 ± 0. 039 ） and IL-10 OD （ 0. 187 ± 0. 048 ） in sirolimus group as compared with those when ITBLs were diagnosed（ t = - 3. 822 and - 4. 350, both P 〈 0. 01 ）. There was a significant increase in serum levels of ALT, AST, total bilirubin, T-glutamyl transpeptidase and ALP at the time ITBLs were diagnosedcompared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased （4. 4 ~ 2. 4, Z = - 2. 568, P = 0. 010）. The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the simlimus group （X2 = 7. 166, P = 0. 007; X2 = 5. 398, P = O. 020, respectively）. Conclusions Sirolimus can downregnlate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3 ＋ Treg ceils, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.