他克莫司对大鼠重症急性胰腺炎和其相关的肺损伤的保护作用

Protection Effect of Tacrolimus on Severe Acute Pancreatitis and Associated Lung Injury in Rats

目的:观察他克莫司(Tacrolimus)对重症急性胰腺炎(SAP)大鼠的潜在治疗作用并探究其机制。方法:健康雌性SD大鼠90只,随机分为对照组、SAP模型组、SAP+Tacrolimus治疗组(0.5、1.0、1.5mg/kg),逆行胆胰管注射5%牛磺胆酸钠制备SAP模型。观察肺组织及胰腺组织的病理变化,检测各组大鼠血清TNF-α及MMP-9表达、支气管肺泡灌洗液(BALF)蛋白含量、胰腺组织髓过氧化物酶(MPO)活性。结果:SAP组胰腺、肺组织病理损伤随病情进展而逐渐加重,经tacrolimus治疗后缓解。SAP大鼠组血清TNF-α及MMP-9表达、肺灌洗液(BALF)蛋白含量及胰腺组织MPO活性较对照显著升高(P<0.01),但是经tacrolimus治疗后升高幅度呈非浓度依赖性的明显降低(P<0.01),各组大鼠存活率提高(P<0.01)。结论:Tacrolimus可有效降低SAP大鼠急性重症胰腺炎的严重程度,其机制可能包括减少肺脏的毛细血管渗透性,抑制由TNF-α,MMP-9以及中性粒细胞(PMN)所释放的MPO等炎症介质产生的炎症反应。

Objective To observe the potential therapeutic effect of tacrolimus against rats severe acute pancreatitis （SAP） and to unravel the underlying mechanisms. Methods Ninety female SD rats were randomly divided into five groups： the control group, the sodium taurocholate group, and the sodium taurocholate groups received 0.5,1.0 and 1.5 mg/kg tacrolimus （n=18 per group）. The SAP model was developed in rats by retrograde injection of 5% sodium taurocholate into biliopancreatic duct through duodenal wall. Histopathological changes of lung and pancreas were observed. Expression of tumor necrosis factor-alpha （TNF-α） and MMP-9 in serum, myeloperoxidase（MPO） activity of pancreatic tissue, and the protein content ofbronchoalveolar lavage fluids（BALF） were detected. The survival rates of each group were evaluated. Results Histopathological stain revealed the gradually aggravated injuries of lung and pancreas in SAP rats which were relieved after exposing to tacrolimus. The expression of TNF-α and MMP-9, the MPO activity of pancreas tissue, and the protein content of BALF were significantly increased in SAP rats （P〈0.01）. However, the increases were significantly down-regulated （P 〈0.01） while the survival rates was raised （P 〈0.01） after treatment with tacrolimus at a non-dose-dependent fashion. Conclusions Tacrolimus could effectively relieve the acute pancreatitis severity and the associated lung injury. The mechanisms may be related to the reduction of lung blood capillarypermeability, the down-regulated inflammatory reaction mediated by TNF-α, MMP-9 and other inflammatory factors, and the decreased MPO activity of pancreas.