4-苯基丁酸对重症急性胰腺炎大鼠肝损伤的保护作用

Protective effect of 4-phenylbutyric acid on severe acute pancreatitis-induced liver injury in rats

目的探讨4-苯基丁酸(4-phenylbutyric acid,PBA)对重症急性胰腺炎(severe acute pancreatitis,SAP)大鼠肝损伤的影响及可能的分子机制。方法采用逆行胰胆管注射5%牛磺胆酸钠溶液(1 mL/kg)建立大鼠SAP肝损伤模型,将24只成年雄性SPF级SD大鼠随机分为假手术组(SO组)、SAP组和PBA组,每组8只。PBA组在SAP造模前3 d经腹腔注射PBA生理盐水溶液(50 mg/kg),SAP组及SO组则经腹腔注射等体积的生理盐水。造模后12 h处死大鼠,采集各组大鼠的血液、胰腺及肝组织,采用全自动多功能生化分析仪检测大鼠血清淀粉酶(amylase,AMY)、谷丙转氨酶(alanine aminotransferase,ALT)及谷草转氨酶(aspartate transaminase,AST)的含量变化;苏木精-伊红(HE)染色光镜下观察大鼠胰腺及肝脏的形态学变化;免疫组织化学法检测各组大鼠肝脏葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)、CCAAT/增强子结合蛋白同源蛋白(CCAAT/enhancer binding protein homologous protein,CHOP)及Caspase-3的表达。结果 SAP组血AMY、ALT和AST水平,胰腺病理学评分,肝脏病理学评级以及肝脏GRP78、CHOP和Caspase-3蛋白的表达均高于SO组(P<0.05),除AMY水平外(P>0.05),PBA组上述各项指标与SAP组相比均降低(P<0.05)。结论 PBA有减轻SAP肝损伤的作用,其机制可能与抑制内质网应激(ERS)并减少细胞凋亡有关。

Objective To investigate the protective effect of 4-phenylbutyric acid （PBA） on liver injury induced by severe acute pancreatitis （SAP） in rats and its possible mechanism. Methods Twenty-four SPF adult male Sprague Dawley rats were randomly divided into three groups： shame operation group （SO group,n=8）, SAP group （n=8）, and PBA group （n=8）. SAP model was induced by retrograde injection of 5% sodium taurocholate （1 mL/kg） in biliopancreatic duct in SAP group and PBA group. PBA solution （50 mg/kg） was administeredvia intraperitoneal injection for 3 days prior to establishing models in PBA group. Rats were injected equivalent saline solution instead of PBA solution in SAP group and SO group. All rats were sacrificed at 12 h after modeling. Blood samples were collected by inferior vena cava puncture, and serum levels of amylase （AMY）, alanine aminotransferase （ALT）, and aspartate transaminase （AST） were measured using a fully automatic chemistry analyzer. The head of pancreas and right lobe of hepatic tissues were harvested and pathological examination was observed under the light microscope. Expressions of glucose-regulated protein 78 （GRP78）, CCAAT/enhancer binding protein homologous protein （CHOP） and Caspase-3 in hepatic tissues were evaluated by immunohistochemistry assay. Results Compared with SO group, the serum levels of AMY, ALT and AST were significantly increased in SAP group （P〈0.05）. The serum levels of ALT and AST in PBA group were significantly lower than those in SAP group （P〈0.05）. There was no difference of the serum levels of AMY between in PBA group and SAP group （P〉0.05）. Compared with SO group, the damages of the pancreas and liver tissues and the expressions of GRP78, CHOP and Caspase-3 in hepatic tissues were significantly increased in SAP group （P〈0.05）. And the above indices in PBA group were significantly decreased when compared with SAP group. Conclusions PBA can alleviate severe acute pancreatitis-induced liver injury, and the mechanism may be associated with inhibition of endoplasmic reticulum stress （ERS） and reduction of hepatocyte apoptosis.