4-苯基丁酸经肌醇需求酶1α信号通路在大鼠重症急性胰腺炎肝损伤中的作用

Effects of 4-Phenylbutyric acid on severe acute pancreatitis-induced liver injury in rats by inositol requiring enzyme-1α signaling pathway

目的探讨4-苯基丁酸(PBA)经肌醇需求酶1α(IRE1α)信号通路在重症急性胰腺炎(SAP)肝损伤中的作用及其机制。方法将36只SD大鼠随机分为3组(n=12):假手术组(SO组)、重症急性胰腺炎组(SAP组)和4-苯基丁酸组(PBA组)。建立大鼠SAP肝损伤模型12 h后处死大鼠,检测血清淀粉酶(AMY)、谷丙转氨酶(ALT)、谷草转氨酶(AST)水平及肿瘤坏死因子-α(TNF-α)的表达;观察肝脏病理学改变及细胞凋亡情况,检测肝脏葡萄糖调节蛋白78(GRP78)、IRE1α、核因子-B p65(NF-κB p65)、人核因子κB抑制蛋白(IκB)、磷酸化c-Jun氨基末端激酶(p-JNK)、B细胞淋巴瘤-2(bcl-2)、半胱氨酰天冬氨酸特异性蛋白酶(Caspase)-3的蛋白水平表达。结果与SO组比较,SAP组大鼠血清AMY[(5 570.6±564.2)比(871.6±222.5)]、ALT[(130.3±23.1)比(42.4±12.3)]、AST[(462.9±63.3)比(166.5±41.8)]水平及TNF-α[(264.8±30.9)比(118.6±30.3)]表达上升(P<0.05);肝细胞坏死及凋亡程度增加;肝脏GRP78、IRE1α、p-JNK、NF-κB p65、Caspase-3蛋白[(0.73±0.07)比(0.55±0.03)、(0.79±0.08)比(0.57±0.04)、(0.58±0.04)比(0.33±0.01)、(0.59±0.05)比(0.45±0.02)、(0.80±0.06)比(0.51±0.03)]表达增加,IκB、bcl-2蛋白[(0.36±0.03)比(0.47±0.02)、(0.52±0.04)比(0.73±0.03)]表达水平降低(P<0.05)。与SAP组比较,PBA组大鼠血清AMY[(4 816.9±797.8)比(5 570.6±564.2)]、ALT[(93.3±11.2)比(130.3±23.1)]、AST[(232.8±28.6)比(462.9±63.3)]水平及TNF-α[(186.7±25.1)比(264.8±30.9)]表达下降(P<0.05);肝细胞坏死及凋亡程度降低;肝脏GRP78、IRE1α、p-JNK、NF-κB p65、Caspase-3蛋白水平[(0.65±0.05)比(0.73±0.07)、(0.63±0.03)比(0.79±0.08)、(0.46±0.03)比(0.58±0.04)、(0.52±0.04)比(0.59±0.05)、(0.66±0.05)比(0.80±0.06)]表达降低,IκB、bcl-2蛋白[(0.42±0.04)比(0.36±0.03)、(0.61±0.02)比(0.52±0.04)]表达水平升高(P<0.05)。结论PBA可能通过阻断IRE1α信号通路,减轻炎性反应,减少细胞凋亡,对重症急性胰腺炎大鼠肝损伤起保护作用。

Objective To explore the effects of 4-Phenylbutyric acid (PBA) on severe acute pancreatitis (SAP)-induced liver injury in rats by inositol requiring enzyme-1α(IRE1α) signaling pathway. Methods Thirty-six SD rats were randomly divided into three groups (n=12): shame operation (SO) group, SAP group and 4-Phenylbutyric acid (PBA) group. All rats were sacrificed at 12 h after the SAP model to measure the serum levels of anylase (AMY), alanine aminotransferase (ALT), glutamic oxalacetic transaminase (AST) and the contents of tumor necrosis factor-α(TNF-α). Liver was collected to exam the pathological changes, the apoptosis and the expression of GRP78, IRE1α, nuclear factor-κB (NF-κB) p65, inhibitor of NF-κB (IκB), phosphorylated c-Jun N-terminal kinase (p-JNK), bcl-2, cysteinyl aspartate-specific protease (Caspase)-3. Results Compared with SO group, the serum levels of AMY [(5 570.6±564.2) vs.(871.6±222.5)], ALT [(130.3±23.1) vs.(42.4±12.3)] and AST [(462.9±63.3) vs.(166.5±41.8)], as well as the expression of TNF-α[(264.8±30.9) vs.(118.6±30.3)] were raised (P<0.05);the degree of hepatic necrosis and apoptosis was higher;the expression of GRP78, IRE1α, p-JNK, NF-κB p65, Caspase-3 [(0.73±0.07) vs.(0.55±0.03),(0.79±0.08) vs.(0.57±0.04),(0.58±0.04) vs.(0.33±0.01),(0.59±0.05) vs.(0.45±0.02),(0.80±0.06) vs.(0.51±0.03)] was increased and the expression of IκB and bcl-2 [(0.36±0.03) vs.(0.47±0.02),(0.52±0.04) vs.(0.73±0.03)] was decreased in SAP group (P<0.05). Compared with SAP group, the serum levels of AMY [(4 816.9±797.8) vs.(5 570.6±564.2)], ALT [(93.3±11.2) vs.(130.3±23.1)] and AST [(232.8±28.6) vs.(462.9±63.3)], as well as the expression of TNF-α[(186.7±25.1) vs.(264.8±30.9)] were reduced (P<0.05);the degree of hepatic necrosis and apoptosis was lower;the expression of GRP78, IRE1α, p-JNK, NF-κB p65, Caspase-3 [(0.65±0.05) vs.(0.73±0.07),(0.63±0.03) vs.(0.79±0.08),(0.46±0.03) vs.(0.58±0.04),(0.52±0.04) vs.(0.59±0.05),(0.66±0.05) vs.(0.80±0.06)] was decreased and the expression of IκB and bcl-2 [(0.42±0.04) vs.(0.36±0.03),(0.61±0.02) vs.(0.52±0.04)] was increased in PBA group (P<0.05). Conclusion PBA may reduce inflammation and apoptosis by inhibiting the IRE1α signaling pathway to protect severe acute pancreatitis-induced liver injury in rats.