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目的观察小剂量N-乙酰半胱氨酸(NAC)注射液对慢性肝损伤大鼠核因子相关因子2(Nrf2)及下游分子血红素氧合酶1(HO-1)和γ谷氨酸-半胱氨酸合成酶(γ-GCS)的影响。方法雄性SD大鼠sc给予25%CCl4橄榄油溶液(1 m L·kg~(-1)),每周3次,连续4周。4周末,将造模成功的大鼠分别ip给予NAC 45,90和180 mg·kg~(-1)及阳性对照谷胱甘肽(GSH)54 mg·kg~(-1),每日1次连续4周。检测血清中谷丙转氨酶(GPT)、谷草转氨酶(GOT)活性及肝组织中超氧化物歧化酶(SOD)、丙二醛(MDA)、GSH、羟脯氨酸(Hyp)含量或活性;HE染色法观察肝组织病理变化;免疫组化检测肝组织Nrf2,HO-1和γ-GCS蛋白表达。结果与正常对照组相比,模型组大鼠血清GPT,GOT,MDA和Hyp明显升高(P<0.01),Nrf2,HO-1和γ-GCS蛋白表达及SOD活性和GSH含量无明显变化;模型组肝细胞广泛脂肪变性,肝组织可见许多大小不等的圆形空泡,部分肝细胞水肿,汇管区伴炎症细胞灶性浸润;与模型组相比,NAC各治疗组大鼠血清GPT和GOT活性明显降低(P<0.01),肝组织SOD活性、GSH和Hyp含量下降(P<0.01,P<0.05),Nrf2,HO-1和γ-GCS蛋白表达增加(P<0.01,P<0.05)。与阳性对照组比较,NAC 45,90和180 mg·kg~(-1)组肝组织Hyp明显降低(P<0.01),NAC 45 mg·kg~(-1)组肝组织Nrf2蛋白表达明显升高(P<0.01)。与NAC 45 mg·kg~(-1)组比较,90和180 mg·kg~(-1)组Nrf2蛋白表达较低(P<0.01)。结论小剂量NAC可能通过调节Nrf2及下游因子HO-1和γ-GCS的表达发挥抗氧化应激作用进而发挥防治慢性肝损伤进展的目的。
Objective To observe the effects of low dose N-acetylcysteine (NAC) injection on the expression of Nrf2 and HO-1 and γ-glutamate in chronic hepatic injury rats. Effect of cysteine synthase (γ-GCS). Methods Male Sprague-Dawley rats were given 25% CCl4 olive oil solution (1 mL · kg -1) sc for 3 weeks a week for 4 weeks. At the end of the 4th week, rats were given NAC 45, 90 and 180 mg · kg -1, and positive control glutathione (GSH) 54 mg · kg -1, ip Times for 4 weeks. Serum alanine aminotransferase (GPT), aspartate aminotransferase (GOT) activity and liver tissue superoxide dismutase (SOD), malondialdehyde (MDA), GSH, hydroxyproline content or activity; HE staining The pathological changes of liver were observed. The expression of Nrf2, HO-1 and γ-GCS in liver tissues were detected by immunohistochemistry. Results Compared with the normal control group, the levels of GPT, GOT, MDA and Hyp in model group were significantly increased (P <0.01), while the expression of Nrf2, HO-1 and γ-GCS did not change significantly. Compared with the model group, the serum levels of GPT and NGF in the NAC groups were significantly lower than those in the untreated group (P <0.01, P <0.05). The activity of GOT decreased significantly (P <0.01), while the activities of SOD, GSH and Hyp in hepatic tissue decreased ). Compared with the positive control group, the Hyp levels in liver tissue of NAC 45,90 and 180 mg · kg -1 group were significantly decreased (P <0.01), and the Nrf2 protein expression of NAC 45 mg · kg -1 group was significantly increased High (P <0.01). Compared with NAC 45 mg · kg -1 group, Nrf2 protein expression was lower in 90 and 180 mg · kg -1 groups (P <0.01). Conclusion Low-dose NAC may play an anti-oxidative stress role by regulating the expression of Nrf2 and downstream factors HO-1 and γ-GCS and thus play a role in prevention and treatment of chronic liver injury.