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Title: [Recombinant Schistosoma japonicum cystatin alleviates acute liver injury in mice by inhibiting endoplasmic reticulum stress, inflammation and hepatocyte apoptosis].
Author: Lu L, Yang X, Zhang H, Liang Y, Shi X, Zhou X.
Journal: Nan Fang Yi Ke Da Xue Xue Bao; 2024 Jun 20; 44(6):1126-1134. PubMed ID: 38977342.
Abstract:
OBJECTIVE: To investigate the protective effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) against acute liver injury induced by lipopolysaccharide (LPS) and D-GalN in mice. METHODS: Adult male C57BL/6J mice with or without LPS/D-GaIN-induced acute liver injury were given intraperitoneal injections of rSj-Cys or PBS 30 min after modeling (n=18), and serum and liver tissues samples were collected from 8 mice in each group 6 h after modeling. The survival of the remaining 10 mice in each group within 24 h was observed. Serum levels of ALT, AST, TNF-α and IL-6 of the mice were measured, and liver pathologies was observed with HE staining. The hepatic expressions of macrophage marker CD68, Bax, Bcl-2 and endoplasmic reticulum stress (ERS)-related proteins were detected using immunohistochemistry or immunoblotting, and TUNEL staining was used to detect hepatocyte apoptosis. RESULTS: The survival rates of PBS- and rSj-Cys-treated mouse models of acute liver injury were 30% and 80% at 12 h and were 10% and 60% at 24 h after modeling, respectively; no death occurred in the two control groups within 24 h. The mouse models showed significantly increased serum levels of AST, ALT, IL-6 and TNF-α and serious liver pathologies with increased hepatic expressions of CD68 and Bax, lowered expression of Bcl-2, increased hepatocyte apoptosis, and up-regulated expressions of ERS-related signaling pathway proteins GRP78, CHOP and NF-κB p-p65. Treatment of the mouse models significantly lowered the levels of AST, ALT, IL-6 and TNF-α, alleviated liver pathologies, reduced hepatic expressions of CD68, Bax, GRP78, CHOP and NF-κB p-p65, and enhanced the expression of Bcl-2. In the normal control mice, rSj-Cys injection did not produce any significant changes in these parameters compared with PBS. CONCLUSION: rSj-Cys alleviates LPS/D-GalN-induced acute liver injury in mice by suppressing ERS, attenuating inflammation and inhibiting hepatocyte apoptosis. 目的: 探讨重组日本血吸虫半胱氨酸蛋白酶抑制剂对LPS/D-GalN诱导的急性肝损伤小鼠的保护作用及机制。方法: 将72只雄性C57BL/6J小鼠（6~8周龄）随机分为正常对照组、LPS/D-GaIN模型组、LPS/D-GaIN+rSj-Cys治疗组和rSj-Cys对照组（n=18）。LPS/D-GaIN组和LPS/D-GaIN+rSj-Cys组小鼠均腹腔注射LPS（10 μg/kg）和D-GaIN（700 mg/kg）造模；造模后30 min，LPS/D-GaIN+rSj-Cys组及rSj-Cys对照组小鼠均腹腔注射rSj-Cys（1.25 mg/kg），正常对照组小鼠注射等体积PBS。造模6 h后，每组随机挑选8只小鼠处死，收集小鼠血清及肝组织，进行后续检测，每组剩余10只分别在3、6、12、24 h观察其生存情况，并计算生存率。检测血清丙氨酸转移酶（ALT）、天冬氨酸转移酶（AST）水平，苏木精-伊红（HE）染色观察各组小鼠肝脏组织病理形态，采用ELISA检测小鼠血清炎性因子肿瘤坏死因子（TNF-α）和白细胞介素（IL-6）表达，采用免疫组化法检测肝组织巨噬细胞表面标记物CD68表达水平，采用免疫组化和免疫印迹法检测肝组织Bax、Bcl-2蛋白水平，采用TUNEL检测肝细胞凋亡情况，采用免疫印迹法检测肝组织内质网应激相关蛋白表达水平。结果: 模型组小鼠12 h生存率为30%，rSj-Cys治疗组小鼠12 h生存率为80%。模型组小鼠24 h生存率为10%，rSj-Cys治疗组小鼠24 h生存率为60%；与正常对照组相比，LPS/D-GaIN模型组小鼠血清中AST、ALT、IL-6、TNF-α含量均显著上升（P<0.01），病理结构损伤严重，肝脏巨噬细胞标志物CD68表达明显增强（P<0.01），促凋亡蛋白Bax表达显著增加（P<0.01），抗凋亡蛋白Bcl-2表达显著降低（P<0.01），肝细胞凋亡水平显著增加，肝组织内质网应激相关信号通路GRP78、CHOP、NF-κB p-p65的蛋白表达水平显著上调（P<0.05或P<0.01）；而LPS/D-GaIN+rSj-Cys治疗组小鼠转氨酶AST、ALT和炎症因子IL-6、TNF-α水平显著下降（P<0.01），肝脏病理损伤程度减轻，肝脏巨噬细胞标志物CD68表达明显降低（P<0.01），Bax表达显著降低（P<0.01），Bcl-2表达显著增强（P<0.01），肝组织内质网应激相关信号通路GRP78、CHOP、NF-κB p-p65的蛋白表达水平下调（P<0.05或P<0.01）；rSj-Cys对照组与正常对照组相比，各指标无统计学差异（P>0.05）。结论: rSj-Cys通过抑制内质网应激，减轻炎症和肝细胞凋亡缓解LPS/D-GalN引起的小鼠急性肝损伤。

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