Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
PLoS One. 2013 Jul 16;8(7):e68757. doi: 10.1371/journal.pone.0068757. Print 2013.
Acute-on-chronic liver failure (ACLF) is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc]) prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55) pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF.
Chronic liver disease (liver fibrosis/cirrhosis) was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA), and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN)/lipopolysaccharide (LPS) i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations.
Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL)-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA). This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats.
sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.
慢加急性肝衰竭（ACLF）是一种已确诊的肝脏疾病的急性恶化。阻断 TNF（肿瘤坏死因子）/TNFR（肿瘤坏死因子受体）1 通路可能会减少肝细胞凋亡/坏死，从而降低 ACLF 发展过程中的死亡率。我们已经证明，长效 TNF 拮抗剂（可溶性 TNF 受体：IgG Fc [sTNFR：IgG-Fc]）通过阻断 TNF/TNFR1（TNFRp55）通路来预防/减少急性肝衰竭的发生。然而，目前尚不清楚 sTNFR：IgG-Fc 是否可以在 ACLF 发展过程中抑制肝细胞损伤。
通过反复用人血清白蛋白（HSA）刺激 Wistar 大鼠，诱导慢性肝病（肝纤维化/肝硬化），并通过组织病理学进行确认。用 D-半乳糖胺（D-GalN）/脂多糖（LPS）腹腔内注射诱导有慢性肝病的大鼠发生 ACLF。采集血清和肝脏进行生化、病理和分子生物学检查。
与模拟治疗组相比，sTNFR：IgG-Fc 治疗的 ACLF 大鼠死亡率降低，血清和肝脏中的白细胞介素（IL）-6 水平降低，肝组织中半胱天冬酶-3 活性降低。sTNFR：IgG-Fc 治疗组的肝组织损伤减轻，组织病理学检查结果一致，即肝组织中 Bcl-2 和 Bax 的 mRNA 和蛋白水平降低，但肝细胞增殖（PCNA）增加。这也得到了以下发现的支持，即与模拟治疗组相比，ACLF 组中 caspase-3 的产生明显上调。此外，sTNFR：IgG-Fc 治疗后，caspase-3 的产生被显著抑制。最后，sTNFR：IgG-Fc 治疗的 ACLF 大鼠肝组织中 IL-22R 上调。
sTNFR：IgG-Fc 通过改善肝损伤提高 ACLF 发展过程中的生存率，具有潜在的治疗价值。
