Acute liver injury attenuation of a novel recombinant sTNFR through blocking hepatic apoptosis

Abstract

Context: Tumor necrosis factor (TNF) α plays a key role in acute liver injury (ALI) induced by injection of d-galactosamine (D-Gal)/lipopolysaccharide (LPS). A novel recombinant trimeric sTNFRII, sTNFRII-gAD, has been tested to be effective in ameliorating ALI, when administered prior to ALI establishment. This study aims to validate the protective effect of sTNFRII-gAD when given after ALI setup and further explore its effect on hepatic apoptosis.

Materials and methods: The treatments were carried out concomitantly with ALI establishment with clinically approved sTNFRII-Fc (the dimeric sTNFRII) as a positive control. Lethality, liver weight, and serum alanine transaminase were measured, and histological analysis was performed to evaluate liver injury induced by D-Gal/LPS. Additionally, Terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) and Western blot analyses of caspase-3 were used to examine hepatocellular apoptosis.

Results: sTNFRII-gAD given after D-Gal/LPS injection turned out to attenuate animal mortality significantly (p < 0.01), and had better hepatic protection. In terms of apoptosis, both sTNFRII-gAD and sTNFRII-Fc displayed noticeable improvement of apoptosis evidenced by dramatic decline of active caspase-3 compared to the control group.

Conclusions: The results demonstrated that sTNFRII-gAD therapeutically diminished the lethality induced by D-Gal/LPS, possibly through blocking hepatic apoptosis initiated by TNFα. Of note, sTNFRII-gAD was superior to sTNFRII-Fc in some respects, indicating a promising alternative for the therapeutic strategy against the diseases associated with excessive TNFα.

• Acute liver injury
• adiponectin
• apoptosis
• sTNFR
• TNFα

Declaration of interest

This work was sponsored partly by National Major Specific Project for Innovation of New Pharmaceuticals (2009ZX09103-649), Chinese National 863 plan (2012AA02A407), The Scientific Research Fund of Ministry of Public Health (201231029), the Natural Science Foundation of Zhejiang Province (Y2110580, LY12C07001, LY13H100003, LZ14H260001), Zhejiang Provincial Major Research Program (2010C13007), Key Science and Technology Innovation Team of Zhejiang Province, Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, Research Program of Zhejiang Provincial Department of Education (84610007), Science & Technology Innovation Program for College/University Students in Zhejiang Province (2012R413039, 2012R413041). The authors report no declarations of interest.