Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Jiang,Xueqiang; Li,Zhihao; Jiang,Shengfang; Tong,Xuefei; Zou,Xiaojing; Wang,Wan; Zhang,Zhengang; Wu,Liang; Tian,Deying

doi:10.3892/ijmm.2016.2483

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Authors:
- Xueqiang Jiang
- Zhihao Li
- Shengfang Jiang
- Xuefei Tong
- Xiaojing Zou
- Wan Wang
- Zhengang Zhang
- Liang Wu
- Deying Tian
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Affiliations: Department of Infection, Dongfeng Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442008, P.R. China, Department of Pharmacy, Dongfeng General Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442008, P.R. China, Center of Reproductive Medicine, People's Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442000, P.R. China, Shennong Wudang Institute of Traditional Chinese Medicine, Shiyan Hospital of TCM Affiliated to Hubei University of Chinese Medicine, Shiyan, Hubei 442012, P.R. China, Department of Emergency, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Infection, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: February 5, 2016 https://doi.org/10.3892/ijmm.2016.2483
Pages: 773-780

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Abstract

Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 µg/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 µg/kg), medium dose (1 µg/kg), and high dose (2 µg/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-κB). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro‑inflammatory cytokines TNF-α and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-κB activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-α and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-α and IL-6 mRNA expression, TUNEL‑positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-κB expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-κB activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.

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