title: Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway.
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.
authors: Department of Infection, Dongfeng Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442008, P.R. China.
authors: Xueqiang
authors: X
authors: Jiang
authors: Department of Pharmacy, Dongfeng General Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442008, P.R. China.
authors: Zhihao
authors: Z
authors: Li
authors: Center of Reproductive Medicine, People's Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442000, P.R. China.
authors: Shengfang
authors: S
authors: Jiang
authors: Shennong Wudang Institute of Traditional Chinese Medicine, Shiyan Hospital of TCM Affiliated to Hubei University of Chinese Medicine, Shiyan, Hubei 442012, P.R. China.
authors: Xuefei
authors: X
authors: Tong
authors: Department of Emergency, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors: Xiaojing
authors: X
authors: Zou
authors: Department of Infection, Dongfeng Hospital Affiliated to Hubei Medical University, Shiyan, Hubei 442008, P.R. China.
authors: Wan
authors: W
authors: Wang
authors: Department of Infection, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors: Zhengang
authors: Z
authors: Zhang
authors: Department of Infection, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors: Liang
authors: L
authors: Wu
authors: Department of Infection, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors: Deying
authors: D
authors: Tian
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects; D044045:Lipoxins / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D044045:Lipoxins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3