Background and Objective:
Background and Objective: Acetaminophen (APAP) is a widely used antipyretic and analgesic. If taken in excess, it can cause severe drug-induced acute liver injury The purpose of this study was to investigate the effects of anti-TLR4 IgG2 in APAP-induced liver injury and its underlying mechanisms.
Methods:
We injected APAP into the abdominal cavity of mice to establish a liver injury model. Mice were divided into Control group, APAP group, APAP + anti-TLR4 IgG2 group. In order to verify the implication of the toll-like receptor4 and mitogen-activated protein kinases activation (TLR4/MAPKs) signaling pathway, mice were intraperitoneally injected with a TLR4 / MAPKs inhibitor anti-TLR4 IgG2. We evaluated the effects of TLR4 IgG2 on the antioxidant, anti-apoptotic, anti-inflammatory and liver histopathology of APAP mice. In addition, the expression of TLR4 / MAPKs signaling pathway was detected by Western blot.
Results:
Our study showed that APAP mouse models were successfully established, however, pretreatment with anti-TLR4 IgG2 alleviated APAP-induced hepatic injury, as evidenced by 24-h survival rate. Meanwhile, anti-TLR4 IgG2 prevented the elevation of serum biochemical parameters and lipid profile. Furthermore, compared with the APAP group, hepatic antioxidants, including 3-Nitrotyrosine, High mobility group protein B1, superoxide dismutase, catalase, and glutathionewere increased of APAP + anti-TLR4 IgG2 group. In contrast, a significant decrease in levels of the malondialdehyde, which is lipid peroxidation product. Moreover, western blotting analysis showed that anti-TLR4 IgG2 treatment inhibited the activation of apoptotic pathway by increasing Bcl-2 and decreasing Bax, P53, and cleaving caspase-3 / caspase-3 protein expression. These results were further validated by TUNEL staining and immunohistochemical. Histopathological observation also revealed that pretreatment with anti-TLR4 IgG2 can significantly reversed hepatocyte inflammatory infiltration, congestion, and necrosis in liver tissues by APAP. Importantly, anti-TLR4 IgG2 effectively alleviated APAP-induced liver injury by inhibiting toll-like receptor4 and mitogen-activated protein kinases activation signaling pathway (TLR4/MAPKs).
Conclusion:
The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of anti-TLR4 IgG2 in APAP-induced hepatotoxicity may be due to its anti-oxidation, anti-apoptosis, and anti-inflammation effects through inhibition of the TLR4/MAPKs signaling axis.