Study On Relevance Of The Injury Effects Of Extracellular Histories On Liver Tissue In The Pathogenesis Of Liver Failure

Objective To investigate the injury effects and mechanisms of extracellular histoneson the liver tissue cells of liver failure patients. Methods Observing the changesof the hepatocytes and endothelial cells in liver tissue by HE staining andImmunohistochemistry. The liver failure patients and healthy volunteers were enrolledin the study. The level of serum histone H3, histone H4, PTA, TBil, Cr andinternational normalized ratio (INR) of the patients were measured. Model for end-stage liver disease (MELD) score was also calculated in the patients. The relevance ofhistones with the MELD score and PTA in the patients was statistically analyzed andthe serum histones levels of the patients and the healthy volunteers were compared.The human liver cell line L-02cells and HUVEC cells were cultured and treated withthe serum of patients or L-02cellular lysate supernatant preincubated with or withoutanti-histone H3and H4antibodies. The cellular morphology and apoptosis wereobserved. Intracellular calcium ion concentration and caspase-3activity were detectedin the cultured L-02cells treated with histones. The L-02cells and HUVEC cells werecultured and treated with histones preincubated with APC. Results It is that severinjury in liver tissue with the death of hepatocytes and endothelial cells and theinflammatory cells infiltrate widely. The levels of serum histones in the LF patients[H3：(5390.29±1032.03) μg/mL/H4：（4205.09±662.34）μg/mL] were muchhigher than those in the healthy volunteers [H3：(42.67±12.80) μg/mL/H4：（40.34±14.56）μg/mL, t=32.76/t=39.74, both P<0.01]. In the patients, serumhistones (H3/H4) levels were negatively correlated with serum PTA（r=-0.325,P=0.038/r=-0.572，P=0.028）, but positively with the MELD score（r=0.359,P=0.021/r=0.568, P=0.007）. Both the serum of patients and L-02lysate was inhibited by anti-histone antibodies. Cellular toxicity of histones result in calciumoverload and caspase-3activation and APC can reduce the cytotoxicity of histones.Conclusion The elevated extracellular histones in the LF patients may aggravatethe liver damage and can be a new target for therapy.