| Background:Acute liver failure(ALF)is the rapid development of hepatocellular dysfunction with a high mortality,characterized with impaired protein synthesis and hepatic encephalopathy in a patient without known prior liver disease.The imbalance of immunity is an important pathogenesis of ALF.Neutrophils are the hallmark of acute inflammation,which have an essential role in immune regulation.Outcomes have improved by use of liver transplantation.However,the shortage of donor liver and lifetime immunosuppressant therapy greatly limit its widespread use.Mesenchymal stem cells(MSCs),with the biological characteristics of low immunogenicity,immune regulation and chemotaxis,are considered to be the most promising stem cells to inhibit inflammation and repair tissues.Recent studies showed that MSCs transplantation exhibited considerable effect on ALF.However the underlying mechanism was still unclear.MSCs could modulate phagocytosis and oxidative burst of neutrophil in vitro.Interaction between MSCs and neutrophils in ALF rats may be an underlying therapeutical mechanism.High mobility group box-1 protein(HMGB1),as a late inflammatory mediator,can induce systemic inflammatory.The level of HMGB1 in injured tissue is consistent with recruitment of neutrophil.The expression and release of HMGB1 is closly related to nuclear translocation of NF-?B.The role of neutrophil recruitment mediated by NF-?B-HMGB 1 signal pathway in MSCs treated ALF rats deserves further exploration.Purpose:1.To evaluate the therapeutic effect of MSCs transplantation in ALF rats and to investigate the changes of neutrophils during the treatment.2.To discuss the potential mechanisms of HMGB1 and NF-?B signal pathways on the chemiotaxis and activity of neutrophil in MSCs transplantation for ALF rats.3.To evaluate the therapeutic effect of the combined treatment with MSCs transplantation and neutrophil depletion in ALF rats.Methods:ALF model was induced by D-galactosamine(D-GalN)and lipopolysaccharides(LPS)in rats.The number and activity of neutrophils in both peripheral blood and liver were observed.Bone marrow derived MSCs were cultured in vitro and tanslated to ALF rats by tail vein injection.The therapeutic effect of MSCs and the changes of neutrophils were both detected.Recombinated HMGB1,HMGB1 inhibitor and NF-?B inhibitor were employed to explore the role of NF-?B-HMGB1 sigal pathway in neutrophil modulation.The mechanism underlying the role of HMGB1 and NF-?B signaling pathway was investigated by Immunofluorescence,Western Blot and real-time quantitative PCR.The theraphic effect of combined treatment with MSCs transplantation and neutrophil depletion were eluavated.Results:1.The number and activity of neutrophils was increased in D-GalN/LPS induced ALF rats in both peripheral blood and liver.2.MSCs transplantation could improve the liver function and reduce inflammation in ALF rats by decresing the number and activity of neutrophils.3.HMGB1 could recruit and activate neutrophil;intervention of HMGB1 could reduce neutrophil related liver injury.4.MSC transplantation could decrease HMGB1 and NF-?B level in liver tissues,blockage of NF-?B-HMGB1 signal pathway could reduce the number and activity of neutrophil.5.The combined treatment of MSCs transplantation and neutrophil depletion was better in liver function of ALF rats than single treatment.Conclusion1.MSC transplantation ameliorated liver injury in D-GalN/LPS induced acute liver failure rats,and down-regulated the number and activity of neutrophils in both liver and peripheral blood2.NF-?B-HMGB1 signal pathway may be involved in down-regulation of the number and activity of neutrophil in MSCs treated ALF rats.3.Combined treatment with MSCs transplantation and neutrophil deletion exhibited a better therapeutic effect in ALF rats than monotherapy. |
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