The Mechanism Research Of MAPK/ERK1/2 Signaling Pathway In Progression Of Liver Fibrosis

Liver fibrosis is a sign in progression of chronic liver disease.Thus,to control the progression of chronic liver disease is an effective way to reduce the incidence of end-stage liver diseases.In recent years,the roles of signal pathway in choronic liver disease progression to become a research focus.A meaningful signal pathway can reduce and prevent the incidence of end-stage liver diseases,which could be a therapy target for end-stage liver diseases.This research is divided into two parts,first of all,we found the important role of MAPK/ERK1/2 pathway in chronic hepatitis B viral hepatitis progression.Further,we found the pivotal role of SDF-1/CXCR4 axis and MAPK/ERK1/2 pathway which mediated by it in the process of dimethylnitrosamine-induced liver fibrosis mice.Part? The Role of MAPK/ERK1/2 signaling pathway in the development of chronic hepatitis B fibrosisAims: Explore the role of MAPK/ERK1/2 in Chronic Hepatitis B(CHB)fibrosis progression.Observe the expression levels of ERK1/2 and the downstream factor of NF-k B p65 in chronic hepatitis B in different development phase of Liver stiffness values(LSM),and the level of HBV DNA and HBe Ag,which play an important role to determine the degree of chronic hepatitis B,intervention therapy and control the progression to the end-stage liver disease.Methods: 99 CHB patients were selected in the department of Infectious Disease in the First Affiliated Hospital of Dalian Medical University from June to December 2015 in this study.The clinical history information and serum were collected.Serum liver function,HBV DNA,HBe Ag,the expression of ERK1/2 and NF-k B p65 were measured respectively.The number of LSM measured in patients.According to thenumber of HBV DNA,99 CHB patients were divided into HBV DNA<500IU/ML and HBV DNA?500IU/ML;according to the expression of HBe Ag,all of them were divided into HBe Ag(+)and HBe Ag(-);according to the different number of LSM,99 CHB patients were divided into F0-F1(<7.4KPA),F2(7.4-9.4KPA),F3(9.4-17.5KPA)and F4(>17.5KPA).To compare the expression levels of liver function,ERK1/2 and NF-k B P65 between the different LSM graded group respectively.Results: 1.With the degree of the liver fibrosis increased in CHB patients.The expression levels of liver function ALT,AST,Glob,ALP,GGT,TBil,DBil increased,Alb and CHE decreased.2.The expression levels of ERK1/2 and NF-k B p65 increased when HBV DNA?500IU/ML.Further,the level of ERK1/2 increased significantly(P<0.05).3.The expression levels of ERK1/2 and NF-k B p65 increased when HBe Ag(+).Further,the level of ERK1/2 increased significantly(P<0.05).4.The LSM period was positively to the expression levels of ERK1/2 and NF-k B p65.Compared with the F0-F1 period,the expression levels of ERK1/2 and NF-k B p65 increased(P<0.05).Compared with F2 period,the expression levels of ERK1/2 and NF-k B p65 increased(P<0.05)in F3 period.Compared with F3 period,only the expression level of ERK1/2 increased(P<0.05)in F4 period.Conclusion: 1.With the degree of the liver fibrosis increased in CHB patients.The liver function was sustained damage status.2.The expression levels of ERK1/2 and NF-k B p65 were related to the number of HBV DNA.The level upragulation when HBV DNA?500IU/ML.3.The expression levels of ERK1/2 and NF-k B p65 were related to the expression of HBe Ag.The level upragulation when HBe Ag(+).4.The expression levels of ERK1/2 and NF-k B p65 were proportional to the degree of LSM,which can used to measure the degree of liver fibrosis.Part? The Role of MAPK/ERK1/2 Signaling Pathway in Dimethylnitrosamine-induced Mice Liver Fibrosis Aims: To investigate the mechanism of MAPK/ERK1/2 signaling pathway in dimethylnitrosamine-induced liver fibrosis.Methods: A dimethylnitrosamine-induced liver cirrhosis model was established.General situation,liver function,histological changes,immunofluorescent co-staining,the expression of ?-SMA,ERK1/2 and NF-k B p65 was measured by immunohistochemistry,Western blot and real-time PCR respectively.Results: 1.After dimethylnitrosamine-injected,the general situation and pathological significantly damaged.The liver function ALT,AST,TBil,DBil,ALP in M(model group)1-4W and GGT in M 1-3W increased(P<0.05),Alb in M 1-4W and CHE in M 2-4W decreased(P<0.05).Among the model groups,the liver function damaged was sustained.2.The co-localization staining found that there was only a small amount of the co-localization between CD90 and Alb or CK18 in M 1,2W,while in M 3,4W the co-localization cells have a gradually enhancement.3.The expression of ?-SMA,ERK1/2 and NF-k B p65 levels dramatically up-regulated by Immunohistochemistry(IHC),Western Blot and RT-PCR.Conclusion: 1.In the process of DMN-induced liver fibrosis mice can induce the differentiation of bone marrow mesenchymal stem cells(BMSCs)into hepatocyte-like cells(HLCs);2.By upregulation MAPK/ERK1/2 pathway and the downstream signal of NF-k B p65 lead to the DMN-induced liver fibrosis mice.