Study On The Expression And Pathogenesis Of MMP-2 And MMP-9 In Patients With Intrahepatic Cholestasis Of Pregnancy

Part I Pathogenesis and identification of novel biomarker for the diagnosis of intrahepatic cholestasis of pregnancy(ICP)Objective: Intrahepatic cholestasis of pregnancy(ICP)is a severe liver disease uniquely occurring during pregnancy.Elevated serum total bile acids(TBA)level was considered as the most sensitive laboratory sign of abnormality in ICP.However,serum TBA level also varies depending on the study population.In this study we aimed to To investigate the role of matrix metalloproteinase(MMP)-2 and MMP-9 in the genesis of ICP and identify novel biomarker for the diagnosis of ICP.Methods: 50 healthy pregnant women,50 mild ICP patients and 48 severe ICP patients were enrolled for this study.Liver function tests,including serum total bilirubin(TBIL),direct bilirubin(DBIL),alanine transaminase(ALT),aspartate aminotransferase(AST)and cholyglycine(CG),were performed in all participants.After an overnight fast,serum levels of TBA,MMP-2 and MMP-9 were measured,and their correlation with liver function tests were analyzed.Results:(1)The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP.(2)Both MMP-2 and MMP-9serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women.(3)There are consistent and significant positive correlations between increases in MMP-2 and MMP-9 levels with almost all liver function test parameters(? > 0.5).Conclusion:(1)MMP-2 and MMP-9 are secreted mainly by syncytiotrophoblast in human placenta.The significant increase of expression levels of MMP-2 and MMP-9might be related to inadequate blood vessel formation and the abnormal invasions oftrophoblast and might play an important role in the pathogenic mechanism of ICP.(2)Serum TBA might not serve as a laboratory abnormality sensitive enough for the diagnosis of ICP,while serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP.Part II Resveratrol reduces matrix metalloproteinases and alleviates intrahepatic cholestasis of pregnancy in ratsObjective: ICP is a severe liver disorder occurring specifically in pregnancy,and MMP-2 and MMP-9 were found to be elevated in ICP patients.Resveratrol(RE),a natural polyphenol commonly existing in many fruits,functions to inhibit both MMP-2 and MMP-9 activities in several animal studies.We therefore aimed to investigate whether RE also functions to inhibit MMP-2 and MMP-9 in ICP,and more importantly whether this function of RE leads to the alleviation of ICP symptoms.Methods: Aiming to study ICP,we first started with setting up an animal ICP model using 17?-ethinylestradiol(EE)to establish an ICP rat model.Using ethinylestradiol-induced ICP rats as the model,we examined the effect of resveratrol on ICP symptoms such as bile flow rate,serum enzymatic activities(ALT,AST,ALP and GGT)and TBA concentration as well as MMP levels,and compared with the known ICP drug ursodeoxycholic acid.Results:(1)EE treatment in pregnant rats could clearly induce symptoms closely mimicking human ICP patients,in another word,EE induced ICP in pregnant rats in our current study.(2)Both MMP-2 and MMP-9 were upregulated in ICP rats,and resveratrol treatment could inhibit the elevation of both MMPs,whereas ursodeoxycholic acid didn't exhibit any effect.(3)Although ursodeoxycholic acid alleviated ICP symptoms,resveratrol treatment in general exhibited better outcome in restoring bile flow rate,serum enzymatic activities(ALT,AST,ALP and GGT)and TBA concentration.Conclusions: To conclude,in our current study,we first administered EE to pregnantrats and established that these EE-induced rats manifested symptoms closely mimicking those of human ICP patients,therefore could serve as ideal animal model for the study of the disease.The significant increase of expression levels of MMP-2 and MMP-9 might play an important role in the pathogenic mechanism of ICP.Moreover,Our results for the first instance strongly supported the potential of RE as a new therapeutic agent in treating ICP,possibly through inhibiting MMP-2 and MMP-9.