组织蛋白酶B及胱蛋白酶抑制剂C在正常妊娠及子痫前期变化的研究
摘要
本文为研究组织蛋白酶B(cathepsin B,CB)及胱蛋白酶抑制剂C(cystatin C,CysC)与正常妊娠及子痫前期(preeclampsia,PE)、子痫的关系,采用酶联免疫吸附试验(ELISA)检测健康未孕妇女、正常妊娠各期妇女和PE、子痫妇女肘静脉血清中CB及CysC的水平;采用免疫组织化学方法检测正常晚孕妇女及子痫前期、子痫患者胎盘中CB的表达。结果表明:1.妊娠妇女血清中CB明显低于未孕妇女,随孕周增加有下降趋势;2.母血中CysC在早期妊娠妇女较未孕妇女明显减低,中期妊娠及晚期妊娠又有明显升高。3.PE、子痫组母血中CB与正常晚孕组无明显变化;4.PE组母血中CysC较正常晚孕组明显升高,且与疾病严重程度正相关;5.免疫组化发现CB主要表达于绒毛及蜕膜细胞及间质中。PE组胎盘表达CB较正常晚孕组明显增强,且与疾病的严重程度呈正相关。推测CC和CysC与生理妊娠胎盘的发育生长及子痫前期子痫的发生发展有关。
Hypertensive disorder complicating pregnancy is a specific complication , characterized by hypertension and proteinuria with women during their gestational age after 20 weeks.There are systemic organic damage in preeclampsia and eclamsia.The basic pathological change is generalized spasm of arteriolae.It may worsen to be swith,comacerebral hemorrhage,heart failure,placental abruption, DIC,even death. Cathepsin B is a crucial proteo- lysis enzyme with srong function of protein hydrolyze.Cathepsin B participates in the degradation and translation of many proteins,cell apoptosis ,regeneration of blood vessel,froliferation and metastasis of tumors.So,the activity of CB must be controled by the inhibitors,in which cystatin C is the most effective one. Cathepsin B and cystatin C play an important role in physiological pregnancy and preeclampsia.
Objective:
We first invesigated the expression of CB and CysC in materal blood from normal pregnant women at three terms and preeclamptic pregnant women at term pregnancy.Then we studied the expression of CB in the placentae of normal and preeclamptic pregancy women at term.Through investigaging the changes of CB and CysC,we try to study the effect of CB-CysC in the development of normal pregnancy and pathogenesis of hypertensive disorder complicating pregnancy.It may help us to determine the etiology and to defend and treat the disease.
Methodes:
This study by enzyme-linked immunosorbent assay (ELISA) detected healthy women 15 cases, 55 cases of normal pregnant women (including 15 cases of early pregnancy, the medium-term pregnancy 20 cases, 20 cases of late pregnancy), 50 cases of preeclamptic and eclamptic women (including 15 patients with mild preeclampsia, severe preeclampsia 20 cases, 15 cases of eclampsia group) CB and intravenous serum inhibitor CysC level in cubital wein . We also use immunohistochemical methods to detect the placental CB expression in 10 cases of late pregnancy women , and preeclampsia-eclampsia women 30 cases (including 10 cases of mild preeclampsia, severe preeclampsia 10 cases, 10 cases of eclampsia group).
Results:
1. Blood comparison of CB and CysC among non-pregnant group and different periods of pregnancy.
(1)Compare to the non-pregant group ,CB in early pregnancy group is lower,but the difference was not statistically significant (p = 0.39). CB level in the serum of medium-term pregnancy women is lower than early pregnancy group (p = 0.09), there was no significant difference. And CB level in the serum of medium-term pregnancy women is lower than non-pregnant group significantly (p <0.01).CB in late pregnancy group is lower than non-pregant group and early pregnancy group(p <0.01). There was no significant difference between medium-term pregnancy women and late pregnancy women(p = 0.09).
(2)Maternal blood CysC level in early pregnancy group is significantly lower than non-pregnant group (p <0.05), and CysC in medium-term pregnancy women increased significantly compared with early pregnant group(p <0.05), there was no significant difference between non-pregnant group and medium-term pregnancy group(p = 0.46). CysC in late pregnancy women was significantly higher than that of non-pregnant women (p <0.01),early pregnancy women (p <0.01) and medium-term pregnancy (p <0.01).
2. The alteration of serum CB and CysC in pre-eclamptic and eclamptic women.
(1)There is not significant difference in the serum CB among mild, severe pre-eclampsia and eclampsia and the normal late pregnancy (p>0.05).
(2)Serum CysC in patients with mild pre-eclampsia group is higher than late uncomplicated pregnancy women, but the difference was not significant (p = 0.48).Maternal blood CysC in severe preeclampsia group compared with late pregnancy significantly increased (p <0.01).CysC in severe preeclampsia group compared with mild preeclampsia group was significantly increased (p <0.05). There was no significant difference in maternal blood CysC between severe preeclampsia and eclampsia group(P = 0.63).
3. CB expression in the placentae of preeclamptic and eclamptic women .
(1)The placental expression and distribution of CB are consistent among normal pregnancy group,preeclamptic group,and eclamptic group.CB expres- sed in the cells and matrix of decidua and chorionic villi. There is no difference in the expression of CB between the decidua and the villi.
(2)CB expression in the placentae of mild preeclampsia compared with normal pregnancy group noticeably increased(P <0.05).CB expression in the placentae of severe preeclampsia increased obviously compared with normal pregnancy group (P <0.01)and mild preeclampsia group(P <0.05) .
(3)Eclamptic CB expression in the placentae is obviously stronger than normal pregnancy group(P <0.01)and mild preeclampsia group(P <0.05). Severe preeclampsia and eclampsia group CB expression group showed no significant difference(P = 0.353).
Conclusion:
(1)CB and CysC play an important role in the growth and development of the placenta and the occurrence of preeclampsia and eclampsia .
(2)CB in the serum of pregnancy women was lower than non-pregant women, and there is downward trend with the pregnancy week increased.
(3)CysC in maternal blood of early pregnancy women significantly reduced compared with non-pregant women,but the CysC level of pregnantcy women in medium-term pregnancy and late pregnancy increased significantly.
(4)CB levels in maternal blood group has no obvious correlation with the severity of PE and eclampsia.
(5)CysC in maternal blood group was significantly increased than the normal pregnancy women,and the level is related with the severity of PE .
(6)CB expressed mainly in the matrix and cells of decidua and villus. The expression of CB in PE group is significantly enhanced than normal placentae and with the severity of the disease was positively correlated.
Hypertensive disorder complicating pregnancy is a specific complication , characterized by hypertension and proteinuria with women during their gestational age after 20 weeks.There are systemic organic damage in preeclampsia and eclamsia.The basic pathological change is generalized spasm of arteriolae.It may worsen to be swith,comacerebral hemorrhage,heart failure,placental abruption, DIC,even death. Cathepsin B is a crucial proteo- lysis enzyme with srong function of protein hydrolyze.Cathepsin B participates in the degradation and translation of many proteins,cell apoptosis ,regeneration of blood vessel,froliferation and metastasis of tumors.So,the activity of CB must be controled by the inhibitors,in which cystatin C is the most effective one. Cathepsin B and cystatin C play an important role in physiological pregnancy and preeclampsia.
Objective:
We first invesigated the expression of CB and CysC in materal blood from normal pregnant women at three terms and preeclamptic pregnant women at term pregnancy.Then we studied the expression of CB in the placentae of normal and preeclamptic pregancy women at term.Through investigaging the changes of CB and CysC,we try to study the effect of CB-CysC in the development of normal pregnancy and pathogenesis of hypertensive disorder complicating pregnancy.It may help us to determine the etiology and to defend and treat the disease.
Methodes:
This study by enzyme-linked immunosorbent assay (ELISA) detected healthy women 15 cases, 55 cases of normal pregnant women (including 15 cases of early pregnancy, the medium-term pregnancy 20 cases, 20 cases of late pregnancy), 50 cases of preeclamptic and eclamptic women (including 15 patients with mild preeclampsia, severe preeclampsia 20 cases, 15 cases of eclampsia group) CB and intravenous serum inhibitor CysC level in cubital wein . We also use immunohistochemical methods to detect the placental CB expression in 10 cases of late pregnancy women , and preeclampsia-eclampsia women 30 cases (including 10 cases of mild preeclampsia, severe preeclampsia 10 cases, 10 cases of eclampsia group).
Results:
1. Blood comparison of CB and CysC among non-pregnant group and different periods of pregnancy.
(1)Compare to the non-pregant group ,CB in early pregnancy group is lower,but the difference was not statistically significant (p = 0.39). CB level in the serum of medium-term pregnancy women is lower than early pregnancy group (p = 0.09), there was no significant difference. And CB level in the serum of medium-term pregnancy women is lower than non-pregnant group significantly (p <0.01).CB in late pregnancy group is lower than non-pregant group and early pregnancy group(p <0.01). There was no significant difference between medium-term pregnancy women and late pregnancy women(p = 0.09).
(2)Maternal blood CysC level in early pregnancy group is significantly lower than non-pregnant group (p <0.05), and CysC in medium-term pregnancy women increased significantly compared with early pregnant group(p <0.05), there was no significant difference between non-pregnant group and medium-term pregnancy group(p = 0.46). CysC in late pregnancy women was significantly higher than that of non-pregnant women (p <0.01),early pregnancy women (p <0.01) and medium-term pregnancy (p <0.01).
2. The alteration of serum CB and CysC in pre-eclamptic and eclamptic women.
(1)There is not significant difference in the serum CB among mild, severe pre-eclampsia and eclampsia and the normal late pregnancy (p>0.05).
(2)Serum CysC in patients with mild pre-eclampsia group is higher than late uncomplicated pregnancy women, but the difference was not significant (p = 0.48).Maternal blood CysC in severe preeclampsia group compared with late pregnancy significantly increased (p <0.01).CysC in severe preeclampsia group compared with mild preeclampsia group was significantly increased (p <0.05). There was no significant difference in maternal blood CysC between severe preeclampsia and eclampsia group(P = 0.63).
3. CB expression in the placentae of preeclamptic and eclamptic women .
(1)The placental expression and distribution of CB are consistent among normal pregnancy group,preeclamptic group,and eclamptic group.CB expres- sed in the cells and matrix of decidua and chorionic villi. There is no difference in the expression of CB between the decidua and the villi.
(2)CB expression in the placentae of mild preeclampsia compared with normal pregnancy group noticeably increased(P <0.05).CB expression in the placentae of severe preeclampsia increased obviously compared with normal pregnancy group (P <0.01)and mild preeclampsia group(P <0.05) .
(3)Eclamptic CB expression in the placentae is obviously stronger than normal pregnancy group(P <0.01)and mild preeclampsia group(P <0.05). Severe preeclampsia and eclampsia group CB expression group showed no significant difference(P = 0.353).
Conclusion:
(1)CB and CysC play an important role in the growth and development of the placenta and the occurrence of preeclampsia and eclampsia .
(2)CB in the serum of pregnancy women was lower than non-pregant women, and there is downward trend with the pregnancy week increased.
(3)CysC in maternal blood of early pregnancy women significantly reduced compared with non-pregant women,but the CysC level of pregnantcy women in medium-term pregnancy and late pregnancy increased significantly.
(4)CB levels in maternal blood group has no obvious correlation with the severity of PE and eclampsia.
(5)CysC in maternal blood group was significantly increased than the normal pregnancy women,and the level is related with the severity of PE .
(6)CB expressed mainly in the matrix and cells of decidua and villus. The expression of CB in PE group is significantly enhanced than normal placentae and with the severity of the disease was positively correlated.
引文
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[2]Bromme D et al. Thiol-dependent cathepsins: pathophysiolo- gical implications and recent advances in inhibitor design .Curr Pharm Des, 2002, 8(18): 1639-1658.
[3]Turk V, Turk B, Turk D .Lysosomal cysteine proteases: facts and opportunities. EMBO J ,2001,20(17):4629–4633.
[4]Guieeiardi M E,Deussing J,Miyoshi H,et a1.Cathepsin B ongtributes to TNF-a mediated hepatocyte apoptosis by promo- ting mitoehondrial release of cytochrome C.J Clin Invest, 2000,106(9):l127-1137.
[5]Turk V,Turk B,Turk,D.Lysosomal cysteine proteine proteases: facts and opportunities.EMBOJ.2001,20(17);4629-4633.
[6]Halangk W,Lerch MM ,Brandt-Nedelev B,et a1.Role of cathep- sin B in intracellalar trypsinogen activation and the onset of acute pancreatitis[J].J Clin Invest,2000,106(6):773-781.
[7]Miyake H,Hara I,Eto H.Serum level of cathepsin B and its den- sity in men with prostate cancer as novel markers of disease progression [J].Anticancer Res,2004,24(4):2573-2577.
[8]Yu B,Li SY,An P,et a1. Expression of cathepsin B and its clinical impo- rtance in colorectal cancer[J].Zhonghua Wei Chang Wai Ke Za Zhi. 2005,8(6):507-509.
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