{"id":18124,"date":"2017-12-21T09:56:25","date_gmt":"2017-12-21T09:56:25","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=18124"},"modified":"2018-11-06T07:13:12","modified_gmt":"2018-11-06T07:13:12","slug":"role-of-caspase-3-as-risk-factors-of-premature-rupture-of-membranes","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol10no4\/role-of-caspase-3-as-risk-factors-of-premature-rupture-of-membranes\/","title":{"rendered":"Role of Caspase-3 as Risk Factors of Premature Rupture of Membranes"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Premature rupture of membranes (PROM) is one of the complications of pregnancy and health problems in the field of maternal and neonatal care\u00a0in the world, including Indonesia, which is related to the prevalence, prematurity,\u00a0morbidity,\u00a0and mortality\u00a0in the\u00a0perinatal\u00a0maternal\u00a0side.\u00a0This will increase maternal mortality and infant mortality as a complication of premature rupture of membranes.<\/p>\n

Incidence of premature rupture of membranes (PROM) occurs 10-12% in all pregnancies.\u00a0In term pregnancy the incidence varies from 6 to 19%, whereas in preterm pregnancy the incidence is 6-8%.The incidence of PROMs worldwide varies between 5-10% and almost 80% occurs at the age of term pregnancy (Adeniji et al., 2013; Endale et al., 2016).\u00a0Meanwhile, preterm PROM incidents are estimated at 3-8% (Okeke et al., 2014).\u00a0Under normal circumstances, 8-10% of pregnant women will experience PROM and only 1% occur at preterm gestation (Soewarto, 2010).\u00a0The prevalence of preterm PROM in the world is 3 – 4.5% of pregnancies, and is a contributor of 6 – 40% preterm labor or prematurity (Furman et al., 2000).\u00a0In China the incidence of PROM is higher, around 19.53% of all pregnancies (Yu, 2015), while in Indonesia it ranges from 4.5% to 7.6% (Wiradarma et al., 2013). In Sanglah Hospital in Denpasar, Suwiyoga and Budayasa\u00a0(2006)\u00a0reported the incidence\u00a0of cases PROM 12.92% in which case the term PROM amounted to 83.23% and amounted to 16.77%\u00a0of\u00a0preterm\u00a0deliveries\u00a0in\u00a02113.\u00a0Budijaya and Surya Negara (2016) reported a case of\u00a0premature rupture of membranes (PROM) at Sanglah Hospital Denpasar 212 cases from 1450 deliveries (14.62%).\u00a0The incidence of labor with PROM at gestational age aterm (\u226537 weeks) was 179 cases (84.43%), while in preterm as many as 33 cases (15.57%).<\/p>\n

Complications of PROM can occur either on the\u00a0infants\u00a0or maternal.\u00a0Maternal complications such as chorioamnionitis are found in 9% of pregnancies with premature rupture of membranes, risks of up to 24% if rupture of membranes occurs more than 24 hours.\u00a0In preterm pregnancies, the incidence was greater between 13-60% (Brian and Mercer,\u00a02003;\u00a0Dars et al., 2014).\u00a0Placental abruption occurs in 4-12% of pregnancies with premature rupture of membranes.\u00a0While maternal complications include intra amniotic infections, which occur in 13-60% of pregnant women with PROM, placental abruption and post partum endometritis.\u00a0Maternal sepsis occurs of 0.8%, can cause death (0.14%). PROM complication that occurs in infants such as intrauterine infection, umbilical cord compression, respiratory distress syndrome (RDS), necrotizing enterocolitis, intraventricular hemorrhage and sepsis is a common associated with preterm labor.\u00a0Premature infant care resulting from preterm births occurring in cases of PROM requires considerable cost for intensive care.\u00a0The cases of PROM were associated with perinatal morbidity of 21.4% and mortality by 18-20% (Patil, 2014; Linehan et al., 2016; Rodrigo and Kannamani, 2016).<\/p>\n

The amniotic membrane is an avascular elastic tissue consisting of amnion and chorion.\u00a0The amnion is part of faced directly with\u00a0the amniotic\u00a0cavity\u00a0while chorions a thicker layer and attached to the maternal decidua.\u00a0Amnion and chorionic connected by connective tissue\u00a0that is\u00a0rich in collagen, extracellular matrix. Causes of premature rupture of membrane are multifactorial and the mechanism is unclear.\u00a0Weakening\u00a0of extracellular matrix\u00a0\u00a0in the\u00a0amniochorion layer due to degradation of collagen is one of the processes as predisposing\u00a0to premature rupture of membranes.\u00a0In premature rupture of membrane an\u00a0increase in activity collagenolytic with consequent\u00a0decline\u00a0in\u00a0the\u00a0number of collagen tissue and disruption of the collagen\u00a0structure was occured.\u00a0Collagen degradation caused by\u00a0enzymes, matrix metalloproteinase (MMP) (Brian and Mercer; Areia and Moura 2015).<\/p>\n

One of the factors associated with increased risk of premature rupture of\u00a0membranes both endogenous and exogenous factors is the occurrence\u00a0of programmed cell death\u00a0or\u00a0apoptosis.\u00a0Apoptosis play an integrated role in the occurrence of premature rupture of membranes, where it was found\u00a0that cells undergoing apoptosis in\u00a0layers of\u00a0amnion and chorionic especially in\u00a0about rips membranes known as\u00a0paracervical weak zone<\/em> (Xu and Wang, 2005; Harirah et al., 2012; Saglam\u00a0et\u00a0al.,\u00a02013).<\/p>\n

Signals that cause apoptosis may occur intracellular and extracellular.\u00a0Extrinsic pathway (extracellular) initiated through stimulation of death receptors\u00a0(death receptor pathway)<\/em>\u00a0while the intrinsic pathway is initiated through the release of factors from the mitochondria in the cell signal\u00a0(mitochondrial pathway).<\/em>\u00a0Both intrinsic and extrinsic pathway of\u00a0caspase dependent<\/em>\u00a0ended in the execution phase, which is the final pathway of apoptosis.\u00a0The activation of caspase execution is the stage that begins this stage, where caspase-3 is the most important executor caspase.\u00a0Caspase-3 plays an important role in changes in cell morphology and biochemical events associated with the implementation and complete the process of apoptosis\u00a0(Elmore,\u00a02007; Equils et al., 2014; Estaquier et al., 2014).<\/p>\n

Caspase expression and activation play a very important role in apoptosis.\u00a0Caspase-3 is a major member of the caspase family.\u00a0This is an active factor in apoptosis.\u00a0Activation of caspas -3 is a biochemical reaction prior to apoptosis.\u00a0Almost all apoptosis occurs via a common pathway.\u00a0Investigators expression of Caspase-3 can display cell\u00a0apoptosis.<\/p>\n

Materials and Methods<\/strong><\/p>\n

The study design\u00a0is a case-control study, PROM as cases and non PROM as controls with gestational age 20-42 weeks.\u00a0The study was conducted in the emergency department Sanglah Hospital Denpasar Bali\u00a0between October to\u00a0May,\u00a02017.\u00a0After delivery, the membrane was taken\u00a0from the edge of the tear\u00a0for immunohistochemical examination in the Lab.\u00a0Integrated Biomedics Medical Faculty Udayana University Bali.\u00a0Statistical tests were performed independently -t test and chi-square test.<\/p>\n

Results<\/strong><\/p>\n

In the period from October to May\u00a02017 we found 36 cases PROM and 37 controls.\u00a0In this study it was found that the mean age of the case group was 26.59 \u00b1 6.49 years and the mean age of the control group was 28.72 \u00b1 6.80 years, with p = 0.153.\u00a0The mean of case group parity was 0.68 \u00b1 0.82 people and the control group parity mean was 0.95 \u00b1 1.28 people, with p = 0.184.\u00a0The mean BMI of the case group was 24.63 \u00b1 4.48 kg\/m2,<\/sup>\u00a0and mean BMI of the control group was 24.88 \u00b1 3.87 kg \/ m\u00a02,<\/sup>\u00a0with p = 0.850.<\/p>\n

Statistical test using\u00a0independent\u00a0t-test,<\/em>\u00a0showed that there was no significant difference in age, parity, and BMI in cases and controls.\u00a0 We obtained\u00a0p values for each risk factor is\u00a0p>\u00a00.05, which states that no\u00a0difference of characteristic value\u00a0between the two groups.<\/p>\n

Table 1.1: Distribution Characteristics of Age, parity, and BMI,\u00a0in the Second Group<\/strong><\/p>\n\n\n\n\n\n\n\n
Risk factors<\/strong><\/td>\nThe case\u00a0group<\/strong><\/p>\n

(n =\u00a036)<\/strong><\/td>\n

Control\u00a0group<\/strong><\/p>\n

(n =\u00a037)<\/strong><\/td>\n

P<\/strong><\/td>\n<\/tr>\n
Mean<\/strong><\/td>\nSD<\/strong><\/td>\nMean<\/strong><\/td>\nSD<\/strong><\/td>\n<\/tr>\n
Age\u00a0(years)<\/td>\n26.59<\/td>\n6.49<\/td>\n28.72<\/td>\n6.80<\/td>\n0.153<\/td>\n<\/tr>\n
Parity<\/td>\n0.68<\/td>\n0.82<\/td>\n1.00<\/td>\n1.18<\/td>\n0.158<\/td>\n<\/tr>\n
BMI (kg\/m\u00a02)<\/sup><\/td>\n25.96<\/td>\n4,\u00a089<\/td>\n24.14<\/td>\n4.04<\/td>\n0.066<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

To determine the role of\u00a0caspase-3\u00a0expression\u00a0on the risk of\u00a0premature rupture of membrane\u00a0Chi-Square\u00a0test was\u00a0used.\u00a0For considering the magnitude of the risk to the PROM, we calculated the\u00a0Odds Ratio\u00a0(OR).<\/p>\n

Table 2.2: Risk of premature rupture of membranes in Amnion Cell Caspase-3 Expression<\/strong><\/p>\n\n\n\n\n\n\n
<\/td>\nGroup<\/strong><\/td>\nOR<\/strong><\/td>\nCI 95%<\/strong><\/td>\nP<\/strong><\/td>\n<\/tr>\n
Case<\/strong><\/td>\nControl<\/strong><\/td>\n<\/tr>\n
Caspase-3 expression<\/td>\nPositive<\/td>\n30<\/td>\n17<\/td>\n7.31<\/td>\n2.64 – 20.22<\/td>\n0.001<\/td>\n<\/tr>\n
Negative<\/td>\n7<\/td>\n29<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

In this study,\u00a0showed that the\u00a0expression of\u00a0positive caspase-3\u00a0was a risk factor for\u00a0premature rupture of membranes\u00a0of\u00a07.31\u00a0times (OR\u00a0=\u00a07.31\u00a0\u00a0\u00a0;\u00a0CI 95% =\u00a02.64 to 20.22\u00a0;\u00a0p = 0,\u00a0001)\u00a0than\u00a0the expression of negative caspase-3.<\/p>\n

Discussion<\/strong><\/p>\n

In the study by Budi and Surya (2016), it was found that the incidence of PROM was most common in the 21-30 year age group, 116 cases (54.72%) of 212 cases of PROM, both term pregnancies and preterm.\u00a0The study by Udin Sabarudin (2009) in Dr.Hasan Sadikin Hospital Bandung, show that the most age group of mother in PROM case was 20-35 years.\u00a0The same is also reported by Okeke et al., 2014 in retrospective studies in Nigeria, the highest incidence of preterm PROM cases occurring in the reproductive age group (26-30 years) of 43%.\u00a0Gahwagi et al., 2015 on study\u00a0in Libya that was found 61% and V\u00a0ishwakarma et al., 2015 found that the highest incidence PROM was in the age range 21-25 of 52.1%.\u00a0The study by Endale et al (2016) found the highest incidence of PROM in the 18-35 year age group (74.6%) of the 202 PROM patients.\u00a0Singh et al (2015), reported the most preterm PROM cases was in the 20-30 year age group.\u00a0The study by Emechebe et al (2015) obtained the most cases of PROM was in the age group 25-29 years ie 63 (32.8%) of 192 cases of PROM.\u00a0 Noor et al (2007) report that the incidence of PROM in the age group 15-25 years of 58.8%.\u00a0Study by Gahwagi et al (2015) obtained the most cases of PROM was in the age group of 21-30 years.\u00a0Thombre (2014), found an increased incidence of PPROM in women aged > 35 years.\u00a0Increasing maternal age consistently associated with PROM incident.<\/p>\n

Based on gravida, study by Budi and Surya (2016) in Sanglah Hospital Denpasar found that the highest incidence of PROM occurred in primigravida group that was 87 cases (41.05%).\u00a0Equal with reported by Okeke et al., 2014 on a retrospective study in Nigeria, the highest\u00a0incidence of\u00a0preterm PROM cases\u00a0occurred in primigravida group of \u00a029.1%.\u00a0Patil et al., 2014 in his study at MRMedical College, Gulbarga by 53%.\u00a0Noor et al (2007) reported that the incidence of PROM was also highest in primigravida cases (42.2%).\u00a0Other studies have reported that the incidence of PROM also occurred in primigravida of 68.2%, 52%, 69.7% (Vishwakarma et al., 2015; Gahwagi et al., 2015; Endale et al., 2016).\u00a0Based on parity, study by Milad et al (2015) obtained the most cases of PROM was in nullipara (52%), parity 1-4 (44%).\u00a0Okeke et al (2014) reported the most cases of PROM was in nullipara (29.1%), parity 2 (26.6%), parity 1 (19%).<\/p>\n

Some studies show that a low body mass index (BMI) before pregnancy may increase the risk of PPROM.\u00a0PPROM was strongly associated with increased maternal weight in the second and third trimester with weight gain <0.37 kg \/ week in women with BMI <19.5 kg\/m2<\/sup>.\u00a0PPROM has a very close relationship with weight at the time of pregnancy, and a low body mass index before pregnancy (Thombre, 2014)<\/p>\n

From the study of Xu Jun et al (2005), caspase-3 gene expression was obtained in the PROM case compared to the control group with intact membranes, which led to increased apoptotic cells in the amniotic membrane.\u00a0The expression of MMP-2 increases and TIMP-2 decreases in the case of PROM, which can increase the degradation of the extracellular matrix.\u00a0Apoptotic cells increase and degradation of extra cellular matrix increases, leading to weakening of membrane elasticity and strength and then causing premature rupture of membranes.\u00a0Caspase expression and activation play a very important role in apoptosis.\u00a0Caspase-3 activation is a biochemical reaction prior to the occurrence of apoptosis.\u00a0Caspase-3 expression was higher in the vaginal delivery group than in cesarean section groups.\u00a0This may be due to multifactorial effects after the initial labor process, which increases apoptosis and causes spontaneous membrane rupture.\u00a0Several factors can cause the transformation of cell homeostasis, resulting in increased apoptosis.\u00a0In fetal membranes with PROM via immunohistochemical examination showed caspase-3 expression in amnionic epithelial cells and coronal cyto-trophoblast cells, slightly expressed on mesenchymal cells and reticular cells of the matrix.\u00a0This suggests that apoptosis occurs both in amions and chorion, and plays an important role in fetal membrane regulation (Xu Jun et al., 2005).<\/p>\n

Xu and Wang (2005) conducted study on the role of caspase and MMP in amniocorion during PROM.\u00a0Objective of the study is\u00a0to investigate the role of\u00a0cysteine aspartic acid-specific protease-3(caspase-3),\u00a0matrix metalloproteinase-2\u00a0(MMP-2) and tissue inhibitor of\u00a0matrix metallo proteinase- 2\u00a0(TIMP-2) in the membranes during the experience PROM.\u00a0Amniotic membranes were collected from several groups of women, women with spontaneous PROM (n = 8), women with normal term deliveries with spontaneous vaginal (n = 8) and women undergoing recurrent cesarean section before the onset of labor and no complications (n=8).\u00a0The caspase-3 peptide was examined with immunohistochemical techniques.\u00a0MRNA expression of MMP-2 and TIMP-2 inhibitors examined using\u00a0reverse transcriptase-polymerase chain reaction\u00a0(RT-PCR).\u00a0From the study, we found that the expression of caspase-3 peptide was 62.86\u00a0\u00b1\u00a03.83% in PROM group, 42.33\u00a0\u00b1\u00a02.99% in the vaginal delivery group, and 20.97\u00a0\u00b1\u00a02.94% in C-section group.\u00a0There were statistically significant changes between the three groups (p <0.05).\u00a0Immunohistochemistry shows the presence of expression of caspase-3 in amnionic epithelial cells and cytotrophoblast chorionic cells.\u00a0Expression of MMP-2 was 84.92\u00a0\u00b1\u00a03.68% in the PROM group,\u00a02:34\u00a0\u00b1\u00a032.65%\u00a0in the vaginal delivery group, and 30.65\u00a0\u00b1\u00a02.77% in cesarean section group.\u00a0There were statistically significant differences in the PROM group and cesarean section (p <0.05).\u00a0The expression of\u00a0TIMP-2 was 42.01\u00a0\u00b1\u00a012:17% in PROM group, 73.01\u00a0\u00b1\u00a014.82% in the vaginal delivery group, and 88.47\u00a0\u00b1\u00a06:51% in cesarean section group.\u00a0In conclusion that caspase-3 gene expression is more prevalent in the PROM group, which is due to increased apoptosis in fetal membrane cells.\u00a0Increased expression of MMP-2 and TIMP-2 decreased in PROM, where an increase in the decomposition of the extracellular matrix\u00a0(Xu\u00a0and Wang, 2005).<\/p>\n

Caspase-3 is a major member of the caspase family which is an active factor in apoptosis.\u00a0Caspase-3 activation is a biochemical reaction prior to the occurrence of apoptosis.\u00a0Almost all apoptosis go through this caspase path.\u00a0So investigating caspase-3 expression can show cell apoptosis.\u00a0In fetal membranes with PROM via immunohistochemical examination showed caspase-3 expression in amniotic epithelial cells and coronal cyto-trophoblast cells, slightly expressed on mesenchymal cells and reticular cells of the matrix.\u00a0This suggests that apoptosis occurs in both amnions and chorionics.\u00a0This plays an important role in the regulation of fetal membranes (Xu and Wang, 2005).<\/p>\n

Another study was conducted by Kumagai (2001), on apoptosis in the amniotic membrane fetal.\u00a0This study was conducted to determine the exact number of apoptotic cells in different weeks during pregnancy, and to explain the relationship between apoptosis in amnion and weakness of the membranes at the onset of labor.\u00a0From this study,\u00a0the activity of caspase-3 and caspase-8 in a sample of amniotic higher at 40-41 weeks of gestation at the time of 16-27 weeks gestational age (P <0.01).\u00a0No significant differences in caspase-9 activity were observed between the two groups.\u00a0Concluded\u00a0apoptosis in amniotic epithelial layer is not dependent on the regulation of Bcl-2 and the onset of labor, and the possibility of having an important role that causes weak and rupture of the membranes at the end of pregnancy.\u00a0There is no significant difference in the activity of\u00a0caspase-3, 8, and 9 between gestational age 16-27 weeks and 28-39 weeks gestation (Kumagai, 2001).<\/p>\n

Study of caspase-3 in preterm premature rupture of membranes is also done by Saglam et al,\u00a02013.\u00a0This study aims to determine the active 3-Caspase immunopositivity in preterm premature rupture of membranes and preterm labor with intact membranes compared with term pregnancies\u00a0with normal deliveries.\u00a0The case control study to compare the levels of active caspase-3 immunopositivity in preterm premature rupture of\u00a0membranes,\u00a0pre-term\u00a0labor\u00a0with intact membranes, and in the control group term pregnancies with normal vaginal delivery.\u00a0Amniochorionic\u00a0membranes\u00a0were collected from three\u00a0groups of women: group 1, women with PPROM after\u00a0cesarean\u00a0section\u00a0(n =\u00a010);\u00a0Group 2, women with preterm labor\u00a0with intact membranes after\u00a0cesarean section\u00a0(n = 9);\u00a0and\u00a0group 3, women with full-term labor who delivered vaginally\u00a0after\u00a0pregnancy\u00a0without complications (control) (n = 11).\u00a0It was concluded that active immunopositivity \u00a0 caspase – 3\u00a0(ACPI) on\u00a0PPROM group is significantly higher than with\u00a0Control group (p <0.05).\u00a0Positive\u00a0active caspase-\u00a03\u00a0increase in\u00a0fetal\u00a0membranes\u00a0in women with PPROM (Saglam et al., 2013).<\/p>\n

Caspase-3, a key factor in the execution of apoptosis, is an active form of procaspase-3.\u00a0Caspase-3 is referred to as the most important executor caspase, activated by caspase initiator (caspase-8, caspase-9, and caspase-10).\u00a0Caspase-3 specifically activates CAD endonucleases.\u00a0In cells that are proliferating CAD forms a complex with its inhibitor, ICAD.\u00a0In cells undergoing apoptosis, activated caspase-3 cleaves ICAD so as to release CAD.\u00a0CAD will then elaborate on chromosome DNA in the nucleus and causes chromatin condensation; caspase-3 also triggers cytoskeletal reorganization and disintegration of\u00a0apoptotic bodies\u00a0forming\u00a0cells.\u00a0Phagocytosis is\u00a0the last stage of apoptosis\u00a0(Elmore, 2007).<\/p>\n

An intrinsic pathway is the dominant role in the process of apoptosis in fetal membranes at term.\u00a0This is evidenced by the study findings which suggest that there are significant differences in levels of Bcl-2, caspase-3, caspase-9 in the supracervical region, where such proteins play an intrinsic pathway.\u00a0Fas and ligands, Fas-L initiates extrinsic path apoptosis.\u00a0Although in the study Fas and Fas-L can also be found in all samples of amniotic membranes but the expression did not differ significantly between supracervical region and distal region.\u00a0It is therefore suspected that extrinsic pathways do not play a major role in the remodeling of the membranes.\u00a0Although there was no significant difference in Bax expression, proaptoptotic protein, but Bcl-2 antiapoptosis protein was found to decrease in the paracervical region compared with other regions (Reti et al., 2007).<\/p>\n

In this study, the expression of caspase-3 in the case of the PROM was higher than in the case without PROM, with\u00a07.31 times (OR\u00a0=\u00a07.31;\u00a095% CI =\u00a02.64 to\u00a020.22;\u00a0p = 0,\u00a0000)\u00a0this suggests that caspase-3 as the parameter of their apoptosis\u00a0dependent caspase\u00a0pathway\u00a0and acts as a risk factor for premature rupture of membranes.<\/p>\n

From this study, the expression of caspase-3 in amnion cells shows that there is an apoptotic process on the membranes.\u00a0Caspase-3 is an executioner caspase which is active caspase as the process of apoptosis mechanism of\u00a0caspase dependent\u00a0pathways\u00a0that extrinsic and intrinsic pathways, so that the expression is more dominant.\u00a0This indicates that the\u00a0caspase-dependent\u00a0apoptosis\u00a0plays a role in the mechanism of occurrence of premature rupture of membranes.<\/p>\n

Conclusion<\/strong><\/p>\n

In this study shows that caspase-3 as the parameter of\u00a0caspase-dependent\u00a0apoptosis pathway\u00a0 acts and role as a risk factor for premature rupture of membranes.<\/p>\n

Acknowledgement<\/strong><\/p>\n

The authors gratefully acknowledge this study have no financial conflicts of interest.<\/p>\n

References<\/strong><\/p>\n

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