{"id":20375,"date":"2018-06-25T11:34:52","date_gmt":"2018-06-25T11:34:52","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=20375"},"modified":"2020-04-23T07:01:34","modified_gmt":"2020-04-23T07:01:34","slug":"role-of-apoptosis-inducing-factor-aif-as-risk-factors-of-premature-rupture-of-membranes","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol11no2\/role-of-apoptosis-inducing-factor-aif-as-risk-factors-of-premature-rupture-of-membranes\/","title":{"rendered":"Role of Apoptosis Inducing Factor (AIF) as Risk Factors of Premature Rupture of Membranes"},"content":{"rendered":"

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

Premature rupture of membrane (PROM) is one of the complication in pregnancy and one of the maternal and neonatal problem throughout the world, including Indonesia. It correlates with the prevalence, prematurity, morbidity, and mortality of perinatology and maternal aspect, and increase the maternal mortality and neonatal mortality rate as the complication of PROM. The etiology of PROM is multifactorial and the mechanism is still unclear. The extracellular matrix of the amniochorion that weakens due to the degradation of collagen is one of the predisposing factor of PROM. One of the endogenous and exogenous factor that correlates with the increasing risk of PROM is the programmed cell death or apoptosis.<\/p>\n

The incidence of PROM is about 10-12% out of all pregnancy, which is 6-19% in the term pregnancy and 6-8% in the preterm pregnancy. The incidence of PROM throughout the world varies between 5-10% and almost 80% of all incidence occurs in term pregnancy (Adeniji et al, 2013; Endale et al, 2016). While the incidence of preterm PROM is about 3-8% (Okeke et al, 2014). The prevalence of preterm PROM throughout the world is 3-4.5% of all pregnancy, and becomes as the causes of preterm labor or prematurity as high as 6-40% (Furman et al, 2000). Budijaya and Surya Negara (2016) also reporting PROM cases in Sanglah General Hospital, which were 212 cases out of 1450 labor (14.62%). The incidence of PROM in term pregnancy (\u226537 weeks gestational age) were 179 cases (84.43%), and 33 cases were preterm pregnancy (15.57%).<\/p>\n

Preterm PROM correlates with 30-40% of premature labor, and also known as the major causes of premature labor, which is about 20-50% out of all premature labor (Creasy and Resnik, 2009; Getahun et al, 2010; Cunningham, 2010). Prematurity causes about 85% of all neonatal morbidity and mortality, complicates in 3% of all pregnancy and occurs in about 150,000 cases in United States (Gahwagi et al, 2015). Prematurity is one of the international health problem and causes 80% of all neonatal mortality, and 60% of neurological defect. Prematurity is also one of social problem because it correlates with disability and growth development in children (Menon and Fortunato, 2007). The maternal complications are intraamniotic infection, that occurs in 13-60% of all pregnant women with PROM, placental abruption, and postpartum endometritis. Sepsis maternal occurs in about 0.8% cases, that causes death (0.14%). The neonatal complication of PROM is the intrauterine infection, umbilical cord compression, respiratory distress syndrome (RDS), necrotizing enterocolitis, intraventricular bleeding, and sepsis.<\/p>\n

One of the endogenous and exogenous factors that correlates with the increasing risk of PROM is the programmed cell death or apoptosis. Apoptotic cell was found in the amnion and chorion layer, especially in the area of the ruptured amniotic membrane, which is known as the paracervical weak zone (Xu and Wang, 2005; Harirah et al, 2012; Saglam et al 2013). The process that creates the paracervical weak zone other than remodeling process, correlates with the apoptosis process. The apoptotic cell is found higher in the amnion of the PROM cases compared to the pregnant women without PROM, and the apoptotic rate is found highest around the cervical area compared to the fundal area (Kataoka et al, 2002; El Khwad et al, 2005; Rangaswamy et al, 2012).<\/p>\n

The apoptosis mechanism occurs within two pathway, which are caspase-dependent and caspase-independent. The caspase-dependent pathway can occurs through intrinsic pathway that is triggered by the failure of mitochondrial metabolism or the extrinsic pathway that is triggered by death receptor. The caspase-independent pathway is triggered by mitochondrial protein such as Apoptosis Inducing Factor (AIF) and Endonuclease G mitochondria (Van Loo e tal, 2001; Elmore, 2007; Ashkenazi et al, 2014).<\/p>\n

The mechanism of PROM that is caused by genital tract infection, can be caused by extracellular bacterial infection or intracellular obligatory bacteria. The genital tract infection can cause the apoptosis of amnion cell, where the extracellular bacterial infection can undergo the caspase dependent, while the intracellular obligatory bacteria can undergo the caspase independent pathway. In the caspase dependent pathway, we can analyze the protein caspase-3 parameter and the AIF protein in the caspase independent pathway. The study of apoptosis role in the mechanism of PROM through caspase independent pathway is not defined yet (Gao and Kwaik, 2000; Hongmei, 2012; Prabantoro, 2012). There has been no study yet reported about the role of caspase independent pathyway towards the risk of PROM, especially the AIF as the main apoptosis protein that is involved in the caspase independent pathway.<\/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 \/ m2\u00a0,<\/sub><\/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, as shown in Table\u00a01.<\/p>\n

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

 <\/p>\n

To determine the role of\u00a0AIF\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), as shown in Table\u00a02.<\/p>\n

Table 2: Risk of premature rupture of membranes in Amnion Cell AIF Expression<\/strong><\/p>\n\n\n\n\n\n\n
<\/td>\nGroup<\/strong><\/td>\nOR<\/strong><\/td>\nCI 95%<\/strong><\/td>\np<\/em><\/strong><\/td>\n<\/tr>\n
Case<\/strong><\/td>\nControl<\/strong><\/td>\n<\/tr>\n
AIF expression<\/strong><\/td>\nPositive<\/strong><\/td>\n30<\/td>\n21<\/td>\n5.10<\/td>\n1.86 \u2013 13.96<\/td>\n0.001<\/td>\n<\/tr>\n
Negative<\/strong><\/td>\n7<\/td>\n25<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

In this study,\u00a0showed that the\u00a0expression of\u00a0positive AIF\u00a0was a risk factor for\u00a0premature rupture of membranes\u00a0of\u00a05.10\u00a0times (OR\u00a0=\u00a05.10 ;\u00a0CI 95% =\u00a01.86 \u2013 13.96;\u00a0p<\/em> = 0,\u00a0001)\u00a0than\u00a0the expression of negative AIF.<\/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.\u00a0 The 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 Vishwakarma 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\u00a0 29.1%.\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).\u00a0 Okeke 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 development of some cell death model study, specific caspase inhibitor cannot inhibit the apoptosis that is induced by proapoptosis stimulus, and the activation of caspase is not enough to initiate apoptosis. The excess expression of Bax or Bak induce cell death without involving caspase, and it explains another factor other than caspase that also involved in the cascade of apoptosis. Some of this factor also exist in the mitochondria, such as AIF that can cause condensation of chromatin and the release of cytochrome C when there is no activation of caspase (Perfettini et al, 2002; Elmore, 2007).<\/p>\n

The apoptosis mechanism through caspase independent does not need caspase mediater, and they have different mechanism towards cell death. The involved apoptosis in the caspase independent is the mitochondria proapoptosis protein molecule, which is Apoptosis Inducing Factor (AIF) and Endonuclease G (Arnoult et al, 2003; Elmore, 2007).<\/p>\n

In the apoptosis through caspase independent pathway, if the cell is triggered by the apoptosis, then AIF and endonuclease G will translocated from mitochondria to nucleus and causing fragmentation of nuclear DNA. Protein Bcl-2 will inhibit the permeability of the mitochondrial membrane. If the Bcl-2 is inhibited, then the mitochondrial membrane pore will be opened and the AIF will be released. The AIF is one of the mitochondrial protein that will be released into the cytosol during apoptosis, and is found as the first protein that regulate the apoptosis caspase-independent pathway (Cande et al, 2002; Damien and Brigitte, 2003; Elmore, 2007).<\/p>\n

The mechanism of PROM that is caused by genital tract infection, can be caused by the extracellular bacteria or the intracellular obligatory bacteria. The genital tract infection can cause the apoptosis of the amniotic cell, where the extracellular bacterial infection will go through caspase dependent pathway and the intracellular obligatory bacterial infection will go through caspase independent pathway. The caspase dependent pathway can be seen with the caspase-3 parameter, while the caspase independent pathway can be seen with the AIF parameter. Study about the role\u00a0 of apoptosis in the mechanism of PROM through caspase independent pathway has not been reported yet (Gao and Kwaik, 2000; Hongmei, 2012; Prabantoro, 2012).<\/p>\n

By knowing the apoptosis protein as the AIF expression on the amniotic cell, it can be seen the correlation between AIF expression as the parameter of apoptosis which go through caspase independent on the amniotic membrane. As the result, it can explain the role of AIF as the risk factor of PROM through apoptosis caspase independent pathway.<\/p>\n

Mitochondria can be induced to release cytochrome C through various stress signal that originates from the inner cell or following the activation of caspase, that is triggered by the surface receptor ligand. The integrity of the outer membrane and the release of cytochrome C from the mitochondria is regulated by the Bcl-2 protein family, which consists of antiapoptotic factor such as Bcl-2 and Bcl-XL and proapoptotic protein such as Bax and Bak. These protein can undergo heterodimerization with one another and interact with mitochondria, where they are as important substance to determine whether the cell will stay alive or go through the cell death. As the result, Bcl-2 protein can prevent apoptosis by prevent the release of protein between mitochondria membrane, including cytochrome C and AIF. On the other hand, Bax will trigger the release of cytochrome C from the mitochondria that causing apoptosis (Perfettini et al, 2002).<\/p>\n

The latest study shows that different cell death can occurs without activation of caspase. Certain caspase cannot inhibit apoptosis that is triggered by proapoptotic signal, and the activation caspase is not enough to initiate apoptosis. Moreover, the expression of Bax or Bak can induce cell death without caspase involvement. Some of those factors exist in the mitochondria such as AIF, and shows the swelling in the mitochondria, chromatin condensation, and release of cytochrome C without caspase activation (Perfettini et al, 2002).<\/p>\n

The presence of positive AIF expression in cases with PROM was compared in the case without PROM, with OR 6.60 times (OR = 6.60, 95% CI = 1.48-29.36, p<\/em> = 0.009) in amnionic epithelial cell. The role of AIF as a risk factor of premature rupture of membranes through the path of apoptosis caspase independent. Protein AIF is a proapoptotic protein from the mitochondria through an independent caspase pathway.<\/p>\n

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

In this study shows that AIF as the parameter of\u00a0caspase-independent\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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