Mol. Hum. Reprod. Advance Access originally published online on January 29, 2004
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Molecular Human Reproduction, Vol. 10, No. 3, pp. 167-171, 2004
© European Society of Human Reproduction and Embryology 2004
Effects of 4-hydroxy-2-nonenal, a marker of oxidative stress, on the cyclooxygenase-2 of human placenta in chorioamnionitis
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871 and 2Department of Obstetrics and Gynecology, NTT Osaka Hospital, 2-6-40 Karasugatuji, Tennoji, Osaka City, Osaka 543-8922, Japan
3 To whom correspondence should be addressed. e-mail address: shimoya{at}gyne.med.osaka-u.ac.jp
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Chorioamnionitis (CAM) is one of the causes of preterm labour. A recent study has indicated that NADPH oxidase, a reactive oxygen species (ROS)-producing enzyme, is activated in CAM. CAM is thought to be closely associated with oxidative stress. We have hypothesized that oxidative stress in CAM may induce preterm labour. The purpose of this study is to examine the effect of 4-hydroxy-2-nonenal (HNE), which is a marker of oxidative stress, on human placenta during preterm labour. We initially examined the HNE-modified proteins in human placentas by immunoblotting and immunohistochemistry using anti-HNE antibody. To examine the effect of HNE on human placenta, we stimulated human placental tissue with HNE. The expressions of cyclooxygenase-2 (COX-2) mRNA and protein were observed by RT–PCR and western blot analysis respectively. Furthermore, we measured the peroxidase activity of COX-2 by COX activity assay kit. Prostaglandin E2 (PGE2) in the supernatants of placental tissue was also determined by enzyme-linked immunosorbent assay. Immunoblotting and immunohistochemistry showed that the levels of HNE-modified proteins were increased in the placentas with CAM, compared to the normal placenta. HNE induced the expression of COX-2 mRNA, protein and activity in the placental tissue culture stimulated with HNE. In addition, PGE2 was also released into the medium in a time-dependent fashion. These findings suggest that HNE-modified proteins, which were increased in the placenta with CAM, play an important role in preterm labour.
Key words: Key words: chorioamnionitis/COX-2/HNE/oxidative stress
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Introduction |
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Preterm delivery remains the most important cause of perinatal morbidity and mortality despite recent advances in tocolytic treatment and neonatal intensive care (Cunningham, 2001). Chorioamnionitis (CAM) is one of the causes of preterm labour. In CAM, placental cells are activated by infectious stimuli such as bacterial endotoxins. In this condition, various cytokines, such as interleukin (IL)-1, IL-6 and IL-8, are produced by the placenta (Taniguchi et al., 1991; Shimoya et al., 1992a, 1999; Matsuzaki et al., 1993). Such elevated placental cytokines result in elevation of fetal and amniotic fluid cytokine concentrations (Shimoya et al., 1992b). Activated fetal immunocompetent cells also contribute to elevation of the cytokine concentrations in the cord serum (Taniguchi et al., 1993). These processes participate in the fetomaternal defence mechanism.
Aerobic metabolism produces reactive oxygen species (ROS) in the human. Recent studies have indicated that ROS can regulate the expression of genes by changing the activity of some transcription factors (Kamata et al., 1999; Dubinina, 2001) but that excessive ROS induce cellular damage (Droge, 2002). Oxidative stress, which generates ROS, has been postulated to be involved in the pathophysiology of numerous diseases including arteriosclerosis, diabetes, post-ischaemic reoxygenation injury, alcoholic fatty liver, ageing, and cancer (Halliwel and Gutteridge, 1989; Re et al., 1998; Droge, 2002). In some of these diseases, cyclooxygenase-2 (COX-2) or prostaglandin (PG) overexpression has been detected (Chan et al., 1999; Enomoto et al., 2000; Koki et al., 2002). Preterm labour in CAM may be associated with oxidative stress. In infectious diseases such as CAM, activated phagocytes migrate from the maternal circulation to the fetal membranes, where they encircle and digest bacteria in order to protect the mother (Benirschke and Kaufmann, 2000). In the next step, powerful ROS are produced by phagocyte NADPH oxidase (Robinson et al., 1995). On the other hand, some complications such as preterm premature rupture of membranes (PPROM) during pregnancy are thought to be closely associated with ROS (Woods, 2001). One of the sources of ROS at PPROM might be release by immune cells as they encircle and then kill bacteria.
4-Hydroxy-2-nonenal (HNE)-modified proteins are markers of oxidative stress. HNE is the major end-product of oxidative fatty acid metabolism, and is generated by a free radical chain reaction mechanism during oxidative stress (Esterbauer et al., 1991). We have hypothesized that ROS, i.e. ‘oxidative stress’, in CAM may induce preterm labour, along with the up-regulation of COX-2. In the present study, we examined the accumulation of HNE-modified proteins in the placenta of patients with CAM. We also evaluated the effect of HNE in placental tissue on COX-2 expression and PG synthesis.
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Materials and methods |
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Reagents
Mouse anti-HNE-modified protein monoclonal antibodies were purchased from JICA (Japan). Normal mouse IgG for use as a control in the histochemical analysis was purchased from Zymed Laboratories (USA).
Samples
We collected normal placentas and placentas from women with chorioamnionitis. Normal placentas were obtained at term from healthy women by normal vaginal delivery or elective Caesarean section before onset of labour. Placentas from women with CAM were obtained at 23, 26, 33 and 39 weeks of gestation. CAM was diagnosed by both clinical findings of infection and histopathological analysis of the placenta. A portion of each placenta was fixed in 10% formalin for immunohistochemistry. Then the rest of each placenta was frozen in liquid nitrogen and stored at –80°C until use.
Tissue preparation for western blot analysis
The homogenizing buffer for extraction of protein from the placentas consisted of 0.5 mol/l Tris–HCl (pH 6.8), 10% sodium dodecyl sulphate (SDS), 6% ß-mercaptoethanol, and 1% Bromophenol Blue. Samples of the placentas were homogenized in a 2 ml volume. Homogenates were centrifuged at 4°C for 30 min at 14 000 g to remove debris. Following protein determinations, the samples were aliquoted and subjected to polyacrylamide gel electrophoresis (PAGE).
Western blot analysis of placentas for HNE
To examine HNE-conjugated proteins in the placentas, we performed western blot analysis using a polyclonal antibody specific for HNE-modified proteins. Ten micrograms of placental protein were electrophoresed on a 15% SDS–polyacrylamide gel and transferred onto a nitrocellulose membrane (0.45 µm; Schleicher and Schuell, Germany). The membrane was incubated with 5% dried milk protein followed by anti-HNE polyclonal antibody. The primary antibody was used at a final concentration of 1.0 µg/ml. The HNE immunoreactivity was visualized using the enhanced chemiluminescence (ECL) western blot analysis system (Amersham, UK).
Western blot analysis of placentas for COX-2
To determine the level of COX-2 protein in the placentas stimulated with HNE, we performed western blot analysis using COX-2 polyclonal antibody (No. sc-1745) (Santa Cruz Biotechnology, USA). Ten micrograms of placental protein were electrophoresed on a 10% SDS–polyacrylamide gel and transferred onto a nitrocellulose membrane (0.45 µm; Schleicher and Schuell). The membrane was incubated with 5% dried milk protein followed by anti-COX-2 polyclonal antibody. The primary antibody was used at a final concentration of 1.0 µg/ml. The COX-2 immunoreactivity was visualized using the ECL western blotting analysis system (Amersham).
Protein assay
Protein levels were determined with Bio-Rad (USA) Protein Determination Reagent, according to the method of Bradford (1976).
RNA extraction
RNA was extracted from placental tissue samples of 0.2 g wet weight by acid guanidine thiocyanate–phenol–chloroform extraction according to the method of Chomczynski and Sacchi (1987).
RT–PCR amplification
RT–PCR was performed using an RT–PCR high kit (Toyobo Co., Japan). The reaction was carried out in a mixture containing M-MLV (Maloney murine leukaemia virus) RTase (reverse transcriptase) and 1 µg of RNA sample in 1xRTase buffer, supplemented with random hexamers, and dNTP mix for 40 min at 42°C. PCR amplification was performed using the RT mixture after the incubation described above (10 µl), with sequence-specific primers for COX-2 (5'-TTCAAATGAGATTGTGGGAAAATTGCT-3'/5'-ATATCATCTCTGC CTGAGTATCTT-3') or glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (5'-ACCACAGTCCATGCCATAAC-3'/5'-TCCACCACCCTGTTGCTGTA-3'). PCR was carried out for 35 cycles using a thermal cycler (Perkin–Elmer/Cetus, USA). Each cycle consisted of denaturation at 94°C (40 s), annealing at 52°C (40 s), and extension at 72°C (40 s). For amplification of G3PDH, 25 cycles of 94°C for 40 s, 52°C for 40 s, and 72°C for 40 s were performed. Amplification using COX-2-specific primers yielded a 305 bp DNA product with a sequence that matched the published sequence of the COX-2 gene (Hla and Neilson, 1992). RT was performed with total RNA without reverse transcriptase (a mock RT sample) to detect possible contamination of RNA samples by genomic DNA. Twenty microlitres of a 50 µl PCR mixture was electrophoresed on a 1% agarose gel and stained with ethidium bromide, and the amplified products were visualized by UV illumination. Molecular sizes were estimated by comparison with a 100 bp DNA ladder. All primers were obtained from Life Technologies (Japan).
Immunohistochemical staining of HNE in the placentas
To determine the localization of HNE in the placenta, we performed immunohistochemical staining by using an avidin–biotin peroxidase complex method kit (OminiTags Universal Streptavidin/Biotin Affinity Immunostaining Systems, USA). Paraffin sections of the placentas were incubated in 0.3% hydrogen peroxide to block endogenous peroxidase and covered with 2% goat IgG to minimize non-specific binding. The 1000-fold diluted mouse anti-HNE modified protein monoclonal antibodies or the control IgG was applied at room temperature and left for 1 h. After the sections were rinsed with phosphate-buffered saline solution, they were further incubated for 30 min with biotin-labelled goat anti-mouse IgG, and then with avidin–peroxidase complex at 4°C. Peroxidase activity in the sections was visualized with 0.1% 3,3-diaminobenzidinine tetrahydrochloride containing 0.02% hydrogen peroxide in 0.1 mol/l Tris buffer (pH 7.2). The slides were counterstained with Mayer’s haematoxylin. HE (haematoxylin and eosin) staining was performed on the same sections.
Tissue culture and the effect of HNE in placental tissue on COX-2 expression
Placentas were obtained at term from uncomplicated women undergoing elective Caesarean section without labour because of breech presentation or repeat Caesarean section. The placentas were thoroughly washed, separated from the connective tissue and the deciduas, and minced on ice, to produce tissue blocks 3 mm in diameter. The samples of villous tissue were incubated with 1 ml of medium (Roswell Park Memorial Institute 1640 containing 10% heat-inactivated fetal bovine serum and 1% penicillin) at 37°C in an atmosphere of 95% air and 5% CO2 in 24-well flat-bottomed microplates. The tissues were treated with various concentrations of HNE. After the tissues were cultured for a specific period, the supernatants and tissues were collected and stored at –80°C.
COX activity assay
To measure the COX-2 activity in tissues treated with HNE (n = 3), COX activity assay kit (Cayman Chemical, USA) was used. This kit measures the peroxidase activity of cyclooxygenase. The peroxidase activity is assayed colorimetrically by monitoring the appearance of oxidized N',N',N',N'-tetramethyl-p-phenylenediamine at 590 nm. The peroxidase activity of COX-2 was assayed colorimetrically using COX-1 specific inhibitors. Samples containing COX activity between 3–80 nmol/min/ml can be assayed by the kit. The intra-and interassay CV were <10%.
ELISA (enzyme-linked immunosorbent assay) of PGE2
To measure the level of prostaglandin E2 (PE2) in the culture medium of tissues treated with 25 µmol/l HNE (n = 4), a PE2 enzyme immunoassay kit (EIA)–monoclonal (Cayman chemical, USA) was used. The intra- and inter-assay CV were <10%.
Statistical analysis
The data were subjected to one-way analysis of variance using the Statview statistics package (Abacus Concepts, Inc., USA). P < 0.05 was considered significant.
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We first examined placenta for the presence of HNE-modified proteins as a marker of oxidative stress. To detect HNE-modified proteins in the placenta, we performed immunohistochemistry and Western blotting. As shown in Figure 1, immunohistochemical analysis demonstrated that HNE-modified proteins were strongly stained in the placentas of women with CAM. Western blot analysis revealed that the level of HNE-modified proteins was increased in the placentas of women with CAM in comparison with normal placentas (Figure 2). Previous reports demonstrated that various low-density lipoprotein and certain membrane proteins are modified by HNE (Uchida et al., 1994; Mark et al., 1997). Morikawa et al. (1997) and Shibata et al. (2001) have investigated HNE-modified proteins of placenta. They reported that the molecular masses of HNE-modified proteins are 20–66 or 70–110 kDa. In this study, the smear-like immunopositive signals, ranging in molecular size between 20 and 80 kDa, were enhanced. The smear-like positive signals were increased in the placentas with CAM. These results suggested that placentas with CAM had been exposed to oxidative stress, resulting in the accumulation of HNE-modified proteins. To evaluate the effect of oxidative stress on placental tissue, we treated human placental tissue cultures with HNE. As shown in Figure 3, the level of COX-2 mRNA was increased by HNE treatment in a time-dependent fashion. The increases in the COX-2 mRNA were observed by 6 h. The dose dependency of the effects of HNE is shown in Figure 4. Maximal expression of COX-2 mRNA was observed at 25 µmol/l HNE. The level of COX-2 protein was also examined by western blotting. We observed that HNE-induced COX-2 protein was also increased at 25 µmol/l HNE (Figure 5). To examine the COX-2 activity in the placental tissue, the peroxidase activity of COX-2 was assayed colorimetrically using COX activity kit. The COX-2 activity was significantly increased compared to control (no treated HNE) (Figure 6). The amount of PE2 released into the medium was measured by ELISA. We observed a time-dependent increase of PE2 when the tissue was treated with 25 µmol/l HNE (Figure 7). Preterm labour is thought to be associated with the up-regulation of PG, which is synthesized by COX-2. Our findings therefore suggest that uterine contraction may be induced under oxidative stress, resulting in preterm labour.
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Discussion |
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In CAM, activated phagocytes migrate, encircle and digest bacteria in order to protect the mother and fetus from bacterial infection (Shimoya et al., 1999). Phagocyte NADPH oxidase produces powerful ROS, such as superoxide (O2–), hydrogen peroxide (H2O2), and hydroxyl radical (OH). Recent studies have revealed that this ROS-producing enzyme is also present in term placental trophoblasts. Chorion trophoblasts themselves possess ROS-generating capacity. In CAM, the proportion of chorion NADPH oxidase-positive cells significantly increases (Matsubara and Sato, 2001). ROS produced during these processes have the ability to damage cellular components such as membrane lipids. HNE is a toxic aldehyde generated by lipid peroxidation (White et al., 1984; Michels et al., 1991). In the present study we demonstrated that placentas of patients with CAM appeared to have been exposed to oxidative stress and to have accumulated HNE-modified proteins. Thus, HNE-modified proteins in the placenta can be used as markers that indicate damage due to oxidative stress.
The generated ROS not only damage the cell membrane, but also can alter cellular molecules that then act as second messengers (Kamata, 1999). Recent studies have revealed that cellular signalling pathways are regulated by the intracellular redox state. For example, it is known that cysteine residues in a reduced state are essential for the activity of many transcription factors (Kamata, 1999). In some studies, the association between lipid peroxidation products generated under oxidative stress and transcription factors has been investigated. Uchida et al. (1999) showed that the expression of transcription factor c-Jun was induced in liver cells by treatment with lipid peroxidation product HNE, the major end-product of oxidized fatty acid metabolism. Furthermore, Ruef et al. (2001) showed that HNE activates NF-
B, a redox-sensitive transcription factor, in vascular smooth muscle cells. It is presumed that HNE may regulate the expression of genes via effects on transcription factors under oxidative stress.
Slater et al. (1999) suggested that COX-2 is associated with the onset of labour. Preterm labour is generally thought to be associated with the up-regulation of PG, which is synthesized by COX-2. CAM is one of the causes of preterm labour, because it is associated with the production of PG. A previous study demonstrated that COX-2 overexpression is induced by HNE treatment (Kumagai et al., 2000). In the present study we treated placental tissue cultures with HNE and observed that HNE induced COX-2 mRNA and protein in a time- and dose-dependent fashion. The maximum response was observed at a concentration of 25 µmol/l HNE. Ruef et al. (2001) reported that 100 µmol/l HNE induced the apoptosis of vascular smooth muscle cell. The large amount of HNE might have toxic effects on cells and tissues. PG such as PGE2 act to mediate cervical ripening and stimulate uterine contraction (Crankshaw, 1994). PE2 synthesized in HNE-treated placental tissues by COX-2 was also shown to increase in a time-dependent fashion. These results demonstrate that the COX-2 induced by HNE was enzymatically active in the placenta.
In the present study we demonstrated that HNE was a marker for CAM. Our findings suggest that uterine contraction may be induced under oxidative stress, resulting in preterm labour. HNE might play a role in the preterm onset of labour in CAM via COX-2 induction. Previous studies demonstrated that antioxidants, such as vitamin C, vitamin E, and glutathione had a protective effect against several diseases (Exner et al., 2000). Protection against oxidative stress in the placentas of women with CAM might be effective for preventing preterm labour. Further investigations will be necessary to examine the ability of antioxidants to prevent preterm birth in CAM.
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Acknowledgements |
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This work was supported, in part, by Grants-in-Aid for Scientific Research (Nos. 13671712, 13671713, 13877273, 12671596, 15209054 and 15591746) from the Ministry of Education, Science, and Culture of Japan (Tokyo, Japan) and Akaeda Medical Research Foundation.
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Submitted on November 7, 2003; accepted on November 21, 2003.
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