基质金属蛋白酶-3在早产发动机制中的作用研究

目的:通过检测孕产妇血清及胎盘胎膜中的基质金属蛋白酶-3(MMP-3)水平,探讨其在宫缩发动及胎膜早破中的可能作用机制。方法:选择单胎、头位、初产妇280例作为研究对象,按孕周、胎膜是否破裂和是否临产分为7组:早产临产组、早产胎膜早破组、先兆早产组、足月临产组、足月胎膜早破组、妊娠28～36+6周无任何产兆组(未足月对照组,对照组Ⅰ)、足月妊娠无产兆择期剖宫产组(足月对照组,对照组Ⅱ)。用ELISA法检测孕妇血清中的MMP-3水平,用免疫组化SP法检测胎盘胎膜组织中的MMP-3表达情况。结果:血清MMP-3的平均水平为(212.58±63.03)ng/ml,早产临产组和早产胎膜早破组血清MMP-3水平均高于先兆早产组和对照组Ⅰ(P<0.05);足月临产组和足月胎膜早破组血清MMP-3水平均高于对照组Ⅱ(P<0.05);相关未足月组和足月组之间相比,早产临产组和足月临产组血清MMP-3水平比较差异有统计学意义(P<0.05)。胎盘MMP-3免疫积分在临产组及胎膜早破组升高(P<0.05);胎膜MMP-3免疫积分在早产组表达增加,在各胎膜早破组较同孕期临产组明显升高(P<0.05)。血清MMP-3水平与胎盘胎膜MMP-3水平呈正相关。结论:血清及胎盘胎膜中MMP-3的高表达可能参与早产的发动。     

Molecular epidemiology of preterm delivery: methodology and challenges

Preterm delivery (PTD) appears to be a complex trait determined by both genetic and environmental factors. Few studies have examined genetic influence on PTD. The overall goal of our study is to examine major candidate genes of PTD and to test gene–environment interactions. Our study includes 500 preterm trios, including 500 preterm babies and their parents and 500 maternal age-matched term controls. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamionotic inflammation: interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacental vascular lesions: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We will also perform standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene–environment interactions. The major environmental, nutritional and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene–environment interactions. This study integrates epidemiological and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding of genetic influences on PTD and gene–environment interactions.     

Maternal second-trimester serum ferritin concentrations and subsequent risk of preterm delivery

We studied the relationship between maternal second-trimester serum ferritin concentrations and preterm delivery. The 312 preterm delivery cases, studied in aggregate and in subgroups [spontaneous preterm labour, preterm premature rupture of membranes, medically induced preterm delivery, moderate preterm delivery (gestational age at delivery 34-36 weeks) and very preterm delivery (gestational age at delivery <34 weeks)] were compared with 424 randomly selected women who delivered at term. Maternal ferritin concentrations, measured in serum collected at 17 weeks gestation on average, was determined using a two-site chemiluminometric immunoassay. Using multiple logistic regression, we derived maximum likelihood estimates of adjusted odds ratios (OR) and 95% confidence intervals [CI]. Elevation in maternal second-trimester ferritin was weakly associated with the risk of preterm delivery overall. After adjusting for possible confounding by maternal age, race/ethnicity, parity, Medicaid payment status and smoking during the index pregnancy, the OR for extreme quartiles (>64.5 vs. <26.0 ng/mL) of ferritin was 1.3 [95% CI 0.8, 2.1]. Stratified analyses indicated that elevated maternal serum ferritin was associated with an increased risk of preterm premature rupture of membranes (OR = 2.1; 95% CI 1.1, 4.1), but not with spontaneous preterm labour (OR = 0.9; 95% CI 0.4, 1.7) or medically induced preterm delivery (OR = 1.1; 95% CI 0.6, 2.0). The relationship between elevated maternal second-trimester serum ferritin concentrations and preterm delivery was strongest for spontaneous very preterm deliveries (<34 weeks gestation). Women with ferritin concentrations in the highest decile (>96 ng/mL) experienced a 2.7-fold increased risk of delivering before 34 completed weeks, compared with women with concentrations <26.0 ng/mL. These results are consistent with some previous reports, and further underline the potential for heterogeneity in the aetiology of preterm delivery.     

细胞间黏附分子-1在早产胎膜早破患者胎膜组织中的表达及意义

目的:研究细胞间黏附分子-1(ICAM-1)在早产胎膜早破患者胎膜组织中的表达及意义。方法:收集产科已确诊的早产胎膜早破的38例患者的胎膜为研究组,收集与研究组孕妇孕周相对应的胎膜完整的自发早产的36例孕妇的胎膜为对照组,应用免疫组化二步法检测两组胎膜ICAM-1的表达,并进行临床病理的相关性分析。结果:两组胎膜中均存在不同程度的ICAM-1阳性表达,两组比较差异有统计学意义(P<0.05);研究组中有21例(55.26%)存在绒毛膜羊膜炎,对照组中有13例(36.11%)存在绒毛膜羊膜炎,两组比较差异有统计学意义(P<0.05),研究组ICAM-1的表达与绒毛膜羊膜炎的相关系数为0.90,对照组ICAM-1的表达与绒毛膜羊膜炎的相关系数为0.72,且病理显示炎症越重的胎膜,其ICAM-1的阳性表达越明显。结论:ICAM-1的表达与胎膜的感染程度相关,感染越重的胎膜其ICAM-1的表达越明显,提示妊娠的结局相对严重;ICAM-1在早产早破胎膜中的表达也提示其在早产胎膜早破的发病过程中可能起一定的作用。     

Preterm labour and delivery: a genetic predisposition

Preterm delivery (PTD) complicates as many as 10% of pregnancies in the United States. Moreover, prematurity accounts for more than 70% of the consequent neonatal and infantile morbidity and mortality. Serious long-term complications include cerebral palsy, respiratory disease, blindness and deafness. Despite substantial basic scientific, translational and clinical investigation in recent years, the PTD rate (10%) and the low birthweight rate (7%) remain largely unchanged. Indeed, the very aetiology and pathophysiology of PTD remain unknown in most cases. In short, PTD continues to constitute a major clinical and public health challenge of the highest order, a circumstance further compounded by the controversy surrounding the efficacy of current therapeutic regimens. In an effort to address the relevant knowledge gap, we put forth the hypothesis that PTD results, at least in part, from a genetic predisposition. Evidence supporting the hypothesis that certain women have a genetic predisposition to deliver preterm is growing. Moreover, the discovery of a gene mutation predisposing to PTD would constitute a major breakthrough for future research into the biology, prediction, and therapy of preterm labour. Presented here is a discussion of the evidence to support a genetic predisposition to PTD, molecular techniques proposed to study the genetics of preterm labour, and plausible candidate genes that warrant further investigation.     

基质金属蛋白酶-9表达与早产胎膜早破的相关性研究

目的:研究基质金属蛋白酶-9(MMP-9)在胎膜组织上的表达情况与早产胎膜早破的相关性。方法:荧光定量PCR(SYBR Green法)检测MMP-9mRNA;Western blot法检测MMP-9蛋白表达量;结果:早产胎膜早破组与足月胎膜早破组相比较,MMP9不存在统计学差异(Z=-1.783,P=0.075);与自发性早产组比较,MMP9不存在统计学差异(Z=-0.157,P=0.875);而早产胎膜早破组与正常足月产组比较MMP9存在统计学差异(Z=-3.316,P=0.001)。早产胎膜早破组MMP-9蛋白表达高于足月产组,之间的差异具有统计学意义(t=-12.339,P<0.01)。结论:MMP-9与早产胎膜早破存在相关性,在其发病机制中有着重要作用。     

Regulation of prostaglandin synthesis in the human amnion

An increase in prostaglandin synthesis by intrauterine tissues may be responsible for labour initiation and/or maintenance in humans. In all studies to date, the amnion is the intrauterine tissue whose prostaglandin output consistently increases with the onset of labour. This may be due, in part, to acute activation of the phospholipases A2 and C and to an increase in the specific activity of prostaglandin H synthase (PGHS). A number of factors exist in amniotic fluid, the fetal membranes, the decidua and the placenta that can increase PGHS specific activity. Some of these factors may increase PGHS enzyme activity by gene expression and protein synthesis. Preliminary evidence is presented that suggests the hypothesis that PGHS specific activity increases before the onset of labour rather than as a consequence of labour initiation, and that idiopathic preterm labour may frequently be associated with increased PGHS activity. Hence, activation of PGHS gene expression and/or protein synthesis may be causal for term and preterm labour.     

Pregnancy outcomes and community health: the POUCH study of preterm delivery

In light of the social/ethnic disparity in preterm delivery (PTD) rates, the Pregnancy Outcomes and Community Health (POUCH) Study takes a broad view of the determinants of PTD by attempting to link underlying biological and psychosocial factors. The relationships between placental pathology, maternal biomarkers, and antecedent psychosocial factors are evaluated in three hypothesised pathways of PTD - one characterised primarily by infection, one by maternal vascular disease, and one by premature elevations in corticotropin releasing hormone in the absence of histological evidence of placental pathology. Within each pathway, an emphasis is placed on understanding the roles of stress and of maternal serum alpha-fetoprotein, an early biomarker associated with PTD. The POUCH Study enrolls pregnant women from five Michigan communities. Information about these women and their environments is gathered through detailed interviews and collection of biological samples including hair, urine, saliva, blood, vaginal fluid, and vaginal smear at 15-26 weeks of gestation. We have chosen to focus on the second trimester--a time when pathological processes may have evolved to a detectable stage, but generally before the onset of biological changes that accompany labour. This focus is consistent with the long-range goal of early detection/intervention and prevention of PTD.     

Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: Exposure prevalence,preterm delivery,and specific birth defects

We estimated exposure prevalence and studied potential risks for preterm delivery (PTD) and specific birth defects associated with exposure to the unadjuvanted pH1N1-containing vaccines in the 2009–2010 and 2010–2011 influenza seasons.     

Pregnancy outcomes and community health: the POUCH study of preterm birth

In light of the social/ethnic disparity in preterm delivery (PTD) rates, the Pregnancy Outcomes and Community Health (POUCH) Study takes a broad view of the determinants of PTD by attempting to link underlying biological and psychosocial factors. The relationships between placental pathology, maternal biomarkers, and antecedent psychosocial factors are evaluated in three hypothesised pathways of PTD – one characterised primarily by infection, one by maternal vascular disease, and one by premature elevations in corticotropin releasing hormone in the absence of histological evidence of placental pathology. Within each pathway, an emphasis is placed on understanding the roles of stress and of maternal serum alpha-fetoprotein, an early biomarker associated with PTD. The POUCH Study enrols pregnant women from five Michigan communities. Information about these women and their environments is gathered through detailed interviews and collection of biological samples including hair, urine, saliva, blood, vaginal fluid, and vaginal smear at 15–26 weeks of gestation. We have chosen to focus on the second trimester – a time when pathological processes may have evolved to a detectable stage, but generally before the onset of biological changes that accompany labour. This focus is consistent with the long-range goal of early detection/intervention and prevention of PTD.     

趋化因子MCP-1与妊娠期下生殖道感染及感染性早产的相关性研究

目的研究趋化因子MCP-1在孕妇宫颈分泌物、母血清、脐血清中的表达及其与下生殖道感染及感染性早产的关系。同时，探索孕妇宫颈分泌物中MCP-1水平，对预测感染性早产的可行性。方法以2004年7月至2005年7月分别在四川大学华西第二医院及德阳市人民医院围生门诊行产前检查，并住院分娩的140例孕妇[A组（早产组），n=72；B组（足月组），n=68]为研究对象。收集生殖道感染与未感染孕妇的宫颈分泌物，进行病原微生物学培养。分娩时，对胎盘、胎膜组织作绒毛膜羊膜炎的病理学诊断，采集孕妇宫颈分泌物、母血清、脐血清，用定量双抗体夹心酶联免疫吸附（ELIsA）法分别检测MCP-1水平。按上述测试结果，将A组分为早产宫颈分泌物病原微生物呈阳性组（A1组，n=36），早产宫颈分泌物培养呈阴性组（A2组，n=36）；将B组分为足月产宫颈分泌物病原微生物检测呈阳性组（B1组，n=30），足月产宫颈分泌物病原微生物检测呈阴性组（B2组，n=38）。（本研究遵循的程序符合四川大学华西第二医院及德阳市人民医院人体试验委员会所制定的伦理学标准，得到其批准，取得受试对象的知情同意，并与受试者签署临床研究知情同意书）。结果A组微生物阳性检出率（50．00％，36／72）高于B组（44．12％，30／68），两组比较，差异有显著意义（P〈0．01）；病理学诊断绒毛膜羊膜炎构成比显示，A组（36．11％，26／72）明显高于B组（8．82％，6／68），两组比较，差异有显著意义（P〈0．01）。A1组宫颈分泌物及血清MCP-1蛋白水平较其他三组（A2，B1，B2组）显著升高，差异有显著意义（P〈0．001）。结论有下生殖道感染早产孕妇的宫颈分泌物、母血清及脐血清中MCP-1蛋白的表达水平增强，与绒毛膜羊膜炎相关。宫颈分泌物中趋化因子MCP-1可作为预测感染性早产的指标。     

A review of the literature on the effects of ambient air pollution on fetal growth

A systematic review of the literature on the effects of air pollution on low birth weight (LBW) and its determinants, preterm delivery (PTD) and intrauterine growth restriction (IUGR), was conducted. Twelve epidemiologic investigations that addressed the impact of air pollution on four pregnancy outcomes were identified. Results were analyzed separately for each perinatal outcome because of differences in pathogenic mechanisms. Effects of air pollution were apparent on PTD and IUGR, but not on LBW. Most of the associations reported were rather small. The estimation of summary effects was not meaningful because of the heterogeneity of the effect estimates arising from differences in the measurements of outcome, exposure, and confounders and the small number of studies per outcome (four studies for PTD and six for IUGR). Current scientific knowledge on the impact of air pollution on fetal growth is still limited; thus, several issues should be examined further.     

Leukocyte migration in adipose tissue of mice null for ICAM-1 and Mac-1 adhesion receptors

OBJECTIVE: To determine whether the leukocyte adhesion receptors ICAM-1 and Mac-1, regulators of immune cell migration, have an intrinsic role within adipose tissue by 1) analyzing the expression of ICAM-1 in adipose tissue, 2) identifying leukocyte populations within adipose tissue, and 3) determining whether ICAM-1 and Mac-1 mutant mice exhibit abnormal numbers of adipose tissue leukocytes. RESEARCH METHODS AND PROCEDURES: Wild-type, ICAM-1(-/-), and Mac-1(-/-) mice were fed a long-term high-fat diet. ICAM-1 expression was analyzed by Northern blot and immunohistochemistry. Leukocytes within adipose tissue were identified by immunohistochemistry and flow cytometry. RESULTS: ICAM-1 was expressed in adipose tissue and localized to the vascular endothelium. Macrophages and lymphocytes were prevalent within the stromal-vascular cell fraction of adipose tissue, and gender-specific differences were observed, with adipose tissue from female mice containing significantly more macrophages than tissue from male mice. Numbers of leukocytes in ICAM-1(-/-) and Mac-1(-/-) mice were not different from wild-types, however, indicating that these adhesion receptors are not required for leukocyte migration into adipose tissue. DISCUSSION: Our results documented leukocyte populations within adipose tissue, which may be involved in the development of heightened inflammation that is characteristic of obesity.     

Smoking during pregnancy according to obstetric complications and parity: results of the EUROPOP study

This study aimed to analyse the relationship between smoking and preterm birth (22-36 weeks) according to the main obstetric complications leading to the preterm birth, both overall and by parity. The EUROPOP study is a case-control study carried out between 1994 and 1997; 3,787 preterm and 5,602 full-term births were included, from maternity units in 10 countries, using the same protocol. Social, demographic and medical information was collected after delivery, from obstetric records and interviews with the mothers. Cases were classified according to the main obstetric complication (hypertension, haemorrhage, preterm premature rupture of membranes (PPROM), idiopathic spontaneous preterm labour, intrauterine growth retardation, all other causes). Multiple logistic regression analysis was used to control for confounders. Twenty four percent of cases and 20% of controls were smokers. Smoking during pregnancy, heavy smoking (>or=10 cigarettes per day) in particular, was a risk factor for preterm birth (aOR = 1.39, 95% CI:1.20-1.60). Smoking increased the risk of preterm delivery due to all obstetric complications other than hypertension. For these complications, the risk of preterm delivery associated with smoking was higher for multiparae (aOR = 1.46, 95% CI:1.24-1.71) than for primiparae (aOR = 1.18, 95% CI:1.00-1.38). In conclusion, smoking during pregnancy increases the risk of preterm birth among women with all obstetric complications except hypertension. This association is stronger in multiparae than in primiparae and the risk is higher for heavy smokers.     

State-specific changes in singleton preterm births among black and white women--United States, 1990 and 1997

National infant mortality rates among non-Hispanic black women are twice those of non-Hispanic white women (1). Nearly two-thirds of this disparity is attributable to a higher rate of preterm delivery (PTD) (i.e., < or = 37 weeks' gestation) among blacks (2). To investigate state-specific changes in PTD rates among blacks and whites, natality data for 1990 and 1997 were analyzed from 50 states and the District of Columbia (DC). These data indicated that, although the PTD rate was twice as high among blacks than among whites, the disparity decreased as the result of an increase in preterm births among whites and a decrease among blacks (3).     

Work activity in pregnancy, preventive measures, and the risk of preterm delivery

The objective of this case-control study was to evaluate whether occupational conditions during pregnancy are associated with preterm delivery (PTD). Women whose work conditions changed following the use of a legally justified preventive measure (withdrawal from work or job reassignment) were also compared with those whose work conditions did not change. Cases (n = 1,242) and controls (n = 4,513) were selected from 43,898 women who had single livebirths between January 1997 and March 1999 in Québec, Canada. They were interviewed by telephone after delivery. Results showed association of PTD with demanding posture for at least 3 hours per day, whole-body vibrations, high job strain combined with low or moderate social support, and a cumulative index composed of nine occupational conditions. The adjusted odds ratio increased from 1.0 to 2.0 for PTD (ptrend < 0.0001) and from 1.0 to 2.7 for very PTD (<34 weeks; ptrend = 0.0015) as the number of conditions increased from zero to four or more. The associations for PTD and very PTD with most of the above-mentioned work conditions were weaker when exposures were eliminated following recourse to a legally justified preventive measure. This study provides relevant information on the possible influence of preventive measures on the risk of PTD in pregnant workers.     

Hostility and anomie: links to preterm delivery subtypes and ambulatory blood pressure at mid-pregnancy

Underlying maternal vascular disease has been implicated as one of several pathways contributing to preterm delivery (PTD) and psychosocial factors such as hostility, anomie, effortful coping, and mastery may be associated with PTD by affecting maternal vascular health. Using data from the Pregnancy Outcomes and Community Health (POUCH) study, we included 2018 non-Hispanic White and 743 African American women from 52 clinics in five Michigan, USA communities. Women were interviewed at 15-27 weeks' gestation and followed to delivery. We found that relations between psychosocial factors and PTD subtypes (i.e. medically indicated, premature rupture of membranes, spontaneous labor) varied by race/ethnicity and socio-economic position (Medicaid insurance status). Among African American women not insured by Medicaid, anomie levels in mid-pregnancy were positively associated with medically indicated PTD after adjusting for maternal age and education. Among all women not insured by Medicaid, hostility levels were positively associated with spontaneous PTD after adjusting for maternal race/ethnicity, age, and education. Failure to detect links between psychosocial factors and PTD risk in poorer women may be due to their excess risk in multiple PTD pathways and/or a more complex web of contributing risk factors. In a subset of 395 women monitored for blood pressure, anomie scores were positively associated with systolic blood pressure and heart rate and hostility scores were positively associated with systolic and diastolic blood pressure, heart rate and mean arterial pressure in models that included time, awake/asleep, race/ethnicity, and age as covariates. Further adjustment for body mass index and smoking attenuated the anomie-vascular relations but had little effect on the hostility-vascular relations. Overall this study of pregnant women provides some physiologic evidence to support findings linking levels of anomie and hostility with risk of PTD.     

表皮生长因子受体及PI3K在硫酸锌诱导人呼吸道上皮细胞间粘附分子-1表达过程中的作用

目的探讨硫酸锌对上皮细胞内细胞间粘附分子-1(ICAM-1)表达的影响及其分子生物学机制。方法应用PCR与蛋白质免疫印迹试验检测硫酸锌诱导人呼吸道上皮细胞ICAM-1mRNA与蛋白的表达,以及表皮生长因子受体(EGFR)及PI3K的活化。结果硫酸锌可诱导ICAM-1mRNA与蛋白的过量表达。在同一试验条件下,硫酸锌可诱发EGFR及磷脂酰肌醇3激酶(PI3K)下游激酶Akt的磷酸化或活化。用EGFR抑制剂(PD153035)及PI3K抑制剂(LY294002)预处理上皮细胞,可明显抑制硫酸锌对ICAM-1表达的诱导作用。结论硫酸锌可激活EGFR与PI3K/Akt信号传导通路,进而上调ICAM-1的表达。