多普勒超声检测胎羊炎症反应综合征的实验研究及机制探讨
|
摘要
目的采用多普勒超声检测胎羊炎症反应综合征(FIRS)血流动力学变化,同时分析各种动力学参数与TNF-α、IL-6之间的相关性。并初步探讨FIRS时胎羊心功能改变可能机理。
方法22只晚孕山羊分成3组:1.对照组;2.脐静脉给内毒素(LPS)组;3.羊膜腔内给LPS组。两给LPS组行超声引导下脐静脉穿刺术和羊膜腔穿刺术,注射LPS,并分别于注射LPS前后不同时间点采用多普勒超声心动图检测胎羊各种血流动力学参数,同时取胎羊血检测TNF-α、IL-6含量以及丙二醛(MDA)、心肌肌钙蛋白I(cTnI)含量,评价各种血流动力学参数与TNF-α、IL-6之间的相关性。检测心肌组织Fas mRNA表达水平及心肌细胞核转录因子(NF-κB p65)蛋白含量,免疫组化测量心肌组织胱门蛋白酶3(caspase3)表达。
结果1.实验组给LPS后TNF-α、IL-6随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。2.外周血管中脐动脉(UmA)、肾动脉(RA)、静脉导管(DV)搏动指数(PI)均随时间升高(P＜0.05),并且高于对照组(P＜0.05);大脑中动脉(MCA)PI随时间持续下降(P＜0.05),并且低于对照组(P＜0.05)。3.心功能指标中,左心室、右心室(LV、RV)Tei指数随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05);三尖瓣、二尖瓣(TV、MV)E/A值、(LV、RV)射血分数(EF)先升高,随后持续下降(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。4.胎羊UmAPI,RAPI,DV PI,(LV、RV)Tei指数,与血TNF-α水平呈正相关(r=0.724,r=0.668,r=0.784,r=0.765,r=0.683,P＜0.01),与血IL-6水平呈正相关(r=0.771,r=0.760,r=0.823,r=0.805,r=0.749,P＜0.01),MCA PI与血TNF-α、IL-6水平呈负相关性(r=-0.727,r=-0.728,P＜0.01)。LV EF、RV EF、TV E/A、MV E/A与血TNF-α水平没有相关性(r=-0.195,r=-0.157,r=-0.204,r=-0.156,P＞0.05),与血IL-6水平也没有相关性(r=-0.157,r=-0.128,r=-0.199,r=-0.228,P＞0.05)。5.实验组给LPS后MDA、cTnI随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。6.实验组给LPS后心肌组织的NF-κB p65蛋白含量增加、Fas mRNA表达上调、caspase3表达增加(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。
结论1.外周血管中DV PI与胎羊血TNF-α、IL-6水平之间的相关性最强;心功能指标中Tei指数与胎羊血TNF-α、IL-6水平之间的相关性最强。因此,DV PI与Tei指数可作为预测FIRS简单而有效的参考指标。
2.LPS引发胎羊体内炎症级联反应,多种因素参与其中,导致胎羊发生SIRS,最终能导致多器官功能衰竭(MOF)。
3.心肌细胞的凋亡在SIRS胎羊心肌损伤中可能起着重要的作用。
Objective To evaluate the changes of hemodynamic during fetal inflammatory response syndrome(FIRS) period by Doppler ultrasound,and assess the corrlation between hemodynamic paratmeters and fetal plasma TNF-αand IL-6 concentration, and explore its possible mechanism in fetal cardiac function.
Methods 22 near-term pregnant sheep were used in this study,Uuder ultrasound guidance,10 animals were performed with LPS-cordocentesis,7 animals were performed with LPS-amniocentesis and another 5 animals as a control group.In experiment groups animal,LPS was injected into the umbilical cord vein(10μg/kg of fetal body weight) and amniotic cavity(200μg/kg of maternal body weight) at 120(range 116-130) days gestation(term=145 days ),respectively.Doppler echocardiography were performed at different time during LPS administration.Fetal umbilical cord blood samples were collected and measured for TNF-α,IL-6,MDA and cTnI.The correlation coefficient was calculated to established the relationship between the TNF-α,IL-6 concentation and Doppler scanning values.The mRNA of Fas and protein of nuclear factor-K B p65(NF-κB p65 ) and caspase3 of fetal myocardium were examined with immunohistochemistry.
Results 1.After LPS administration,the fetal plasma TNF-α,IL-6 level significantly increased with time(P<0.05),and still significantly increased as compared with the control animals(P<0.05).2.In the peripheral vessels,the fetal umbilical artery (UmA),renal artery(RA),ductus venous(DV) waveform pulsatility index(PI) values significantly increased with time(P<0.05),and still significantly increased as compared with the control animals(P<0.05).However,the fetal middle cerebral artery(MCA) PI values significantly reduced with time(P<0.05),and still significantly reduced as compared with the control animals(P<0.05).3.In the cardiac function values,left and right ventricle(LV,RV) Tei indices significantly increased with time(P<0.05),and still significantly increased as compared with the control animals (P<0.05),however,LV ejection fraction(EF),RV EF,tricuspid valve(TV) E/A ratio and mitral valve(MV) E/A ratio significantly increased and thus reduced(P<0.05),and still significantly different as compared with the control animals(P<0.05).4.There were significantly positive correlation between UmA PI,RA PI,DV PI,LV Tei index, RV Tei index and TNF-α(r=0.724,r=0.668,r=0.784,r=0.765,r=0.683,P<0.01) and IL-6(r=0.771,r=0.760,r=0.823,r=0.805,r=0.749,P<0.01 ).There were significantly negative correlation between MCA PI and TNF-α,IL-6(r=-0.727, r=-0.728,P<0.01 ).And there were no correlation between LV EF,RV EF,TV E/A ratio,MV E/A ratio and TNF-α(r=-0.195,r=-0.157,r=-0.204,r=-0.156, P>0.05) and IL-6(r=-0.157,r=-0.128,r=-0.199,r=-0.228,P >0.05).5.After LPS administration,the fetal plasma MDA,cTnI level significantly increased with time(P<0.05),and still significantly increased as compared with the control animals (P<0.05).6.FIRS could upregulating the express of Fas mRNA,enhancing the protein quantity of NF-κB p65,increasing the express of caspase3 in fetal myocardium(P<0.05),and still significantly different as compared with the control animals(P<0.05).
Conclusions 1.Mostly Doppler parameters were significantly associated with TNF-αand IL-6 concentration.DV PI exhibits the strongest relationship in peripheral vessels,and Tei index exhibits the strongest relationship in cardiac function values,respectively.Therefore,DV PI and Tei index might be an useful quantitative parameters for assessing FIRS.2.Apotosis of myocardial cell might be associated with cardiac dysfunction.
方法22只晚孕山羊分成3组:1.对照组;2.脐静脉给内毒素(LPS)组;3.羊膜腔内给LPS组。两给LPS组行超声引导下脐静脉穿刺术和羊膜腔穿刺术,注射LPS,并分别于注射LPS前后不同时间点采用多普勒超声心动图检测胎羊各种血流动力学参数,同时取胎羊血检测TNF-α、IL-6含量以及丙二醛(MDA)、心肌肌钙蛋白I(cTnI)含量,评价各种血流动力学参数与TNF-α、IL-6之间的相关性。检测心肌组织Fas mRNA表达水平及心肌细胞核转录因子(NF-κB p65)蛋白含量,免疫组化测量心肌组织胱门蛋白酶3(caspase3)表达。
结果1.实验组给LPS后TNF-α、IL-6随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。2.外周血管中脐动脉(UmA)、肾动脉(RA)、静脉导管(DV)搏动指数(PI)均随时间升高(P＜0.05),并且高于对照组(P＜0.05);大脑中动脉(MCA)PI随时间持续下降(P＜0.05),并且低于对照组(P＜0.05)。3.心功能指标中,左心室、右心室(LV、RV)Tei指数随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05);三尖瓣、二尖瓣(TV、MV)E/A值、(LV、RV)射血分数(EF)先升高,随后持续下降(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。4.胎羊UmAPI,RAPI,DV PI,(LV、RV)Tei指数,与血TNF-α水平呈正相关(r=0.724,r=0.668,r=0.784,r=0.765,r=0.683,P＜0.01),与血IL-6水平呈正相关(r=0.771,r=0.760,r=0.823,r=0.805,r=0.749,P＜0.01),MCA PI与血TNF-α、IL-6水平呈负相关性(r=-0.727,r=-0.728,P＜0.01)。LV EF、RV EF、TV E/A、MV E/A与血TNF-α水平没有相关性(r=-0.195,r=-0.157,r=-0.204,r=-0.156,P＞0.05),与血IL-6水平也没有相关性(r=-0.157,r=-0.128,r=-0.199,r=-0.228,P＞0.05)。5.实验组给LPS后MDA、cTnI随时间升高(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。6.实验组给LPS后心肌组织的NF-κB p65蛋白含量增加、Fas mRNA表达上调、caspase3表达增加(P＜0.05),与对照组比较差异有统计学意义(P＜0.05)。
结论1.外周血管中DV PI与胎羊血TNF-α、IL-6水平之间的相关性最强;心功能指标中Tei指数与胎羊血TNF-α、IL-6水平之间的相关性最强。因此,DV PI与Tei指数可作为预测FIRS简单而有效的参考指标。
2.LPS引发胎羊体内炎症级联反应,多种因素参与其中,导致胎羊发生SIRS,最终能导致多器官功能衰竭(MOF)。
3.心肌细胞的凋亡在SIRS胎羊心肌损伤中可能起着重要的作用。
Objective To evaluate the changes of hemodynamic during fetal inflammatory response syndrome(FIRS) period by Doppler ultrasound,and assess the corrlation between hemodynamic paratmeters and fetal plasma TNF-αand IL-6 concentration, and explore its possible mechanism in fetal cardiac function.
Methods 22 near-term pregnant sheep were used in this study,Uuder ultrasound guidance,10 animals were performed with LPS-cordocentesis,7 animals were performed with LPS-amniocentesis and another 5 animals as a control group.In experiment groups animal,LPS was injected into the umbilical cord vein(10μg/kg of fetal body weight) and amniotic cavity(200μg/kg of maternal body weight) at 120(range 116-130) days gestation(term=145 days ),respectively.Doppler echocardiography were performed at different time during LPS administration.Fetal umbilical cord blood samples were collected and measured for TNF-α,IL-6,MDA and cTnI.The correlation coefficient was calculated to established the relationship between the TNF-α,IL-6 concentation and Doppler scanning values.The mRNA of Fas and protein of nuclear factor-K B p65(NF-κB p65 ) and caspase3 of fetal myocardium were examined with immunohistochemistry.
Results 1.After LPS administration,the fetal plasma TNF-α,IL-6 level significantly increased with time(P<0.05),and still significantly increased as compared with the control animals(P<0.05).2.In the peripheral vessels,the fetal umbilical artery (UmA),renal artery(RA),ductus venous(DV) waveform pulsatility index(PI) values significantly increased with time(P<0.05),and still significantly increased as compared with the control animals(P<0.05).However,the fetal middle cerebral artery(MCA) PI values significantly reduced with time(P<0.05),and still significantly reduced as compared with the control animals(P<0.05).3.In the cardiac function values,left and right ventricle(LV,RV) Tei indices significantly increased with time(P<0.05),and still significantly increased as compared with the control animals (P<0.05),however,LV ejection fraction(EF),RV EF,tricuspid valve(TV) E/A ratio and mitral valve(MV) E/A ratio significantly increased and thus reduced(P<0.05),and still significantly different as compared with the control animals(P<0.05).4.There were significantly positive correlation between UmA PI,RA PI,DV PI,LV Tei index, RV Tei index and TNF-α(r=0.724,r=0.668,r=0.784,r=0.765,r=0.683,P<0.01) and IL-6(r=0.771,r=0.760,r=0.823,r=0.805,r=0.749,P<0.01 ).There were significantly negative correlation between MCA PI and TNF-α,IL-6(r=-0.727, r=-0.728,P<0.01 ).And there were no correlation between LV EF,RV EF,TV E/A ratio,MV E/A ratio and TNF-α(r=-0.195,r=-0.157,r=-0.204,r=-0.156, P>0.05) and IL-6(r=-0.157,r=-0.128,r=-0.199,r=-0.228,P >0.05).5.After LPS administration,the fetal plasma MDA,cTnI level significantly increased with time(P<0.05),and still significantly increased as compared with the control animals (P<0.05).6.FIRS could upregulating the express of Fas mRNA,enhancing the protein quantity of NF-κB p65,increasing the express of caspase3 in fetal myocardium(P<0.05),and still significantly different as compared with the control animals(P<0.05).
Conclusions 1.Mostly Doppler parameters were significantly associated with TNF-αand IL-6 concentration.DV PI exhibits the strongest relationship in peripheral vessels,and Tei index exhibits the strongest relationship in cardiac function values,respectively.Therefore,DV PI and Tei index might be an useful quantitative parameters for assessing FIRS.2.Apotosis of myocardial cell might be associated with cardiac dysfunction.
引文
[1].Miura A,Yoneyama Y,Sawa R,et al.Fetal plasma prostaglandin F2α and cortisol responses to high-dose endotoxin administration in fetal goats.J Nippon Sch,2003,70(2):151-156
[2].Goldenberg RL,Hauth JC,Andrews WW,et al.Intrauterine infection and preterm delivery.N Engl J Med 2000;342(20):1500-1507.
[3].Goncalves LF,Chaiworapongsa T,Romero R,et al.Intrauterine infection and prematurity..Ment Retard Dev Disabil Res Rev,2002,8(1):3-13.
[4].Romero R,Espinoza J,Goncalves LF,et al.The role of inflammation and infection in preterm birth.Semin Reprod Med.2007,25:21-39.
[5].Hagberg H,Mallard C,Jacobsson B.Role of cytokines in preterm labour and brain injury.B JOG.2005,112(suppl 1):16-18.
[6].Romero R,Espinoza J,Goncalves L,et al.The fetal inflammatory response syndrome.UK:Informa Healthcare;2006:149-172.
[7].Evans R,Fernandez P,Salam S,et al.Sepsis during pregnancy.Crit Care Med,2005,33(10):286-293
[8].石俊强,傅颖君.机体免疫应答内毒素的分子机制.实用临床医学,2007,8(4):137-138
[9].Rounioja S,Rasanen J,Ojaniemi M,et al.Mechanism of acute fetal cardiovascular depression after maternal inflammatory challenge in mouse.Am J Pathology,2005,166(6):1585-1592
[10].Porta F,Takala J,Weikert C,et al.Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function.Critical Care,2006,10:R118
[11].孙东明,程亚颖,井丽娟等.全身炎症反应综合征患儿血内毒素、脂多糖结合蛋白/脂多糖受体水平变化的意义[J].实用儿科临床杂志,2007,22(6):426-427
[12].程亚颖,孙东明,井丽娟等.全身炎症反应综合征患儿血清内毒素与脂多糖结合蛋白脂多糖受体及肿瘤坏死因子-α的检测分析.中国实用儿科杂志,2007,22(3):208-211
[13].陈贤楠.全身炎症反应综合征中存在的若干问题.临床儿科杂志,2002,20(11).650-653
[14]Meise C,Germer U,Gembruch U.Arterial Doppler ultrasound in 115 secondand third-trimester fetuses with congenital heart disease.Ultrasound Obstet Gynecol,2001,17:398-402
[15]严英榴,杨秀雄,沈理,主编.产前超声诊断学.第1版.北京:人民卫生出版社,2003,480-489.
[16]吕国荣,姜立新,主编.胎儿超声心动图学.第1版.北京:北京大学医学出版社,2003,53-63.
[17]赵玲变,.朱燕萍,郭岩,等.胎儿颅脑血液动力学指标对预测胎儿宫内缺氧的诊断评价.中国超声医学杂志,2000,16:347-349.
[18]Siristatidis C,Salamalekis E,Kassanos D,et al.Evaluation of fetal intrapartum hypoxia by middle cerebral and umbilical artery Doppler velocimetry with imultaneous cardiotocography and pulse oximetry.Arch Gynecol obstet,2004,270:265-270.
[19]吕国荣,王振华,苏瑞娟,等.多普勒超声检测脐动脉和大脑中动脉血流频谱预测新生儿缺血缺氧性脑病.中国医学影像技术,2005,21:17-20.
[20]Hata T,Dai SY,Inubashiri E,et al.Four-dimensional sonography with B-flow imaging and spatiotemporal image correlation for visualization of the fetal heart.J Clin Ultrasound.2008;36(4):204-207.
[21].DiNaro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographic marker of the fetal inflammatory response syndrome syndrome.Am J Obstet Gynecol,2006,194(1):153-159
[22].Murase M.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch.Child.fetal neonatal.2006,91(2):105-110
[23].Yoon BH,Romero R,Park JS,et al.The relationship among inflammatory lesions of the umbilical cord (funisitis),umbilical cord plasma interleukin 6 concentration,amniotic fluid infection,and neonatal sepsis.Am J Obstet Gynecol.2000,183:1124-1129.
[24].Janeway CA,Travers P,Walport M,et al.Basic concepts in immunology.New York:Garland Publishing;2001:1-34.
[25].Wu R,Dong W,Zhou M,et al.Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1.Cardiovascular Research,2005,68 (2):318-326
[26].Duncan JR,Cock ML,Rees S,et al.The Effects of Repeated Endotoxin Exposure on Placental Structure in Sheep.Placenta,2003,24(7):786-789
[27].Murase M,Ishida A.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch Dis Child Fetal Neonatal Ed,2006,91(2):05-10
[28]Siristatidis C,Salamalekis E,Kassanos D,et al.Evaluation of fetal intrapartum hypoxia by middle cerebral and umbilical artery Doppler velocimetry with imultaneous cardiotocography and pulse oximetry.Arch Gynecol Obstet,2004,270:265-270.
[29]Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[30].Annane D,Bellissant E,Cavaillon JM.Septic shock.Lancet.2005,365:63-78.
[31].Jean-Baptiste E.Cellular mechanisms insepsis.J Intensive Care Med.2007,22:63-72.
[32].Grigsby PL,Hirst JJ,Scheerlinck JP,et al.Fetal Responses to Maternal and Intra-Amniotic Lipopolysaccharide Administration in Sheep.Biology of reproduction,2003,68 (5):1695-1702
[33].王丽杰,刘春峰,袁壮,等.危重患儿全身炎症反应综合征血清细胞因子的动态变化及其意义.中华急诊医学杂志,2003,12(5):298-300.
[34]刘植.全身炎症反应综合征患儿血清TNF-α与IL-6及IL-10的动态观察及意义.实用医技杂志,2007,14(18):2505-2506
[35]Antoine VB,Sebastien P,Karim C,et al.Hemodynamic instability in sepsis.Am J Respir Crit Care Med,2003,168:1270-1276
[1].Bone RC,Balk RA,Cerra FB,et al.(The ACCP/SCCM Consensus Conference Committee & American College of Chest Physicians/ Society of Critical Care Medicine).Definition for sepsis and organ failure and guideline for the use of innorative the rapies in sepsis.Chest,1992,101:1644-1655.
[2]宋国维．危重患儿的识别．中国循证儿科杂志．实用儿科杂志．2008,3(6)：1-3．
[3]Rastogi D,Wang C,Mao X,et al.Antigen-specific immune responses to influenza vaccine in utero.J Clin Invest,2007,117(6):1637-1646.
[4].Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[5].Matsuoka T,Matsubara T,KatayamaK,et al.Increase of cord blood cytokine producing T cells in intrauterine infection.Pediatr Int.2001,43:453-457.
[6].Yoneyama Y,Suzuki S,Sawa R,et al.Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes.Arch Gynecol Obstet.2003,267:217-220.
[7].Gerber S,Vial Y,Hohlfeld P,et al.Prenatal diagnosis of congenital cytomegalo virus infection by detection of immunoglobulin M antibodies to the70-kd heat shock protein in fetal serum.Am J Obstet Gynecol.2002,187:955-959.
[8].Miura A,Yoneyama Y,Sawa R,et al.Fetal plasma prostaglandin F2a and Cortisol responses to high-dose endotoxin administration in fetal goats.J Nippon Sch,2003,70(2):151-156
[9]Gamier Y,Berger R,Alm S,et al.Systemic endotoxin administration results in increased S100P protein blood levels and periventricular brain white matter injury in the preterm fetal sheep.Eur J Obstet Gynecol Reprod Biol,2006,124(1):15-22.
[10]Gamier Y,Coumans AB,Berger R,et al.Pulmonary perfusion during lipopolysaccharide(LPS) induced fetal endotoxemian in the preterm fetal sheep.Eur J Obstet Gynecol Reprod Biol,2006,124(1):150-157.
[11]Romero R,Espinoza J,Goncalves LF,et al.Fetal cardiac dysfunction in preterm premature rupture of membrabes.J Matem Fetal Neonatal Med,2004,16(3):146-157.
[12]Rounioja S,Rasanen J,Glumoff V,et al.Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction.A mouse model for fetal inflammatory response.Cardiovase Res,2003,60(1):156-164.
[13]Di Naro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographicmarker of the fetal inflammatory responsesyndrome.Am J Obstet Gynecol.2006,194:153-159.
[14].Murase M,Ishida A.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch.Child.fetal neonatal 2006,91(2):105-110.
[15]Makikallio K,Vuolteenaho O,Jouppila P,et al.Ultrasonographic and biochemical markers of human fetal cardiac dysfunction in placental insufficiency.Circulation 2002,105:2058-2063.
[16]Kitzman DW,Gardin JM,Gottdiener JS,et al.Importance of heart failure with reserved systolic function in patients ≥ 65 years of age.Am J Cardiol,2001,87:413-419.
[17].Chang CH,Chang FM,Yu CH,et al.Systemic assessment of fetal hemodynamics by Doppler ultrasound.Ultrasound Med Biol,2000,26:777-785.
[18].Fernandez PL,Tamariz MM,Maitre AM,et al.Contribution of Doppler atrioventricular flow waves to ventricular filling in the human fetus.Pediatr Cardiol,2000,21:422-428.
[19]Gardiner H,Brodszki J,Marsal K.Ventriculovascular physiology of the growthrestricted fetus.Ultrasound Obstet Gynecol,2001,18:47-53
[20]张崔华,徐湘滨,Barry J,et al.TNF在缺血/再灌注损伤中内皮功能障碍的作用.动脉硬化血栓血管生物学杂志,2006,26(3):807-813.
[21]Alpert JS,Thygesen K,Antman E.Myocardial infarction redefined-a consensus document of The European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.J Am Coll Cardiol,2000,36(3):959-969.
[22]张向隆.对40例急性心肌梗死患者肌钙蛋白T动态观察与预后相关性分析.中华医药杂志,2008,8(1):26-27.
[23]黄新冲,曾因明.体外循环中心肌保护措施的评价.国外医学·麻醉与复苏分册,2001,22(5):294-296.
[24]Mann K,Doerre S,Schlezinger JJ,et al.The role of NF-B as a survival factor in environmental chemical-induced pre-B cell apoptosis.Mol Pharmacol,2001,59:302-309.
[25]Yamamoto Y,Gaynor RB.IkappaBkinases:key regulators of the NF-kappaB pathway.Trends BiochemlSci,2004;29:72-79.
[26]Pueyo ME,Nicoletti A,Conzalez,et al.Angiotensin II stimulates endothelial vascular cell adhesion molecule-lvia nuclear factor-kappaB activation induced by intracellular oxidative stress.Arterioscler Thromb Vase Biol,2000;20:645-651.
[27]Kavurma MM,Schoppet M,Bobryshev YV,et al.Trail stimulates proliferation of vascular smooth muscle cells via activation of NF-kappa B and induction of insulin-like growth factor-1 receptor.J Biol Chem,2008,21:7754-7762.
[28]dwin K,Marion JJ,Gijbels.Ingeborg van der Made,Hematopoietic NF-kBI deficiency results in small atherosclerotic lesions with an inflammatory phenotypeC.Blood,2004;103:934-940.
[29]Li YH,Zhuo YH,Lv L,et al.Caspase-dependent retinal ganglion cell apoptosis in the rat model of acute diabetes.J Chin Medic,2008,121(24):2566-2571.
[30]Jendrossek V,Handrick R,Belka C.Celecoxib activates a novel mitochondrial apoptosis signaling pathway.Faseb J,2003,17:1547-1549.
[31]Cowling V,Downward J.Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway:absolute requirement for removal of caspase-6 prodomain.Cell Death Differ,2002,9:1046-1056
[32]Lopez-Hernandez FJ,Ortiz MA,Bayon Y,et al.Z-FA-fmk inhibits effector caspases but not initiator caspases 8 and 10 and demonstrates that novel anticancer retinoid-related molecules induce apoptosis via the intrinsic pathway.Mol Cancer Ther,2003,2:255-263.
[33]Murphy BM,Creagh EM,Martin SJ.Interchain proteolysis,in the absence of a dimerization stimulus,can initiate apoptosis-associated caspase-8 activation.J Biol Chem,2004,279:36916-36922.
[34]Kockx MM,Herman AG.Apoptosis in atherosclerosis:beneficial or detrimental?.Cardiovasc Res 2000;45:736-746.
[35].Bartha JL,Romero CR,Comino DR.Inflammatory cytokines in intrauterine growth retardation.Acta Obstet Gynecol Scand,2003,82(12):1099-1102.
[36].Hatzidaki E,Gourgiotis D,Manoura A,et al.Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome.Acta Obstet Gynecol Scand.2005,84(7):632-638.
[37]Roberto R,Tinnakorn CP,Jimmy EM.Micronutrients and intrauterine infection,preterm birth and the fetal inflammatory response syndrome infection and inflammation.2003,133:1668-1673
[38]Laudanski P,Pierzynski P,Laudanski T.Reductionist and system approaches to study the role of infection in preterm labor and delivery.BMC Pregnancy and Child birth,2007,7(Suppl 1):9-12.
[1].GomezR,RomeroR,GhezziF,et al.The fetal inflammatory response syndrome.Am J Obstet Gynecol.1998,179:194-202.
[2]American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.Crit Care Med.1992,20:864-874.
[3].Angus DC,Linde-Zwirble WT,Lidicker J,et al.Epidemiology of severe sepsis in the United States:analysis of incidence,outcome,and associated costs of care.Crit Care Med.2001,29:1303-1310.
[4].Riedemann NC,Guo RF,Ward PA.Novel strategies for the treatment of sepsis.Nat Med.2003,9:517-524.
[5].Muckart DJ,Bhagwanjee S.American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients.Crit Care Med.1997,25:1789-1795.
[6].Gomez R,Ghezzi F,Romero R,et al.Two thirds of human fetuses with microbial invasion of the amniotic cavity have a detectable systemic cytokine response before birth [Abstract].Am J Obstet Gynecol.1997,176:514.
[7].Levy MM,Fink MP,Marshall JC,et al.2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Intensive Care Med.2003,29:530-538.
[8].Romero R,Espinoza J,Goncalves L,et al.The fetal inflammatory response syndrome.UK:Informa Healthcare;2006:149-172.
[9].Romero R,Espinoza J,Goncalves LF,et al.The role of inflammation and infection in preterm birth.Semin Reprod Med.2007,25:21-39.
[10].Henson PM.Dampening inflammation.Nat Immunol.2005;6:1179-1181.
[11].Ley K.History of inflammation research.Oxford:Oxford University Press;2001:1-10.
[12].Gallin JI,Snyderman R.Inflammation:historical perspective.Philadelphia:Lippincott Williams & Wilkins;1999:5-12.
[13].Janeway C,Travers P,Walport M,et al.Innate immunity.New York:Garland Science Publishing;2005:37-102.
[14].Salamonsen LA,Lathbury LJ.Endometrial leukocytes and menstruation.Hum Reprod Update.2000,6:16-27.
[15].Kiviat NB,Wolner-Hanssen P,Eschenbach DA,et al.Endometrial histopathology in patients with culture proved upper genital tract infection and laparoscopically diagnosed acute salpingitis.Am J Surg Pathol.1990,14:167-175.
[16].Haddad R,Tromp G,Kuivaniemi H,et al.Spontaneous labor at term is characterized by a genomic signature of acute inflammation in the chorioamniotic membranes but not in the systemic.circulation.Am J Obstet Gynecol.2004,191:138.
[17].Yoon BH,Romero R,Park JS,et al.The relationship among inflammatory lesions of the umbilical cord (funisitis),umbilical cord plasma interleukin 6 concentration,amniotic fluid infection,and neonatal sepsis.Am J Obstet Gynecol.2000,183:1124-1129.
[18].Yoon BH,Romero R,Moon JB,et al.Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes.Am J Obstet Gynecol.2001,185:1130-1136.
[19].Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[20].Brannstrom M,Enskog A.Leukocyte networks and ovulation.J Reprod Immunol.2002,57:47-60.
[21].Chard T.Cytokines in implantation.Hum Reprod Update.1995,1:385-396.
[22].Kelly RW,King AE,Critchley HO.Inflammatory mediators and endometrial Function-focus on the perivascular cell.J Reprod Immunol.2002,57:81-93.
[23].Keelan JA,Blumenstein M,HelliwellRJ,et al.Cytokines,prostaglandins and parturition-a review.Placenta.2003,24(suppl A):33-46.
[24].Salvemini D,Cuzzocrea S.Oxidativestress in septic shock and disseminated intravascular coagulation.Free Radic Biol Med.2002,33:1173-1185.
[25]Hoffman M,Cooper ST.Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms.Blood Cells Mol Dis.1995;21:156-167.
[26].Matzinger P.The danger model:a renewed sense of self.Science.2002,296:301 -305.
[27].Medzhitov R,Janeway J.The Toll receptor family and microbial recognition.Trends Microbiol.2000,8:452-456.
[28].Beg AA.Endogenous ligands of Tolllike receptors:implications for regulating inflammatory and immune responses.Trends Immunol.2002,23:509-512.
[29].Janeway CA,Travers P,Walport M,et al.Basic concepts in immunology.New York:Garland Publishing;2001:1-34.
[30].Romero R,Sirtori M,Oyarzun E,et al.Infection and labor.V.Prevalence,microbiology,and clinical significance of intra-amniotic infection in women with preterm labor and intact membranes.Am J Obstet Gynecol.1999,161:817-824.
[31].King AE,Critchley HO,Kelly RW.Innate immune defences in the human endometrium.Reprod Biol Endocrinol.2003,1:116.
[32].Condon JC,Jeyasuria P,Faust JM,et al.Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition.Proc Natl Acad Sci USA.2004,101:4978-4983.
[33].Kishore U,Bernal AL,Kamran MF,et al.Surfactant proteins SP-A and SP-D in human health and disease.Arch Immunol Ther Exp (Warsz).2005,53:399-417.
[34].Costerton W,Veeh R,Shirtliff M,et al.The application of bio-film science to the study and control of chronic bacterial infections.J Clin Invest.2003,112:1466-1477.
[35].Hargreaves DC,Medzhitov R.Innate sensors of microbial infection.J Clin Immunol.2005,25:503-510.
[36]Pasare C,Medzhitov R.Toll-like receptors:linking innate and adaptive immunity.Microbes Infect.2004,6:1382-1387.
[37].Elovitz MA,Wang Z,Chien EK,et al.A new model for inflammation-induced preterm birth:the role of platelet-activatingfactor and Toll-like receptor-4.Am J Pathol.2003,163:2103-2111.
[38].Kim YM,Romero R,Chaiworapongsa T,et al.Toll-like receptor-2 and-4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis.Am J Obstet Gynecol.2004,191:1346-1355.
[39].Annane D,Bellissant E,Cavaillon JM.Septic shock.Lancet.2005,365:63-78.
[40].Jean-Baptiste E.Cellular mechanisms insepsis.J Intensive Care Med.2007,22:63-72.
[41].Romero R,Wu YK,Brody DT,et al.Humandecidua:a source of interleukin-1.Obstet Gynecol.1989,73:31-34.
[42].Romero R,Durum S,Dinarello CA,et al.Interleukin-1 stimulates prostaglandin biosynthesis by human amnion.Prostaglandins.1989,37:13-22.
[43].Romero R,Brody DT,Oyarzun E,et al.Infection and labor.Ⅲ.Interleukin-1:a signal for the onset of parturition.Am J Obstet Gynecol.1989,160:1117-1123.
[44].Sadowsky DW,Novy MJ,Witkin SS,et al.Dexamethasone or interleukin-10 blocks interleukin-1 beta-induced uterinecontractions in pregnant rhesusmonkeys.Am J Obstet Gynecol.2003,188:252-263.
[45].Romero R,Tartakovsky B.The natural interleukin-1 receptor antagonist prevents interleukin-1 induced preterm delivery in mice.Am J Obstet Gynecol.1992,167:1041-1045.
[46].Romero R,Mazor M,Wu YK,et al.Infection in the pathogenesis of preterm labor.Semin Perinatol.1988,12:262-279.
[47].Romero R,Mazor M,Manogue K,et al.Human decidua:a source of cachectin tumor necrosis factor.Eur J Obstet Gynecol Reprod Biol.1991,41:123-127.
[48].Fortunato SJ,Menon R,Lombardi SJ.Role of tumor necrosis factor-[alpha]in the premature rupture of membranesand preterm labor pathways.Am JObstet Gynecol.2002,187:1159-1162.
[49].Romero R,Chaiworapongsa T,Espinoza J,et al.Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes.Am J Obstet Gynecol.2002,187:1125-1130.
[50].Chwalisz K,Benson M,Scholz P,et al.Cervical ripening with the cytokines interleukin 8,interleukin 1[beta]and tumour necrosis factor [alpha]in guinea pigs.Hum Reprod.1994,9:2173-2181.
[51].Fidel PL Jr,Romero R,Cutright J,et al.Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor Fc fusion protein does not prevent endotoxin-induced preterm parturition in mice.J Soc Gynecol Invest.1997,4:22-26.
[52].Van Parijs L,Abbas AK.Homeostasis and self-tolerance in the immune system:turning lymphocytes off.Science.1998,280:243-248.
[53].Sakaguchi S.Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses.Annu Rev Immunol.2004,22:531-562.
[54].Cupedo T,Nagasawa M,Weijer K,et al.Development and activation of regulatory T cells in the human fetus.Eur JImmunol.2005,35:383-390.
[55].Billingham RE,Brent L,Medawar PB.Actively acquired tolerance of foreign cells.Nature.1953,172:603-606.
[56].Berry SM,Romero R,Gomez R,et al.Premature parturition is characterized by in utero activation of the fetal immune system.Am J Obstet Gynecol.1995,173:1315-1320.
[57].Thompson PJ,Greenough A,Davies E,et al.Fetal C-reactive protein.Early Hum Dev.1993,32:81-85.
[58].Sarzotti M,Robbins DS,Hoffman PM.Induction of protective CTL responses in newborn mice by a murine retrovirus.Science.1996,271:1726-1728.
[59].Matsuoka T,Matsubara T,KatayamaK,et al.Increase of cord blood cytokine producing T cells in intrauterine infection.Pediatr Int.2001,43:453-457.
[60].Yoneyama Y,Suzuki S,Sawa R,et al.Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes.Arch Gynecol Obstet.2003,267:217-220.
[61].Gerber S,Vial Y,Hohlfeld P,et al.Prenatal diagnosis of congenital cytomegalo virus infection by detection of immunoglobulin M antibodies to the70-kd heat shock protein in fetal serum.Am J Obstet Gynecol.2002,187:955-959.
[62].Chaiworapongsa T,Romero R,Kim JC,et al.Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis.Am J Obstet Gynecol.2002;186:1178-1182.
[63]Witt A,Berger A,Gruber CJ,et al.IL-8 concentrations in maternal serum,amniotic fluid and cord blood in relation to different pathogens within the amniotic cavity.J Perinat Med.2005,33:22-26.
[64].Pacora P,Chaiworapongsa T,MaymonE,et al.Funisitis and chorionic vasculitis:the histological counterpart of the fetal inflammatory response syndrome.J Matern Fetal Neonatal Med.2002,11:18-25.
[65].D'AlquenD,Kramer BW,SeidenspinnerS,et al.Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.Pediatr Res.2005,57:263-269.
[66]Yoon BH,Romero R,Park JS,et al.Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years.AmJ Obstet Gynecol.2000,182:675-681.
[67].Yoon BH,Romero R,Shim JY,et al.Creactive protein in umbilical cord blood:a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis.J Matern Fetal Neonatal Med.2003,14:85-90.
[68].Sampson JE,Theve RP,Blatman RN,et al.Fetal origin of amniotic fluid polymorpho nuclear leukocytes.Am J Obstet Gynecol.1997,176:77-81.
[69].Shim SS,Romero R,Hong JS,et al.Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes.Am J Obstet Gynecol.2004,191:1339-1345.
[70].Romero R,Athayde N,Gomez R,et al.The fetal inflammatory response syndrome is characterized by the out pouring of a potent extracellular matrix degrading enzyme into the fetal circulation.Am J Obstet Gynecol.1998,178:3.
[71].Gomez R,Berry S,Yoon BH,et al.The hematologic profile of the fetus with systemic inflammatory response syndrome.Am J Obstet Gynecol.1998,178:202.
[72].Berry SM,Gomez R,Athayde N,et al.The role of granulocyte colony stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome.Am J Obstet Gynecol.1998,178:202.
[73].Gomez R,Romero R,Ghezzi F,et al.Are fetal hypoxia and acidemia causes of preterm labor and delivery? [Abstract].Am J Obstet Gynecol.1997,176:115.
[74].Baschat AA,Gembruch U,Reiss I,et al.Neonatal nucleated red blood cell counts in growth-restricted fetuses:relationship to arterial and venous Doppler studies.Am J Obstet Gynecol.1999,181:190-195.
[75].FerberA,MiniorVK,Bornstein E,et al.Fetal “non reassuring status” is associated with elevation of nucleated red blood cell counts and interleukin-6.Am J Obstet Gynecol.2005,192:1427-1429.
[76].Di Naro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographicmarker of the fetal inflammatory responsesyndrome.Am J Obstet Gynecol.2006,194:153-159.
[77].Haeryfar SM,Berczi I.The thymus and the acute phase response.Cell Mole Biol.2001,47:145-156.
[78].Kuban JD,Allred EN,Leviton A.Thymus involution and cerebral white matter damage in extremely low gestational age neonates.Biol Neonate.2006,90:252-257.
[79].Li L,Hsu HC,Stockard CR,et al.IL-12 inhibits thymic involution by enhancing IL-7-and IL-2-induced thymocyte proliferation.J Immunol.2004,172:2909-2916.
[80]Yoon BH,Romero R,Jun JK,et al.An increase in fetal plasma Cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes.Am J Obstet Gynecol.1998,179:1107-1114.
[81].Nathanielsz PW,Berghorn KA,DerksJB,et al.Life before birth:effects of Cortisol on future cardiovascular andmetabolic function.Acta Paediatr.2003,92:766-772.
[82]Moritz KM,Boon WM,Wintour EM.Glucocorticoid programming of adult disease.Cell Tissue Res.2005,322:81-88.
[83].Kim YM,Romero R,Chaiworapongsa T,et al.Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes.Histopathology.2006,49:506-514.
[84].Yoon BH,Kim YA,Romero R,et al.Association of oligohydramnios in women with preterm premature rupture of membranes with an inflammatory response in fetal,amniotic,and maternal compartments.Am J Obstet Gynecol.1999,181:784-788.
[85].EspinozaJ,ChaiworapongsaT,RomeroR,et al.Antimicrobial peptides in amniotic fluid:defensins,calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity,intra-amniotic inflammation,preterm labor and premature rupture of membranes.J Matern Fetal Neonatal Med.2003,13:2-21.
[86].Romero R,Espinoza J,Goncalves LF,et al.Fetal cardiac dysfunction in preterm premature rupture of membranes.J Matern Fetal Neonatal Med.2004,16:146-157.
[87].Court O,Kumar A,Parrillo JE,et al.Clinical review:myocardial depression in sepsis and septic shock.Crit Care.2002,6:500-508.
[88].Yanowitz TD,Jordan JA,Gilmour CH,et al.Hemodynamic disturbances in premature infants born after chorioamnionitis:association with cord blood cytokine concentrations.Pediatr Res.2002,51:310-316.
[89].Gamier Y,Coumans AB,Jensen A,et al.Infection-related perinatal brain injury:the pathogenic role of impaired fetal cardiovascular control.J Soc Gynecol Investi.2003,10:450-459.
[90]Kaukola T,Herva R,Perhomaa M,et al.Population cohort associating chorioamnionitis,cord inflammatory cytokines and neurologic outcome in very preterm,extremely low birth weight infants.Pediatr Res.2006,59:478-483.
[91].Kalache KD,Chaoui R,Bollmann R.Doppler assessment of tracheal and nasal fluid flow during fetal breathing movements:preliminary observations.Ultrasound Obstet Gynecol.1997,9:257-261.
[92].Speer CP.Pulmonary inflammation andbronchopulmonary dysplasia.JPerinatol.2006,26(suppl 1):57-62.
[93].Speer CP.Inflammation and bronchopulmonarydysplasia.Semin Neonatol.2003,8:29-38.
[94].Jobe AH.Antenatal associations withlung maturation and infection.J Perinatol.2005,25(suppl 2):31-35.
[95]Moss T,Jobe A.Amniotic fluid inflammationand fetal lung development.In:Peebles D,Myatt L,eds.Inflammationand Pregnancy.Abingdon,Oxon,UK:Informa Healthcare;2006:173-186.
[96].Bry K,Lappalainen U,Hallman M.Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth.J Clin Invest.1997,99:2992-2999.
[97].Kallapur SG,Willet KE,Jobe AH,et al.Intra-amniotic endotoxin:chorioamnionitis precedes lung maturation in preterm lambs.Am J Physiol Lung Cell Mol Physiol.2001,280:527-536.
[98].Jobe AH,Newnham JP,Willet KE,et al.Endotoxin-induced lung maturation in preterm lambs is not mediated by Cortisol.Am J Respir Crit Care Med.2000,162:1656-1661.
[99].Kallapur SG,Moss TJ,IkegamiM,et al.Recruited inflammatory cells mediate endotoxin-induced lung maturation in preterm fetal lambs.Am J Respir Crit Care Med.2005;172:1315-1321.
[100].Prince LS,Okoh VO,Moninger TO,et al.Lipopolysaccharide increases alveolar type Ⅱ cell number in fetal mouse lungs through Toll-like receptor4 and NF-kappaB.Am J Physiol Lung Cell Mol Physiol.2004;287:999-1006.
[101].Moss TJ,Nitsos I,Ikegami M,et al.Experimental intrauterine Ureaplasma infection in sheep.Am J Obstet Gynecol.2005;192:1179-1186.
[102]Nelson KB,Dambrosia JM,Grether JK,et al.Neonatal cytokines and coagulation factors in children with cerebral palsy.Ann Neurol.1998,44:665-675.
[103].Verma U,Tejani N,Klein S,et al.Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.Am J Obstet Gynecol.1997,176:275-281.
[104].Alexander JM,Gilstrap LC,Cox SM,et al.Clinical chorioamnionitis and the prognosis for very low birth weight infants.Obstet Gynecol.1998,91:725-729.
[105].O'Shea TM,Klinepeter KL,Dillard RG.Prenatal events and the risk of cerebral palsy in very low birth weight infants.Am J Epidemiol.1998,147:362-369.
[106].Dammann O,Leviton A.Role of the fetus in perinatal infection and neonatal brain damage.Curr Opin Pediatr.2000,12:99-104.
[107].Nelson KB.The epidemiology of cerebral palsy in term infants.Ment Retard Dev Disabil Res Rev.2002,8:146-150.
[108].Dammann O,Kuban KC,Leviton A.Perinatal infection,fetal inflammatory response,white matter damage,andcognitive limitations in children bornpreterm.Ment Retard Dev Disabil ResRev.2002,8:46-50.
[109]Duncan JR,Cock ML,Scheerlinck JP,et al.White matter injury after repeated endotoxin exposure in the pretermovinefetus.Pediatr Res.2002;52:941-949.
[110].Mehta R,Nanjundaswamy S,Shen-Schwarz S,et al.Neonatal morbidity and placental pathology.Indian J Pediatr.2006;73:25-28.
[111].Grafe MR.The correlation of prenatal brain damage with placental pathology.J Neuropathol Exp Neurol.1994;53:407-415.
[112].Hagberg H,Mallard C,Jacobsson B.Role of cytokines in preterm labour and brain injury.BJOG.2005,112(suppl 1):16-18.
[113]Dammann O,Leviton A,Gappa M,et al.Lung and brain damage in preterm newborns,and their association with gestational age,prematurity subgroup,infection /inflammation and long term outcome.BJOG.2005,112(suppl l):4-9.
[114].Nelson KB,Dambrosia JM,IovannisciDM,et al.Genetic polymorphisms and cerebral palsy in very preterm infants.Pediatr Res.2005,57:494-499.
[115].Grether JK,Nelson KB,Walsh E,et al.Intrauterine exposure to infection and risk of cerebral palsy in very preterminfants.Arch Pediatr Adolesc Med.2003,157:26-32.
[116].Wu YW.Systematic review of chorioamnionitisand cerebral palsy.Ment Retard Dev Disabil Res Rev.2002,8:25-29.
[117].Nelson KB.Can we prevent cerebral palsy? N Engl J Med.2003,349:1765-1769.
[118].Duggan PJ,Maalouf EF,Watts TL,et al.Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions.Lancet.2001,358:1699-1700.
[119].Kaukola T,Satyaraj E,Patel DD,et al.Cerebral palsy is characterized by protein mediators in cord serum.Ann Neurol.2004;55:186-194.
[120].deVries LS,Groenendaal F.Neuro imagingin the preterm infant.Ment Retard Dev Disabil Res Rev.2002.8:273-280.
[121].Hagberg B,Hagberg G,Beckung E,ei al.Changing panorama of cerebral palsy in Sweden.Ⅷ.Acta Paediatr.2001;90:271-277.
[122].Debillon T,Gras-Leguen C,Leroy S,et al.Patterns of cerebral inflammatory response in a rabbit model of intrauterineinfection-mediated brain lesion.Brain Res Dev Brain Res.2003,145:39-48.
[123].Kadhim H,Tabarki B,De Prez C,et al.Interleukin-2 in the pathogenesis of perinatal white matter damage.Neurology.2002,58:l 125-1128.
[124].Kadhim H,Tabarki B,De Prez C,et al.Cytokine immuno reactivity in cortical and subcortical neurons in periventricular leukomalacia:are cytokines implicated in neuronal dysfunction in cerebral palsy? Acta Neuropathol (Berl).2003,105:209-216.
[125].Edwards AD,Tan S.Perinatal infections,prematurity and brain injury.Curr Opin Pediatr.2006,18:119-124.
[126].Wong D,Dorovini-Zis K,Vincent SR.Cytokines,nitric oxide,and cGMP.modulate the permeability of an in vitromodel of the human blood-brain barrier.Exp Neurol.2004,190:446-455.
[127]HagbergH,Mallard C.Effect of inflammation on central nervous system development and vulnerability.Curr Opin Neurol.2005,18:117-123.
[128].Nelson KB,Grether JK,Dambrosia JM,et al.Neonatal cytokines and cerebral palsy in very preterm infants.Pediatr Res.2003;53:600-607.
[129]Tan S,Peebles D,Edwards D.Infection,inflammation,and perinatal brain injury.UK:Informa Healthcare;2006:187-201.
[130].Wang X,Svedin P,Nie C,et al.N-acetylcysteine reduces lipopolysaccharidesensitized hypoxic-ischemicbrain injury.Ann Neurol.2007,61:263-271.
[131].Witkin SS,Gerber S,Ledger WJ.Influenceof interleukin-1 receptor antagonist gene polymorphism on disease.Clinlnfect Dis.2002,34:204-209.
[132].Gerber S,Vardhana S,Meagher-Villemure,et al.Association between fetal interleukin-1 receptor antagonistgene polymorphism and unexplained fetal death.Am J Obstet Gynecol.2005,193:1472-1477.
[133]Blackwell S,Romero R,ChaiworapongsaT,et al.Unexplained fetal death is associated with changes in the adaptive limb of the maternal immune response consistent with prior antigenic exposure.J Matern Fetal Neonatal Med.2003,14:241-246.
[134].Moyo SR,Hagerstrand I,Nystrom L,et al.Stillbirths and intrauterine infection,histologic chorioamnionitis andmicrobiological findings.Int J GynaecolObstet.1996;54:115-123.
[135].Mwanyumba F,Inion I,Gaillard P,et al.Placental inflammation and perinatal outcome.Eur J Obstet GynecolReprod Biol.2003,108:164-170.
[2].Goldenberg RL,Hauth JC,Andrews WW,et al.Intrauterine infection and preterm delivery.N Engl J Med 2000;342(20):1500-1507.
[3].Goncalves LF,Chaiworapongsa T,Romero R,et al.Intrauterine infection and prematurity..Ment Retard Dev Disabil Res Rev,2002,8(1):3-13.
[4].Romero R,Espinoza J,Goncalves LF,et al.The role of inflammation and infection in preterm birth.Semin Reprod Med.2007,25:21-39.
[5].Hagberg H,Mallard C,Jacobsson B.Role of cytokines in preterm labour and brain injury.B JOG.2005,112(suppl 1):16-18.
[6].Romero R,Espinoza J,Goncalves L,et al.The fetal inflammatory response syndrome.UK:Informa Healthcare;2006:149-172.
[7].Evans R,Fernandez P,Salam S,et al.Sepsis during pregnancy.Crit Care Med,2005,33(10):286-293
[8].石俊强,傅颖君.机体免疫应答内毒素的分子机制.实用临床医学,2007,8(4):137-138
[9].Rounioja S,Rasanen J,Ojaniemi M,et al.Mechanism of acute fetal cardiovascular depression after maternal inflammatory challenge in mouse.Am J Pathology,2005,166(6):1585-1592
[10].Porta F,Takala J,Weikert C,et al.Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function.Critical Care,2006,10:R118
[11].孙东明,程亚颖,井丽娟等.全身炎症反应综合征患儿血内毒素、脂多糖结合蛋白/脂多糖受体水平变化的意义[J].实用儿科临床杂志,2007,22(6):426-427
[12].程亚颖,孙东明,井丽娟等.全身炎症反应综合征患儿血清内毒素与脂多糖结合蛋白脂多糖受体及肿瘤坏死因子-α的检测分析.中国实用儿科杂志,2007,22(3):208-211
[13].陈贤楠.全身炎症反应综合征中存在的若干问题.临床儿科杂志,2002,20(11).650-653
[14]Meise C,Germer U,Gembruch U.Arterial Doppler ultrasound in 115 secondand third-trimester fetuses with congenital heart disease.Ultrasound Obstet Gynecol,2001,17:398-402
[15]严英榴,杨秀雄,沈理,主编.产前超声诊断学.第1版.北京:人民卫生出版社,2003,480-489.
[16]吕国荣,姜立新,主编.胎儿超声心动图学.第1版.北京:北京大学医学出版社,2003,53-63.
[17]赵玲变,.朱燕萍,郭岩,等.胎儿颅脑血液动力学指标对预测胎儿宫内缺氧的诊断评价.中国超声医学杂志,2000,16:347-349.
[18]Siristatidis C,Salamalekis E,Kassanos D,et al.Evaluation of fetal intrapartum hypoxia by middle cerebral and umbilical artery Doppler velocimetry with imultaneous cardiotocography and pulse oximetry.Arch Gynecol obstet,2004,270:265-270.
[19]吕国荣,王振华,苏瑞娟,等.多普勒超声检测脐动脉和大脑中动脉血流频谱预测新生儿缺血缺氧性脑病.中国医学影像技术,2005,21:17-20.
[20]Hata T,Dai SY,Inubashiri E,et al.Four-dimensional sonography with B-flow imaging and spatiotemporal image correlation for visualization of the fetal heart.J Clin Ultrasound.2008;36(4):204-207.
[21].DiNaro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographic marker of the fetal inflammatory response syndrome syndrome.Am J Obstet Gynecol,2006,194(1):153-159
[22].Murase M.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch.Child.fetal neonatal.2006,91(2):105-110
[23].Yoon BH,Romero R,Park JS,et al.The relationship among inflammatory lesions of the umbilical cord (funisitis),umbilical cord plasma interleukin 6 concentration,amniotic fluid infection,and neonatal sepsis.Am J Obstet Gynecol.2000,183:1124-1129.
[24].Janeway CA,Travers P,Walport M,et al.Basic concepts in immunology.New York:Garland Publishing;2001:1-34.
[25].Wu R,Dong W,Zhou M,et al.Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1.Cardiovascular Research,2005,68 (2):318-326
[26].Duncan JR,Cock ML,Rees S,et al.The Effects of Repeated Endotoxin Exposure on Placental Structure in Sheep.Placenta,2003,24(7):786-789
[27].Murase M,Ishida A.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch Dis Child Fetal Neonatal Ed,2006,91(2):05-10
[28]Siristatidis C,Salamalekis E,Kassanos D,et al.Evaluation of fetal intrapartum hypoxia by middle cerebral and umbilical artery Doppler velocimetry with imultaneous cardiotocography and pulse oximetry.Arch Gynecol Obstet,2004,270:265-270.
[29]Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[30].Annane D,Bellissant E,Cavaillon JM.Septic shock.Lancet.2005,365:63-78.
[31].Jean-Baptiste E.Cellular mechanisms insepsis.J Intensive Care Med.2007,22:63-72.
[32].Grigsby PL,Hirst JJ,Scheerlinck JP,et al.Fetal Responses to Maternal and Intra-Amniotic Lipopolysaccharide Administration in Sheep.Biology of reproduction,2003,68 (5):1695-1702
[33].王丽杰,刘春峰,袁壮,等.危重患儿全身炎症反应综合征血清细胞因子的动态变化及其意义.中华急诊医学杂志,2003,12(5):298-300.
[34]刘植.全身炎症反应综合征患儿血清TNF-α与IL-6及IL-10的动态观察及意义.实用医技杂志,2007,14(18):2505-2506
[35]Antoine VB,Sebastien P,Karim C,et al.Hemodynamic instability in sepsis.Am J Respir Crit Care Med,2003,168:1270-1276
[1].Bone RC,Balk RA,Cerra FB,et al.(The ACCP/SCCM Consensus Conference Committee & American College of Chest Physicians/ Society of Critical Care Medicine).Definition for sepsis and organ failure and guideline for the use of innorative the rapies in sepsis.Chest,1992,101:1644-1655.
[2]宋国维．危重患儿的识别．中国循证儿科杂志．实用儿科杂志．2008,3(6)：1-3．
[3]Rastogi D,Wang C,Mao X,et al.Antigen-specific immune responses to influenza vaccine in utero.J Clin Invest,2007,117(6):1637-1646.
[4].Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[5].Matsuoka T,Matsubara T,KatayamaK,et al.Increase of cord blood cytokine producing T cells in intrauterine infection.Pediatr Int.2001,43:453-457.
[6].Yoneyama Y,Suzuki S,Sawa R,et al.Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes.Arch Gynecol Obstet.2003,267:217-220.
[7].Gerber S,Vial Y,Hohlfeld P,et al.Prenatal diagnosis of congenital cytomegalo virus infection by detection of immunoglobulin M antibodies to the70-kd heat shock protein in fetal serum.Am J Obstet Gynecol.2002,187:955-959.
[8].Miura A,Yoneyama Y,Sawa R,et al.Fetal plasma prostaglandin F2a and Cortisol responses to high-dose endotoxin administration in fetal goats.J Nippon Sch,2003,70(2):151-156
[9]Gamier Y,Berger R,Alm S,et al.Systemic endotoxin administration results in increased S100P protein blood levels and periventricular brain white matter injury in the preterm fetal sheep.Eur J Obstet Gynecol Reprod Biol,2006,124(1):15-22.
[10]Gamier Y,Coumans AB,Berger R,et al.Pulmonary perfusion during lipopolysaccharide(LPS) induced fetal endotoxemian in the preterm fetal sheep.Eur J Obstet Gynecol Reprod Biol,2006,124(1):150-157.
[11]Romero R,Espinoza J,Goncalves LF,et al.Fetal cardiac dysfunction in preterm premature rupture of membrabes.J Matem Fetal Neonatal Med,2004,16(3):146-157.
[12]Rounioja S,Rasanen J,Glumoff V,et al.Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction.A mouse model for fetal inflammatory response.Cardiovase Res,2003,60(1):156-164.
[13]Di Naro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographicmarker of the fetal inflammatory responsesyndrome.Am J Obstet Gynecol.2006,194:153-159.
[14].Murase M,Ishida A.Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection.Arch.Child.fetal neonatal 2006,91(2):105-110.
[15]Makikallio K,Vuolteenaho O,Jouppila P,et al.Ultrasonographic and biochemical markers of human fetal cardiac dysfunction in placental insufficiency.Circulation 2002,105:2058-2063.
[16]Kitzman DW,Gardin JM,Gottdiener JS,et al.Importance of heart failure with reserved systolic function in patients ≥ 65 years of age.Am J Cardiol,2001,87:413-419.
[17].Chang CH,Chang FM,Yu CH,et al.Systemic assessment of fetal hemodynamics by Doppler ultrasound.Ultrasound Med Biol,2000,26:777-785.
[18].Fernandez PL,Tamariz MM,Maitre AM,et al.Contribution of Doppler atrioventricular flow waves to ventricular filling in the human fetus.Pediatr Cardiol,2000,21:422-428.
[19]Gardiner H,Brodszki J,Marsal K.Ventriculovascular physiology of the growthrestricted fetus.Ultrasound Obstet Gynecol,2001,18:47-53
[20]张崔华,徐湘滨,Barry J,et al.TNF在缺血/再灌注损伤中内皮功能障碍的作用.动脉硬化血栓血管生物学杂志,2006,26(3):807-813.
[21]Alpert JS,Thygesen K,Antman E.Myocardial infarction redefined-a consensus document of The European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.J Am Coll Cardiol,2000,36(3):959-969.
[22]张向隆.对40例急性心肌梗死患者肌钙蛋白T动态观察与预后相关性分析.中华医药杂志,2008,8(1):26-27.
[23]黄新冲,曾因明.体外循环中心肌保护措施的评价.国外医学·麻醉与复苏分册,2001,22(5):294-296.
[24]Mann K,Doerre S,Schlezinger JJ,et al.The role of NF-B as a survival factor in environmental chemical-induced pre-B cell apoptosis.Mol Pharmacol,2001,59:302-309.
[25]Yamamoto Y,Gaynor RB.IkappaBkinases:key regulators of the NF-kappaB pathway.Trends BiochemlSci,2004;29:72-79.
[26]Pueyo ME,Nicoletti A,Conzalez,et al.Angiotensin II stimulates endothelial vascular cell adhesion molecule-lvia nuclear factor-kappaB activation induced by intracellular oxidative stress.Arterioscler Thromb Vase Biol,2000;20:645-651.
[27]Kavurma MM,Schoppet M,Bobryshev YV,et al.Trail stimulates proliferation of vascular smooth muscle cells via activation of NF-kappa B and induction of insulin-like growth factor-1 receptor.J Biol Chem,2008,21:7754-7762.
[28]dwin K,Marion JJ,Gijbels.Ingeborg van der Made,Hematopoietic NF-kBI deficiency results in small atherosclerotic lesions with an inflammatory phenotypeC.Blood,2004;103:934-940.
[29]Li YH,Zhuo YH,Lv L,et al.Caspase-dependent retinal ganglion cell apoptosis in the rat model of acute diabetes.J Chin Medic,2008,121(24):2566-2571.
[30]Jendrossek V,Handrick R,Belka C.Celecoxib activates a novel mitochondrial apoptosis signaling pathway.Faseb J,2003,17:1547-1549.
[31]Cowling V,Downward J.Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway:absolute requirement for removal of caspase-6 prodomain.Cell Death Differ,2002,9:1046-1056
[32]Lopez-Hernandez FJ,Ortiz MA,Bayon Y,et al.Z-FA-fmk inhibits effector caspases but not initiator caspases 8 and 10 and demonstrates that novel anticancer retinoid-related molecules induce apoptosis via the intrinsic pathway.Mol Cancer Ther,2003,2:255-263.
[33]Murphy BM,Creagh EM,Martin SJ.Interchain proteolysis,in the absence of a dimerization stimulus,can initiate apoptosis-associated caspase-8 activation.J Biol Chem,2004,279:36916-36922.
[34]Kockx MM,Herman AG.Apoptosis in atherosclerosis:beneficial or detrimental?.Cardiovasc Res 2000;45:736-746.
[35].Bartha JL,Romero CR,Comino DR.Inflammatory cytokines in intrauterine growth retardation.Acta Obstet Gynecol Scand,2003,82(12):1099-1102.
[36].Hatzidaki E,Gourgiotis D,Manoura A,et al.Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome.Acta Obstet Gynecol Scand.2005,84(7):632-638.
[37]Roberto R,Tinnakorn CP,Jimmy EM.Micronutrients and intrauterine infection,preterm birth and the fetal inflammatory response syndrome infection and inflammation.2003,133:1668-1673
[38]Laudanski P,Pierzynski P,Laudanski T.Reductionist and system approaches to study the role of infection in preterm labor and delivery.BMC Pregnancy and Child birth,2007,7(Suppl 1):9-12.
[1].GomezR,RomeroR,GhezziF,et al.The fetal inflammatory response syndrome.Am J Obstet Gynecol.1998,179:194-202.
[2]American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.Crit Care Med.1992,20:864-874.
[3].Angus DC,Linde-Zwirble WT,Lidicker J,et al.Epidemiology of severe sepsis in the United States:analysis of incidence,outcome,and associated costs of care.Crit Care Med.2001,29:1303-1310.
[4].Riedemann NC,Guo RF,Ward PA.Novel strategies for the treatment of sepsis.Nat Med.2003,9:517-524.
[5].Muckart DJ,Bhagwanjee S.American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients.Crit Care Med.1997,25:1789-1795.
[6].Gomez R,Ghezzi F,Romero R,et al.Two thirds of human fetuses with microbial invasion of the amniotic cavity have a detectable systemic cytokine response before birth [Abstract].Am J Obstet Gynecol.1997,176:514.
[7].Levy MM,Fink MP,Marshall JC,et al.2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Intensive Care Med.2003,29:530-538.
[8].Romero R,Espinoza J,Goncalves L,et al.The fetal inflammatory response syndrome.UK:Informa Healthcare;2006:149-172.
[9].Romero R,Espinoza J,Goncalves LF,et al.The role of inflammation and infection in preterm birth.Semin Reprod Med.2007,25:21-39.
[10].Henson PM.Dampening inflammation.Nat Immunol.2005;6:1179-1181.
[11].Ley K.History of inflammation research.Oxford:Oxford University Press;2001:1-10.
[12].Gallin JI,Snyderman R.Inflammation:historical perspective.Philadelphia:Lippincott Williams & Wilkins;1999:5-12.
[13].Janeway C,Travers P,Walport M,et al.Innate immunity.New York:Garland Science Publishing;2005:37-102.
[14].Salamonsen LA,Lathbury LJ.Endometrial leukocytes and menstruation.Hum Reprod Update.2000,6:16-27.
[15].Kiviat NB,Wolner-Hanssen P,Eschenbach DA,et al.Endometrial histopathology in patients with culture proved upper genital tract infection and laparoscopically diagnosed acute salpingitis.Am J Surg Pathol.1990,14:167-175.
[16].Haddad R,Tromp G,Kuivaniemi H,et al.Spontaneous labor at term is characterized by a genomic signature of acute inflammation in the chorioamniotic membranes but not in the systemic.circulation.Am J Obstet Gynecol.2004,191:138.
[17].Yoon BH,Romero R,Park JS,et al.The relationship among inflammatory lesions of the umbilical cord (funisitis),umbilical cord plasma interleukin 6 concentration,amniotic fluid infection,and neonatal sepsis.Am J Obstet Gynecol.2000,183:1124-1129.
[18].Yoon BH,Romero R,Moon JB,et al.Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes.Am J Obstet Gynecol.2001,185:1130-1136.
[19].Gotsch F,Romero R,Kusanovic JP,et al.The Fetal Inflammatory Response Syndrome.Clin Obstet Gynecol,2007,50(3):652-683
[20].Brannstrom M,Enskog A.Leukocyte networks and ovulation.J Reprod Immunol.2002,57:47-60.
[21].Chard T.Cytokines in implantation.Hum Reprod Update.1995,1:385-396.
[22].Kelly RW,King AE,Critchley HO.Inflammatory mediators and endometrial Function-focus on the perivascular cell.J Reprod Immunol.2002,57:81-93.
[23].Keelan JA,Blumenstein M,HelliwellRJ,et al.Cytokines,prostaglandins and parturition-a review.Placenta.2003,24(suppl A):33-46.
[24].Salvemini D,Cuzzocrea S.Oxidativestress in septic shock and disseminated intravascular coagulation.Free Radic Biol Med.2002,33:1173-1185.
[25]Hoffman M,Cooper ST.Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms.Blood Cells Mol Dis.1995;21:156-167.
[26].Matzinger P.The danger model:a renewed sense of self.Science.2002,296:301 -305.
[27].Medzhitov R,Janeway J.The Toll receptor family and microbial recognition.Trends Microbiol.2000,8:452-456.
[28].Beg AA.Endogenous ligands of Tolllike receptors:implications for regulating inflammatory and immune responses.Trends Immunol.2002,23:509-512.
[29].Janeway CA,Travers P,Walport M,et al.Basic concepts in immunology.New York:Garland Publishing;2001:1-34.
[30].Romero R,Sirtori M,Oyarzun E,et al.Infection and labor.V.Prevalence,microbiology,and clinical significance of intra-amniotic infection in women with preterm labor and intact membranes.Am J Obstet Gynecol.1999,161:817-824.
[31].King AE,Critchley HO,Kelly RW.Innate immune defences in the human endometrium.Reprod Biol Endocrinol.2003,1:116.
[32].Condon JC,Jeyasuria P,Faust JM,et al.Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition.Proc Natl Acad Sci USA.2004,101:4978-4983.
[33].Kishore U,Bernal AL,Kamran MF,et al.Surfactant proteins SP-A and SP-D in human health and disease.Arch Immunol Ther Exp (Warsz).2005,53:399-417.
[34].Costerton W,Veeh R,Shirtliff M,et al.The application of bio-film science to the study and control of chronic bacterial infections.J Clin Invest.2003,112:1466-1477.
[35].Hargreaves DC,Medzhitov R.Innate sensors of microbial infection.J Clin Immunol.2005,25:503-510.
[36]Pasare C,Medzhitov R.Toll-like receptors:linking innate and adaptive immunity.Microbes Infect.2004,6:1382-1387.
[37].Elovitz MA,Wang Z,Chien EK,et al.A new model for inflammation-induced preterm birth:the role of platelet-activatingfactor and Toll-like receptor-4.Am J Pathol.2003,163:2103-2111.
[38].Kim YM,Romero R,Chaiworapongsa T,et al.Toll-like receptor-2 and-4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis.Am J Obstet Gynecol.2004,191:1346-1355.
[39].Annane D,Bellissant E,Cavaillon JM.Septic shock.Lancet.2005,365:63-78.
[40].Jean-Baptiste E.Cellular mechanisms insepsis.J Intensive Care Med.2007,22:63-72.
[41].Romero R,Wu YK,Brody DT,et al.Humandecidua:a source of interleukin-1.Obstet Gynecol.1989,73:31-34.
[42].Romero R,Durum S,Dinarello CA,et al.Interleukin-1 stimulates prostaglandin biosynthesis by human amnion.Prostaglandins.1989,37:13-22.
[43].Romero R,Brody DT,Oyarzun E,et al.Infection and labor.Ⅲ.Interleukin-1:a signal for the onset of parturition.Am J Obstet Gynecol.1989,160:1117-1123.
[44].Sadowsky DW,Novy MJ,Witkin SS,et al.Dexamethasone or interleukin-10 blocks interleukin-1 beta-induced uterinecontractions in pregnant rhesusmonkeys.Am J Obstet Gynecol.2003,188:252-263.
[45].Romero R,Tartakovsky B.The natural interleukin-1 receptor antagonist prevents interleukin-1 induced preterm delivery in mice.Am J Obstet Gynecol.1992,167:1041-1045.
[46].Romero R,Mazor M,Wu YK,et al.Infection in the pathogenesis of preterm labor.Semin Perinatol.1988,12:262-279.
[47].Romero R,Mazor M,Manogue K,et al.Human decidua:a source of cachectin tumor necrosis factor.Eur J Obstet Gynecol Reprod Biol.1991,41:123-127.
[48].Fortunato SJ,Menon R,Lombardi SJ.Role of tumor necrosis factor-[alpha]in the premature rupture of membranesand preterm labor pathways.Am JObstet Gynecol.2002,187:1159-1162.
[49].Romero R,Chaiworapongsa T,Espinoza J,et al.Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes.Am J Obstet Gynecol.2002,187:1125-1130.
[50].Chwalisz K,Benson M,Scholz P,et al.Cervical ripening with the cytokines interleukin 8,interleukin 1[beta]and tumour necrosis factor [alpha]in guinea pigs.Hum Reprod.1994,9:2173-2181.
[51].Fidel PL Jr,Romero R,Cutright J,et al.Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor Fc fusion protein does not prevent endotoxin-induced preterm parturition in mice.J Soc Gynecol Invest.1997,4:22-26.
[52].Van Parijs L,Abbas AK.Homeostasis and self-tolerance in the immune system:turning lymphocytes off.Science.1998,280:243-248.
[53].Sakaguchi S.Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses.Annu Rev Immunol.2004,22:531-562.
[54].Cupedo T,Nagasawa M,Weijer K,et al.Development and activation of regulatory T cells in the human fetus.Eur JImmunol.2005,35:383-390.
[55].Billingham RE,Brent L,Medawar PB.Actively acquired tolerance of foreign cells.Nature.1953,172:603-606.
[56].Berry SM,Romero R,Gomez R,et al.Premature parturition is characterized by in utero activation of the fetal immune system.Am J Obstet Gynecol.1995,173:1315-1320.
[57].Thompson PJ,Greenough A,Davies E,et al.Fetal C-reactive protein.Early Hum Dev.1993,32:81-85.
[58].Sarzotti M,Robbins DS,Hoffman PM.Induction of protective CTL responses in newborn mice by a murine retrovirus.Science.1996,271:1726-1728.
[59].Matsuoka T,Matsubara T,KatayamaK,et al.Increase of cord blood cytokine producing T cells in intrauterine infection.Pediatr Int.2001,43:453-457.
[60].Yoneyama Y,Suzuki S,Sawa R,et al.Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes.Arch Gynecol Obstet.2003,267:217-220.
[61].Gerber S,Vial Y,Hohlfeld P,et al.Prenatal diagnosis of congenital cytomegalo virus infection by detection of immunoglobulin M antibodies to the70-kd heat shock protein in fetal serum.Am J Obstet Gynecol.2002,187:955-959.
[62].Chaiworapongsa T,Romero R,Kim JC,et al.Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis.Am J Obstet Gynecol.2002;186:1178-1182.
[63]Witt A,Berger A,Gruber CJ,et al.IL-8 concentrations in maternal serum,amniotic fluid and cord blood in relation to different pathogens within the amniotic cavity.J Perinat Med.2005,33:22-26.
[64].Pacora P,Chaiworapongsa T,MaymonE,et al.Funisitis and chorionic vasculitis:the histological counterpart of the fetal inflammatory response syndrome.J Matern Fetal Neonatal Med.2002,11:18-25.
[65].D'AlquenD,Kramer BW,SeidenspinnerS,et al.Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.Pediatr Res.2005,57:263-269.
[66]Yoon BH,Romero R,Park JS,et al.Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years.AmJ Obstet Gynecol.2000,182:675-681.
[67].Yoon BH,Romero R,Shim JY,et al.Creactive protein in umbilical cord blood:a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis.J Matern Fetal Neonatal Med.2003,14:85-90.
[68].Sampson JE,Theve RP,Blatman RN,et al.Fetal origin of amniotic fluid polymorpho nuclear leukocytes.Am J Obstet Gynecol.1997,176:77-81.
[69].Shim SS,Romero R,Hong JS,et al.Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes.Am J Obstet Gynecol.2004,191:1339-1345.
[70].Romero R,Athayde N,Gomez R,et al.The fetal inflammatory response syndrome is characterized by the out pouring of a potent extracellular matrix degrading enzyme into the fetal circulation.Am J Obstet Gynecol.1998,178:3.
[71].Gomez R,Berry S,Yoon BH,et al.The hematologic profile of the fetus with systemic inflammatory response syndrome.Am J Obstet Gynecol.1998,178:202.
[72].Berry SM,Gomez R,Athayde N,et al.The role of granulocyte colony stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome.Am J Obstet Gynecol.1998,178:202.
[73].Gomez R,Romero R,Ghezzi F,et al.Are fetal hypoxia and acidemia causes of preterm labor and delivery? [Abstract].Am J Obstet Gynecol.1997,176:115.
[74].Baschat AA,Gembruch U,Reiss I,et al.Neonatal nucleated red blood cell counts in growth-restricted fetuses:relationship to arterial and venous Doppler studies.Am J Obstet Gynecol.1999,181:190-195.
[75].FerberA,MiniorVK,Bornstein E,et al.Fetal “non reassuring status” is associated with elevation of nucleated red blood cell counts and interleukin-6.Am J Obstet Gynecol.2005,192:1427-1429.
[76].Di Naro E,Cromi A,Ghezzi F,et al.Fetal thymic involution:a sonographicmarker of the fetal inflammatory responsesyndrome.Am J Obstet Gynecol.2006,194:153-159.
[77].Haeryfar SM,Berczi I.The thymus and the acute phase response.Cell Mole Biol.2001,47:145-156.
[78].Kuban JD,Allred EN,Leviton A.Thymus involution and cerebral white matter damage in extremely low gestational age neonates.Biol Neonate.2006,90:252-257.
[79].Li L,Hsu HC,Stockard CR,et al.IL-12 inhibits thymic involution by enhancing IL-7-and IL-2-induced thymocyte proliferation.J Immunol.2004,172:2909-2916.
[80]Yoon BH,Romero R,Jun JK,et al.An increase in fetal plasma Cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes.Am J Obstet Gynecol.1998,179:1107-1114.
[81].Nathanielsz PW,Berghorn KA,DerksJB,et al.Life before birth:effects of Cortisol on future cardiovascular andmetabolic function.Acta Paediatr.2003,92:766-772.
[82]Moritz KM,Boon WM,Wintour EM.Glucocorticoid programming of adult disease.Cell Tissue Res.2005,322:81-88.
[83].Kim YM,Romero R,Chaiworapongsa T,et al.Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes.Histopathology.2006,49:506-514.
[84].Yoon BH,Kim YA,Romero R,et al.Association of oligohydramnios in women with preterm premature rupture of membranes with an inflammatory response in fetal,amniotic,and maternal compartments.Am J Obstet Gynecol.1999,181:784-788.
[85].EspinozaJ,ChaiworapongsaT,RomeroR,et al.Antimicrobial peptides in amniotic fluid:defensins,calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity,intra-amniotic inflammation,preterm labor and premature rupture of membranes.J Matern Fetal Neonatal Med.2003,13:2-21.
[86].Romero R,Espinoza J,Goncalves LF,et al.Fetal cardiac dysfunction in preterm premature rupture of membranes.J Matern Fetal Neonatal Med.2004,16:146-157.
[87].Court O,Kumar A,Parrillo JE,et al.Clinical review:myocardial depression in sepsis and septic shock.Crit Care.2002,6:500-508.
[88].Yanowitz TD,Jordan JA,Gilmour CH,et al.Hemodynamic disturbances in premature infants born after chorioamnionitis:association with cord blood cytokine concentrations.Pediatr Res.2002,51:310-316.
[89].Gamier Y,Coumans AB,Jensen A,et al.Infection-related perinatal brain injury:the pathogenic role of impaired fetal cardiovascular control.J Soc Gynecol Investi.2003,10:450-459.
[90]Kaukola T,Herva R,Perhomaa M,et al.Population cohort associating chorioamnionitis,cord inflammatory cytokines and neurologic outcome in very preterm,extremely low birth weight infants.Pediatr Res.2006,59:478-483.
[91].Kalache KD,Chaoui R,Bollmann R.Doppler assessment of tracheal and nasal fluid flow during fetal breathing movements:preliminary observations.Ultrasound Obstet Gynecol.1997,9:257-261.
[92].Speer CP.Pulmonary inflammation andbronchopulmonary dysplasia.JPerinatol.2006,26(suppl 1):57-62.
[93].Speer CP.Inflammation and bronchopulmonarydysplasia.Semin Neonatol.2003,8:29-38.
[94].Jobe AH.Antenatal associations withlung maturation and infection.J Perinatol.2005,25(suppl 2):31-35.
[95]Moss T,Jobe A.Amniotic fluid inflammationand fetal lung development.In:Peebles D,Myatt L,eds.Inflammationand Pregnancy.Abingdon,Oxon,UK:Informa Healthcare;2006:173-186.
[96].Bry K,Lappalainen U,Hallman M.Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth.J Clin Invest.1997,99:2992-2999.
[97].Kallapur SG,Willet KE,Jobe AH,et al.Intra-amniotic endotoxin:chorioamnionitis precedes lung maturation in preterm lambs.Am J Physiol Lung Cell Mol Physiol.2001,280:527-536.
[98].Jobe AH,Newnham JP,Willet KE,et al.Endotoxin-induced lung maturation in preterm lambs is not mediated by Cortisol.Am J Respir Crit Care Med.2000,162:1656-1661.
[99].Kallapur SG,Moss TJ,IkegamiM,et al.Recruited inflammatory cells mediate endotoxin-induced lung maturation in preterm fetal lambs.Am J Respir Crit Care Med.2005;172:1315-1321.
[100].Prince LS,Okoh VO,Moninger TO,et al.Lipopolysaccharide increases alveolar type Ⅱ cell number in fetal mouse lungs through Toll-like receptor4 and NF-kappaB.Am J Physiol Lung Cell Mol Physiol.2004;287:999-1006.
[101].Moss TJ,Nitsos I,Ikegami M,et al.Experimental intrauterine Ureaplasma infection in sheep.Am J Obstet Gynecol.2005;192:1179-1186.
[102]Nelson KB,Dambrosia JM,Grether JK,et al.Neonatal cytokines and coagulation factors in children with cerebral palsy.Ann Neurol.1998,44:665-675.
[103].Verma U,Tejani N,Klein S,et al.Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate.Am J Obstet Gynecol.1997,176:275-281.
[104].Alexander JM,Gilstrap LC,Cox SM,et al.Clinical chorioamnionitis and the prognosis for very low birth weight infants.Obstet Gynecol.1998,91:725-729.
[105].O'Shea TM,Klinepeter KL,Dillard RG.Prenatal events and the risk of cerebral palsy in very low birth weight infants.Am J Epidemiol.1998,147:362-369.
[106].Dammann O,Leviton A.Role of the fetus in perinatal infection and neonatal brain damage.Curr Opin Pediatr.2000,12:99-104.
[107].Nelson KB.The epidemiology of cerebral palsy in term infants.Ment Retard Dev Disabil Res Rev.2002,8:146-150.
[108].Dammann O,Kuban KC,Leviton A.Perinatal infection,fetal inflammatory response,white matter damage,andcognitive limitations in children bornpreterm.Ment Retard Dev Disabil ResRev.2002,8:46-50.
[109]Duncan JR,Cock ML,Scheerlinck JP,et al.White matter injury after repeated endotoxin exposure in the pretermovinefetus.Pediatr Res.2002;52:941-949.
[110].Mehta R,Nanjundaswamy S,Shen-Schwarz S,et al.Neonatal morbidity and placental pathology.Indian J Pediatr.2006;73:25-28.
[111].Grafe MR.The correlation of prenatal brain damage with placental pathology.J Neuropathol Exp Neurol.1994;53:407-415.
[112].Hagberg H,Mallard C,Jacobsson B.Role of cytokines in preterm labour and brain injury.BJOG.2005,112(suppl 1):16-18.
[113]Dammann O,Leviton A,Gappa M,et al.Lung and brain damage in preterm newborns,and their association with gestational age,prematurity subgroup,infection /inflammation and long term outcome.BJOG.2005,112(suppl l):4-9.
[114].Nelson KB,Dambrosia JM,IovannisciDM,et al.Genetic polymorphisms and cerebral palsy in very preterm infants.Pediatr Res.2005,57:494-499.
[115].Grether JK,Nelson KB,Walsh E,et al.Intrauterine exposure to infection and risk of cerebral palsy in very preterminfants.Arch Pediatr Adolesc Med.2003,157:26-32.
[116].Wu YW.Systematic review of chorioamnionitisand cerebral palsy.Ment Retard Dev Disabil Res Rev.2002,8:25-29.
[117].Nelson KB.Can we prevent cerebral palsy? N Engl J Med.2003,349:1765-1769.
[118].Duggan PJ,Maalouf EF,Watts TL,et al.Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions.Lancet.2001,358:1699-1700.
[119].Kaukola T,Satyaraj E,Patel DD,et al.Cerebral palsy is characterized by protein mediators in cord serum.Ann Neurol.2004;55:186-194.
[120].deVries LS,Groenendaal F.Neuro imagingin the preterm infant.Ment Retard Dev Disabil Res Rev.2002.8:273-280.
[121].Hagberg B,Hagberg G,Beckung E,ei al.Changing panorama of cerebral palsy in Sweden.Ⅷ.Acta Paediatr.2001;90:271-277.
[122].Debillon T,Gras-Leguen C,Leroy S,et al.Patterns of cerebral inflammatory response in a rabbit model of intrauterineinfection-mediated brain lesion.Brain Res Dev Brain Res.2003,145:39-48.
[123].Kadhim H,Tabarki B,De Prez C,et al.Interleukin-2 in the pathogenesis of perinatal white matter damage.Neurology.2002,58:l 125-1128.
[124].Kadhim H,Tabarki B,De Prez C,et al.Cytokine immuno reactivity in cortical and subcortical neurons in periventricular leukomalacia:are cytokines implicated in neuronal dysfunction in cerebral palsy? Acta Neuropathol (Berl).2003,105:209-216.
[125].Edwards AD,Tan S.Perinatal infections,prematurity and brain injury.Curr Opin Pediatr.2006,18:119-124.
[126].Wong D,Dorovini-Zis K,Vincent SR.Cytokines,nitric oxide,and cGMP.modulate the permeability of an in vitromodel of the human blood-brain barrier.Exp Neurol.2004,190:446-455.
[127]HagbergH,Mallard C.Effect of inflammation on central nervous system development and vulnerability.Curr Opin Neurol.2005,18:117-123.
[128].Nelson KB,Grether JK,Dambrosia JM,et al.Neonatal cytokines and cerebral palsy in very preterm infants.Pediatr Res.2003;53:600-607.
[129]Tan S,Peebles D,Edwards D.Infection,inflammation,and perinatal brain injury.UK:Informa Healthcare;2006:187-201.
[130].Wang X,Svedin P,Nie C,et al.N-acetylcysteine reduces lipopolysaccharidesensitized hypoxic-ischemicbrain injury.Ann Neurol.2007,61:263-271.
[131].Witkin SS,Gerber S,Ledger WJ.Influenceof interleukin-1 receptor antagonist gene polymorphism on disease.Clinlnfect Dis.2002,34:204-209.
[132].Gerber S,Vardhana S,Meagher-Villemure,et al.Association between fetal interleukin-1 receptor antagonistgene polymorphism and unexplained fetal death.Am J Obstet Gynecol.2005,193:1472-1477.
[133]Blackwell S,Romero R,ChaiworapongsaT,et al.Unexplained fetal death is associated with changes in the adaptive limb of the maternal immune response consistent with prior antigenic exposure.J Matern Fetal Neonatal Med.2003,14:241-246.
[134].Moyo SR,Hagerstrand I,Nystrom L,et al.Stillbirths and intrauterine infection,histologic chorioamnionitis andmicrobiological findings.Int J GynaecolObstet.1996;54:115-123.
[135].Mwanyumba F,Inion I,Gaillard P,et al.Placental inflammation and perinatal outcome.Eur J Obstet GynecolReprod Biol.2003,108:164-170.