Inflammation of the fetal ovine skin following in utero exposure to Ureaplasma parvum

There is increasing evidence linking in utero infection and inflammation to preterm birth. Many commensal urogenital tract microorganisms, including the Mycoplasmas and Ureaplasmas, are commonly detected in association with preterm birth. Using an ovine model of sterile fetal inflammation, we demonstrated previously that the fetal skin generates a robust inflammatory response following in utero exposure to lipopolysaccharides from Escherichia coli. The fetal skin's response to colonization of the amniotic fluid by viable microorganisms remains unstudied. We hypothesised that in utero infection with Ureaplasma parvum serovar 3 would induce a proinflammatory response in the fetal skin. We found that (1) cultured fetal keratinocytes (the primary cellular constituent of the epidermis) respond to U. parvum exposure in vitro by increasing the expression of the chemotactant monocyte chemoattractant protein 1 (MCP-1) but not interleukin 1β (IL-1β), IL-6, IL-8, or tumor necrosis factor-α (TNF-α); (2) the fetal skin's response to 7 days of U. parvum exposure is characterized by elevated expression of MCP-1, TNF-α, and IL-10; and (3) the magnitude of inflammatory cytokine/chemokine expression in the fetal skin is dependent on the duration of U parvum exposure. These novel findings provide further support for the role of the fetal skin in the development of fetal inflammation and the preterm birth that may follow.     

The fetal inflammatory response syndrome and cerebral palsy: yet another challenge and dilemma for the obstetrician

There is increasing evidence demonstrating a relationship between intrauterine infection and the development of neonatal intraventricular haemorrhage and periventricular leukomalacia with the subsequent occurrence of cerebral palsy, which is thought to be mediated through the generation of pro-inflammatory cytokines by the fetus. In the light of this relationship, a review of the current management of intrapartum infection and the associated complications of intrauterine infection such as preterm labour and preterm premature rupture of the membranes would seem timely along with the development of potential strategies which might prevent or ameliorate the effects of the fetal inflammatory response syndrome. The suggested changes in the understanding and management of the fetal inflammatory response syndrome provide a challenge and pose a dilemma for the practising obstetrician.     

Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth

The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.     

Cord blood biomarkers of the fetal inflammatory response

Objective. In current, neonatal practice, clinical signs of intrauterine infection (IUI) are often non-specific. From a large panel of immune biomarkers, we seek to identify cord blood markers that are most strongly associated with the fetal inflammatory response (FIR), a specific placental lesion associated with serious neonatal complications.

Methods. We used multiplex immunoassay to measure 27 biomarkers, selected as part of an NIH-funded study of preterm birth, according to gestational age (GA) and extent of placental inflammation: involvement of chorion, amnion, decidua (maternal inflammatory response, MIR); extension to umbilical cord or chorionic plate (FIR). We used false-discovery rate (FDR < 5%, P < 0.001) to account for multiple comparisons.

Results. Among 506 births (GA 23–42 weeks), IL-1β increased with FIR among preterm subgroups (P = 0.0001 for <32 weeks; P = 0.0009 for 33–36 weeks). IL-6 and IL-8 increased with FIR among preterm and full-term infants (P < 0.0001). P-trend for IL-6 and IL-8 with MIR versus FIR was <0.0001. Comparison with respect to clinical IUI yielded persistent elevation with FIR even when clinical signs were absent. The remaining 24 markers were not significantly associated.

Conclusion. We conclude that among 27 cord blood biomarkers, IL-1β, IL-6 and IL-8 are selectively associated with FIR. These markers may be clinically useful indicators of extensive IUI associated with poor neonatal outcome.     

Antenatal infection/inflammation and fetal tissue injury

There is a clear association between antenatal infection/inflammation and preterm labour, with intrauterine infection complicating up to one third of preterm deliveries. In addition to this, there is now accumulating evidence that intrauterine infection and inflammation can lead to the development of a systemic inflammatory response in the fetus and subsequent tissue injury. The fetal inflammatory response is characterized by funisitis, high levels of pro-inflammatory cytokines in the amniotic fluid and cord blood, and systemic immune activation. This review discusses the evidence for this process and focuses on the clinical and experimental data supporting the hypothesis that these inflammatory processes contribute to brain and lung injury in the newborn.     

Baby born too soon: an overview and the impact beyond the infection

Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, immunological factors also appear to be involved. Recently, molecular genetic studies have helped us better understand the underlying pathophysiologic processes. During mammalian pregnancy, maternal–fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. This review focuses on the specific immune parameters that become altered during human pregnancy, the identity and function of some immune modulators that have been best characterized to date, as well as a comprehensive evaluation of the pregnancy-associated mechanisms that downregulate proinflammatory immunity to a level sufficient to prevent the triggering of premature common pathway of labor and damage to developing organs.     

Infection and preterm birth

As many as 50% of spontaneous preterm births are infection-associated. Intrauterine infection leads to a maternal and fetal inflammatory cascade, which produces uterine contractions and may also result in long-term adverse outcomes, such as cerebral palsy. This article addresses the prevalence, microbiology, and management of intrauterine infection in the setting of preterm labor with intact membranes. It also outlines antepartum treatment of infections for the purpose of preventing preterm birth.     

Antenatal diagnosis of chorioamnionitis: A review of the potential role of fetal and placental imaging

Chorioamnionitis is present in up to 70% of spontaneous preterm births. It is defined as an acute inflammation of the chorion, with or without involvement of the amnion, and is evidence of a maternal immunological response to infection. A fetal inflammatory response can coexist and is diagnosed on placental histopathology postnatally. Fetal inflammatory response syndrome (FIRS) is associated with poorer fetal and neonatal outcomes. The only antenatal diagnostic test is amniocentesis which carries risks of miscarriage or preterm birth. Imaging of the fetal immune system, in particular the thymus and the spleen, and the placenta may give valuable information antenatally regarding the diagnosis of fetal inflammatory response. While ultrasound is largely limited to structural information, MRI can complement this with functional information that may provide insight into the metabolic activities of the fetal immune system and placenta. This review discusses fetal and placental imaging in pregnancies complicated by chorioamnionitis and their potential future use in achieving non-invasive antenatal diagnosis.     

新生儿IL-18对Th1/Th2类细胞免疫平衡的作用与HBV宫内感染相关性研究

目的:探讨新生儿IL-18对Th1/Th2类细胞免疫平衡的作用与HBV宫内感染的相关性。方法:选择HBsAg、HBeAg双阳性但肝功能正常孕产妇分娩的新生儿157例,以其中胎儿宫内感染21例为研究组,无宫内感染136例为对照组。用流式细胞仪检测两组脐血白细胞介素-18(IL-18)、γ-干扰素(IFN-γ)、白细胞介素-4(IL-4)的表达水平。结果:(1)研究组IL-18及IFN-γ表达水平明显低于对照组,差异有显著性(P<0.05;P<0.05);研究组IL-4表达水平百分数高于对照组,但差异无显著性(P>0.05);研究组IFN-γ/IL-4高于对照组,差异有显著性(P<0.05);(2)研究组IL-18与IFN-γ、IL-4、IFN-γ/IL-4均呈显著正相关(P均<0.05)。结论:IL-18是Th1/Th2网络平衡的更高层次的调控者;IL-18水平下调,导致新生儿Th1/Th2细胞因子比例下降,以致不利于HBV的清除,IL-18水平下调可能是HBV宫内感染的危险因素之一。     

The role of inflammation in preterm birth—focus on periodontitis

It is universally accepted that acute inflammation is responsible for a substantial fraction of preterm births, particularly early cases. Much of this inflammation is caused by intrauterine infection. There is also evidence that infection and perhaps inflammation remote from the genitourinary tract can trigger preterm labour. Several studies have suggested that periodontitis during pregnancy increases the risk of preterm birth. Periodontitis may cause preterm birth by causing low-grade bacteraemia, which lodges in the decidua, chorion and amnion or by releasing endotoxin into the maternal circulation, which triggers intrauterine inflammation and preterm birth. Alternatively, it may release cytokines and other inflammatory products, which then trigger preterm labour. It is also conceivable that periodontitis might serve as a marker for other unhealthy behaviours, or immune hyperresponsiveness and that hyperresponsiveness to low-grade intrauterine infection itself might cause preterm birth. Currently, there are few data available to distinguish these possibilities. Such distinctions are important since they have clear implications for whether treatment of periodontitis might reduce the incidence of preterm birth. Several clinical trials of treatment of periodontitis are continuing, but until their results are known there is currently little evidence that treatment of periodontitis during pregnancy reduces the incidence of preterm birth.     

Comprehending the role of LPS in Gram-negative bacterial vaginosis: ogling into the causes of unfulfilled child-wish

Introduction Intrauterine infection is frequently associated with pregnancy loss in pregnant women.Discussion This article reviews the role of Gram-negative bacterial infection in various complications related to early pregnancy and subsequent pregnancy loss. Here we discus the pathways of ascending intrauterine infection, microbiology and the pathophysiology of such infections. The clinical impact, therapy, consequences, prevention and implications of Gram-negative bacterial infections in women during their reproductive life span is also discussed. This article also makes an attempt to discuss our studies and findings, related to the effect of the LPS component of the Gram-negative bacterial endotoxin on preimplantation stage embryonic development and implantation. This early phase of pregnancy remains mostly unnoticed by the mother as well as the health care provider, and therefore holds more threat to the life of the fetus and the mother. The molecular mechanisms of LPS-induced pregnancy losses through abnormal embryonic development, implantation failure, and preterm labor and birth with specific references to the role of proinflammatory cytokines like IL-1 and TNF are discussed.Conclusion Once these inflammatory mediators have increased in the feto-maternal tissues, it may be too late or harmful to try and prevent the adverse outcomes of pregnancy.     

基质金属蛋白酶降解胞外基质致未足月胎膜早破研究进展

早产是威胁围生儿生命健康的首要病因。据统计,2012年中国早产发生率为8.1%。未足月胎膜早破(preterm premature rupture of membranes,PPROM)占早产的25%~30%,重要诱因为宫内感染。近年研究发现,PPROM的分子机制为胎膜组织中胞外基质过早降解,主要由基质金属蛋白酶(matrix metalloproteinases,MMPs)在胎膜组织中的激活引起。MMPs的激活原因有炎症因子的表达增高,如白细胞介素1(IL-1),IL-6以及肿瘤坏死因子α(TNF-α),但具体机制尚有待研究。MMPs在正常分娩与PPROM发生过程中的激活、分泌及其影响因素仍需探索,其可能作为预测妊娠结局的标记物,为PPROM的预防与治疗提供突破点。     

The role of infection in preterm birth

Intrauterine infection could be responsible for 25% up to 40% of preterm births. This relationship was initially demonstrated using animal models, inducing their abortion by injecting bacteria or endotoxins. In human research, examination of amniocentesis fluid showed the anteriority of infection over labor induction, and the existence of a subclinical latency phase between these two phenomena. The ascending route is preponderant, and four stages can be distinguished: cervical and vaginal infection, chorio-decidual infection, intra-amniotic infection, fetal infection. The intrauterine infection is very frequent in case of early preterm birth (<30 WG). It is associated with an increase of neurological and pulmonary morbidity. Most commonly found bacterial species are mycoplasma species, but also Escherichia coli, Gardnerella vaginalis and streptococcus B. Several markers of the infection have been studied: a maternal leukocytosis>15,000/mm(3) or a C-Reactive Protein (CRP)>20mg/l, an increase of fibronectin and/or IL-6 cervical, a short cervical length especially before 32 WG, a leukocytosis of the amniotic fluid, and/or high interleukin concentrations. The main marker used for the newborn is the CRP, but other markers can also be used for an early diagnosis of an infection, especially interleukin 6.     

Cytokine production in chorioamnionitis

Lymphohematopoietic cytokines play a significant role in many biological mechanisms including a number of reproductive processes such as ovulation, implantation, placentation, cervical dilation and parturition. Recent experiments have suggested that cytokines play a crucial role in the mechanisms of preterm labor and delivery, which are the leading causes of perinatal morbidity and mortality. Growing evidence suggests that infection is deeply concerned in the pathogenesis of preterm labor and delivery. Chorioamnionitis, a subset of intrauterine infection, has been identified in 20-33% of women with preterm delivery, and the inflammatory and related cytokines, interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8), showed substantial increases in the amniotic fluid at women with intrauterine infection. Although the precise mechanism for chorioamnionitis-driven preterm labor mediated via cytokines is still unknown, both IL-1 and TNF-alpha along with IL-6 enhance prostaglandin production by human amnion cells, chorionic cells and decidual cells. Analysis of the regulatory sequences in the 5' upstream regions of receptor gene for human oxytocin, a potent uterotonic agent, suggests a close relationship between preterm labor and inflammatory cytokines through induction at the oxytocin receptor. Prompt identification of the patients with intra-amniotic infection may be useful in clinical practice. At present, the measurement of IL-8 in maternal serum or the measurement of IL-6 in cervical secretion may be helpful as a non-invasive screening for chorioamnionitis.     

The role of cytokines in the induction of labor, cervical ripening and rupture of the fetal membranes

Even today prematurity is the major cause of perinatal mortality. Prematurity has multiple causes. There is a growing body of evidence supporting the association between silent intrauterine infection and preterm birth. Bacterial products may activate macrophages ubiquitous present in the decidua, placenta and fetal membranes. These cells after activation secrete a large variety of mediators including tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-1. Besides these cytokines IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, epidermal growth factor, granulocyte-colony stimulating factor and transforming growth factor beta have been identified in intrauterine tissues and in the amniotic fluid. The majority of these substances (TNFalpha, IL-1, IL-2, IL-3, IL-6) can stimulate the prostaglandin-biosynthesis by intrauterine tissues (amnion, chorion, decidua), some of them have antiinflammatory effects (IL-10, transforming growth factor alpha). These effects are mediated by receptors on the target cells; specific receptor antagonists (for example for IL-1) were found in high concentrations in amniotic fluid during normal pregnancy. This cytokine network is in a sensitive balance and probably associated with an uncomplicated course of pregnancy. Systemic or localized infections as well as tissue injury initiate the induction of the prostaglandin synthesis cascade thus leading to pregnancy loss via augmented cytokine secretion. Furthermore, cytokines may be involved in the regulation of preterm and term cervical ripening. The changes in mechanical properties of the cervix are associated with a reduction of collagen content and alterations in the glycosaminoglycan pattern within the cervical extracellular matrix. IL-1 can stimulate the synthesis of collagenases, and IL-8 may play an important role in the regulation of the invasion of neutrophilic granulocytes into the cervical stroma with subsequent degranulation and release of proteases. The cytokine-stimulated collagenase production in the fetal membranes is responsible for the reduction of their tensile strength and may be associated with rupture of the membranes. The cytokine network seems to be a sensitive regulation system. Disturbances of its balance by environmental (e.g. infection) or intrauterine influences (e. g. extension by the fetus) may lead to termination of pregnancy.     

Endocrine-immune interactions in pregnant non-human primates with intrauterine infection

Preterm birth remains the most common cause of perinatal mortality. Although the causes of preterm labor are multifactorial and vary according to gestational age, preterm labor and term labor share common cellular and molecular mechanisms, including stimulation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and endocrine/immune system interactions. We have developed a non-human primate experimental model for intrauterine infection and preterm labor using chronically instrumented rhesus monkeys (Macaca mulatta) with timed gestations. We have documented the temporal and quantitative relationships among intrauterine infection, the synthesis and release of proinflammatory cytokines, prostaglandins, and fetal-placental steroid biosynthesis in this model. Infection-induced preterm parturition is characterized by significant elevations in amniotic fluid proinflammatory cytokines and by increases in fetal adrenal steroid biosynthesis, but not by corresponding increases in placental estrogen biosynthesis characteristic of spontaneous parturition. This suggests that activation of the fetal HPA axis by the stress of infection is accompanied by placental dysfunction and also that infection-induced preterm parturition is not dependent upon the increased estrogen biosynthesis observed in spontaneous parturition. These different endocrine and immune responses have important diagnostic and therapeutic implications in the management of preterm labor.