interleukin-8 and Chorioamnionitis

Intrauterine infection is a serious complication during labor at term and is associated with adverse neonatal outcome. Early and accurate diagnosis is of great concern for both obstetrician and pediatrician with the use of current diagnostics. Clinical symptoms are often regarded as the main sign of intrauterine infection but this approach is highly unreliable and leads to both under- and overtreatment. Currently, no distinct fetal heart rate (FHR) patterns have been found that reliably identify neonates with intrauterine infection. Using a systematic literature search, this article reviews possible markers for the early detection of intrauterine or neonatal infection in maternal serum, amniotic fluid, and umbilical cord blood during labor at term. Maternal serum markers, with the possible exception of interleukin (IL)-8, are unreliable for the detection of intrauterine infection. In contrast, amniotic fluid levels of especially IL-6 and IL-8 are significantly associated with intrauterine infection. Umbilical cord blood IL-6 has been extensively investigated and is usually elevated in case of intrauterine or neonatal infection but shows only modest positive and negative predictive values (NPVs) for clinical use. Umbilical cord IL-8 concentration could be a valuable addition in the diagnostic process, as it has shown to have an NPV of 84% to 92% in the detection of neonatal infection and histological chorioamnionitis. Future research is essential and should focus on the combination of different markers and on the development of a prediction model, to improve the positive and NPVs of our arsenal to detect intrauterine and neonatal infections. Amniotic fluid and umbilical cord values of IL-6 and IL-8 levels are likely candidates for such a prediction model.. Obstetricians & Gynecologists and Family Physicians. After the completing the CME activity, physicians should be better able to evaluate the use of clinical chorioamnionitis with regard to histological evidence and as a diagnostic tool in early diagnosis of intra-amniotic infection. Asses the use of amniotic fluid IL-6 and IL-8 as diagnostic tools to detect early intra-amniotic infection and assess umbilical cord blood IL-8 in case of intrauterine- or neonatal infection using positive (PPV) and negative predictive values (NPV).

Topics: Amniotic Fluid; Biomarkers; Chorioamnionitis; Female; Fetal Blood; Fetal Diseases; Fever; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Labor, Obstetric; Pregnancy; Pregnancy Complications, Infectious; Risk Factors

Chronic lung disease (CLD) has been associated with chorioamnionitis and upper respiratory tract colonisation with Ureaplasma urealyticum. The aim of this review is to describe the increasing evidence that inflammation plays a critical role in the early stages of CLD of the neonate. Ongoing lung damage in the premature infant may be caused by failure to downregulate and control this inflammatory response. Tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and IL-8 are important pro-inflammatory cytokines of which IL-8 is an important chemotactic factor in the lung. Data suggest that preterm newborns with lung inflammation may be unable to activate the anti-inflammatory cytokine IL-10. Therefore, early post-natal anti-inflammatory therapy could help in preventing development of CLD. Prophylactic dexamethasone therapy cannot yet be recommended. There are a number of potential interactions between surfactant and cytokine effects on the preterm lung which have not been evaluated. Surfactant protein A may be an important modulator of the immune response to lung injury. The role of high-frequency ventilation in the prevention of CLD still remains unclear.. Many aspects of the pathogenesis of the inflammatory response in the development of chronic lung disease remain to be elucidated. Further research to identify preterm infants at highest risk for the development of this multifactorial and complex disease is needed.

Topics: Chorioamnionitis; Chronic Disease; Cytokines; Female; Humans; Infant, Newborn; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Lung Diseases; Pregnancy; Pulmonary Surfactants; Tumor Necrosis Factor-alpha

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.

Topics: Cervix Uteri; Chorioamnionitis; Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Models, Immunological; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Infectious; Uterine Contraction

Topics: Amnion; Arachidonic Acid; Chorioamnionitis; Cytokines; Dinoprostone; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Infectious; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Uterus

Inflammatory cytokines seem to play a key role in mechanisms initiating labor. Since cytokine levels are higher in preterm than in term labor, it has been hypothesized that labor-inducing effects of cytokines are inhibited by an upregulated production of cytokine antagonists, such as soluble cytokine receptors, at early stages of gestation. In this study, TNF, IL-1, IL-6, IL-8 and soluble TNF receptors (sTNFRs) were measured in amniotic fluid samples from a) 39 women in premature labor, b) 25 women who where not in labor but delivered prematurely, and c) 33 women in term labor. Fifty-four of the placentas from premature deliveries were evaluated for presence of histological chorioamnionitis. Chorioamnionitis was associated with increased levels of TNF, IL-1 and IL-6, whereas elevated IL-1, IL-6 and IL-8 concentrations were found in premature parturition with no signs of infection. Concentrations of sTNFR were lower in preterm than in term deliveries. The present study confirms the participation of inflammatory cytokines in parturition. Multivariate analysis suggests a dominant, role of IL-1 in the presence of chorioamnionitis, whereas IL-6 seems to be more important during idiopathic premature labor. TNFR data do not support the hypothesis that production of cytokine antagonists is upregulated prematurely to prevent partirution.

Topics: Amniotic Fluid; Chorioamnionitis; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; Multivariate Analysis; Obstetric Labor, Premature; Pregnancy; Receptors, Tumor Necrosis Factor; Solubility; Tumor Necrosis Factor-alpha

To establish a clinical method for immediate diagnosis of histological chorioamnionitis, by maternal blood sampling at term.. The sera of 22 mothers with chorioamnionitis and 81 mothers without chorioamnionitis at term delivery were collected. The serum levels of cytokines including interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) were titered and other conventional markers such as white blood cell and CRP were measured simultaneously. Chorioamnionitis was histopathologically confirmed after delivery.. The sera of mothers with histological chorioamnionitis showed a significant increase in IL-8 titer, but not in those of other cytokines or conventional markers, compared with those without chorioamnionitis. A positive correlation was observed between maternal and cord serum IL-8 levels. Maternal IL-8 showed the highest predictive value for diagnosis of histological chorioamnionitis.. Measurement of maternal IL-8 is useful for rapid prenatal screening of histological chorioamnionitis at term.

Topics: Adult; Biomarkers; Chorioamnionitis; Cytokines; Female; Humans; Interleukin-8; Mass Screening; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Third; Prenatal Diagnosis; Reference Values; Retrospective Studies; Sensitivity and Specificity

The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia.. Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1β, IL-2, IL-6, IL-8, TNFα, and IL-10.. IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA»UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA»UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis.. Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects.. The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.

Topics: Chorioamnionitis; Cytokines; Female; Fetal Hypoxia; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Placenta; Pregnancy; Prospective Studies

Determine if chronologic age and/or chorioamnionitis exposure alter normal serum cytokine and chemokine levels in uninfected preterm neonates during their initial NICU stay.. A 7-plex immunoassay measured levels of serum IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL2, and CCL3 longitudinally from chorioamnionitis-exposed and unexposed preterm neonates under 33 weeks' gestation.. Chorioamnionitis-exposed and unexposed preterm neonates demonstrated differences in the trends of IL-1β, IL-6, IL-8, IL-10, TNF-α, and CCL2 over the first month of life. The unexposed neonates demonstrated elevated levels of these inflammatory markers in the first two weeks of life with a decrease by the third week of life, while the chorioamnionitis-exposed neonates demonstrated differences over time without a predictable pattern. Chorioamnionitis-exposed and unexposed neonates demonstrated altered IL-10 and TNF-α trajectories over the first twelve weeks of life.. Chorioamnionitis induces a state of immune dysregulation in preterm neonates that persists beyond the immediate neonatal period.

Topics: Chorioamnionitis; Cytokines; Female; Humans; Infant, Newborn; Interleukin-10; Interleukin-6; Interleukin-8; Pregnancy; Tumor Necrosis Factor-alpha

Chorioamnionitis is a common cause of preterm birth and leads to serious complications in newborns. The objective of this study was to investigate the role of the Hippo signaling pathway in lung branching morphogenesis under a lipopolysaccharide (LPS)-induced inflammation model.. IMR-90 cells and ex vivo fetal lungs were treated with 0, 10, 30, or 50 μg/ml LPS for 24 and 72 h. Supernatant levels of lactate dehydrogenase (LDH), interleukin (IL)-6, IL-8, Chemokine (C-X-C motif) ligand 1(CXCL1), branching and the surface area ratio, Yes-associated protein (YAP), transcription coactivator with PDZ-binding motif (TAZ), fibroblast growth factor 10 (FGF10), fibroblast growth factor receptor II (FGFR2), SRY-box transcription factor 2 (SOX2), SOX9, and sirtuin 1 (SIRT1) levels were examined. Differentially expressed genes in fetal lungs after LPS treatment were identified by RNA-sequencing.. This study showed that regulation of the Hippo pathway in fibroblasts of fetal lungs was involved in branching morphogenesis under an inflammatory disease such as chorioamnionitis.

Topics: Cell Cycle Proteins; Chorioamnionitis; Female; Fibroblasts; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Morphogenesis; Pregnancy; Premature Birth; RNA; Sirtuin 1; Trans-Activators

To investigate whether altered expression of various inflammation-, angiogenesis-, and extracellular matrix-related mediators in cervicovaginal fluid (CVF) could be independently associated with acute histological chorioamnionitis (HCA), microbial-associated HCA, and funisitis in women with preterm premature rupture of membranes (PPROM).. Clinical data of 102 consecutive singleton pregnant women with PPROM at 23+0 to 34+0 weeks were retrospectively analyzed. CVF samples were collected upon admission. Levels of APRIL, DKK-3, IGFBP-1/2, IL-6/8, lipocalin-2, M-CSF, MIP-1α, MMP-8/9, S100A8A9, TGFBI, TIMP-1, TNFR2, uPA, and VDBP were determined by ELISA. Placentas were histologically examined after birth.. Multivariate logistic regression analyses showed that: (1) elevated CVF levels of IL-8 and TNFR2 were independently associated with acute HCA; (2) elevated CVF levels of IL-6, IL-8, M-CSF, MMP-8, and TNFR2 were independently associated with microbial-associated HCA; and (3) elevated CVF IL-8 and MMP-8 levels were independently associated with funisitis when adjusted for gestational age. Areas under the curves of the aforementioned CVF biomarkers ranged within 0.61-0.77, thereby demonstrating poor to fair diagnostic capacity for these clinical endpoints. HCA risk significantly increased as the CVF levels of each inflammatory mediator increased (P for trend < 0.05).. Herein, we identified several inflammatory biomarkers (IL-6/8, M-CSF, MMP-8, and TNFR2) in the CVF that are independently associated with acute HCA, microbial-associated HCA, and funisitis in women with PPROM. Furthermore, the degree of inflammatory response in the CVF, based on the levels of these proteins, demonstrated a direct relationship with HCA risk (especially risk severity).

Topics: Amniotic Fluid; Biomarkers; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Macrophage Colony-Stimulating Factor; Matrix Metalloproteinase 8; Pregnancy; Receptors, Tumor Necrosis Factor, Type II; Retrospective Studies

We investigated the association between altered levels of inflammatory proteins in the cervicovaginal fluid (CVF) and acute histologic chorioamnionitis (HCA) and funisitis in women with preterm labor (PTL).. In this study, a total of 134 consecutive singleton pregnant women with PTL (at 23+0-34+0 weeks) who delivered preterm (at  < 37 weeks) and from whom CVF samples were collected at admission were retrospectively enrolled. The CVF levels of haptoglobin, interleukin-6/8, kallistatin, lipocalin-2, matrix metalloproteinase (MMP)-8, resistin, S100 calcium-binding protein A8, and serpin A1 were determined using enzyme-linked immunosorbent assay. The placentas were histologically analyzed after delivery.. Multiple logistic regression analyses showed significant associations between elevated CVF interleukin-8 and resistin levels and acute HCA after adjusting for baseline covariates (e.g., gestational age at sampling). CVF haptoglobin, interleukin-6/8, kallistatin, MMP-8, and resistin levels were significantly higher in women with funisitis than in those without, whereas the baseline covariates were similar between the two groups (P > 0.1). The area under the receiver operating characteristic curves of the aforementioned biomarkers ranged from 0.61 to 0.77 regarding each outcome. Notably, HCA risk significantly increased with increasing CVF levels of interleukin-8 and resistin (P for trend  < 0.05).. Haptoglobin, interleukin-6/8, kallistatin, MMP-8, and resistin were identified as potential inflammatory CVF biomarkers predictive of acute HCA and funisitis in women with PTL. Moreover, the risk severity of acute HCA may be associated with the degree of the inflammatory response in the CVF (particularly based on interleukin-8 levels).

Topics: Amniotic Fluid; Biomarkers; Chorioamnionitis; Female; Haptoglobins; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 8; Obstetric Labor, Premature; Pregnancy; Resistin; Retrospective Studies

Both infectious and noninfectious causes of maternal fever have been linked to adverse neonatal outcomes including low Apg0ar scores, respiratory distress, hypotonia, and neonatal seizures. Even in the absence of infection, the occurrence of intrapartum fever is a strong risk factor for poor long-term neonatal developmental outcomes, including encephalopathy, cerebral palsy, and neonatal death.. The primary objective of this study was to compare intrapartum and postpartum maternal and fetal umbilical cord serum levels of cytokines RANTES, interferon-ɣ, interleukin-1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-13, and tumor necrosis factor-α among nonfebrile patients, febrile patients without clinical chorioamnionitis, and febrile patient with clinical chorioamnionitis.. This study was conducted at the Richmond University Medical Center from May 15, 2020 to July 16, 2019. During this time, we recruited 30 nonfebrile patients at >36 gestational weeks who were in labor and collected umbilical cord and pre- and postdelivery maternal serum samples to evaluate the cytokine levels. Placentas were collected for pathologic review and to evaluate the histopathologic findings. These results were compared with 121 patients who developed a fever of >38°C during labor. The febrile patients were further divided based on the presence or absence of clinical chorioamnionitis. A secondary analysis was performed based on the presence of absence of histologic chorioamnionitis. Statistical analysis was performed using IBM Statistical Package for the Social Sciences version 25.0. For the 3 group comparisons, a P value of <.017 was considered statistically significant after application of a Bonferroni correction.. A total of 151 patients were included in the study; 30 were nonfebrile patients, 46 were febrile patients with a diagnosis of clinical chorioamnionitis, and 75 were febrile patients without clinical chorioamnionitis. Compared with nonfebrile patients, umbilical cord serum interferon-ɣ, interleukin-1β, interleukin-6, interleukin-8, RANTES, and tumor necrosis factor-α levels were elevated in the presence of maternal hyperthermia irrespective of the diagnosis of clinical chorioamnionitis. Interleukin-6 umbilical cord levels were more than doubled from 63.60 pg/mL (6.09-1769.03 pg/mL) in febrile patients with no clinical chorioamnionitis to 135.77 pg/mL (1.86-6004.78 pg/mL) in febrile patients with clinical chorioamnionitis, making it the only cytokine that was significantly different between these 2 groups. When comparing the intrapartum maternal serum, we found a significant elevation in the interleukin-10, RANTES, and tumor necrosis factor-α levels in the febrile group irrespective of the presence of clinical chorioamnionitis when compared with the nonfebrile group. In the postpartum maternal blood evaluations, tumor necrosis factor-α was the only cytokine that was significantly higher in febrile patients than in nonfebrile controls.. In the setting of intrapartum fever, maternal cytokine profiles were similar irrespective of the diagnosis of clinical chorioamnionitis. Even in the absence of clinical or histologic chorioamnionitis, maternal hyperthermia induced elevations in fetal cytokines.

Topics: Chemokine CCL5; Chorioamnionitis; Cytokines; Female; Fever; Humans; Infant, Newborn; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Pregnancy; Tumor Necrosis Factor-alpha

Secretory phospholipase A2 (sPLA2) regulates the first step of inflammatory cascade and is involved in several pathological processes. sPLA2 also plays a role in preterm labor and parturition, since they are triggered by inflammatory mediators such as prostaglandins. Interestingly, chorioamnionitis (i.e., the presence of intrauterine inflammation) is also often associated with preterm birth. We aimed to verify if chorioamnionitis with fetal involvement modifies sPLA2 activity and expression profile in mothers and neonates delivered prematurely. We collected maternal plasma and amniotic fluid, as well as bronchoalveolar lavage fluid from preterm neonates born to mothers with or without clinical chorioamnionitis with fetal involvement. We measured concentrations of sPLA2 subtype-IIA and -IB, total enzyme activity, and proteins. Urea ratio was used to obtain epithelial lining fluid concentrations. Enzyme activity measured in maternal plasma (

Topics: Chorioamnionitis; Female; Humans; Infant, Newborn; Interleukin-8; Phospholipases A2, Secretory; Pregnancy; Premature Birth; Tumor Necrosis Factor-alpha

We aimed to assess whether a gene expression assay provided insights for understanding the heterogeneity among newborns affected by neonatal encephalopathy (NE).. Analysis by RT-qPCR of the mRNA expression of candidate genes in whole blood from controls (n = 34) and NE (n = 24) patients at <6, 12, 24, 48, 72 and 96 h of life, followed by determination of differences in gene expression between conditions and correlation with clinical variables.. During the first 4 days of life, MMP9, PPARG, IL8, HSPA1A and TLR8 were more expressed and CCR5 less expressed in NE patients compared to controls. MMP9 and PPARG increased and CCR5 decreased in moderate/severe NE patients compared to mild. At 6-12 h of life, increased IL8 correlated with severe NE and death, decreased CCR5 correlated with chorioamnionitis and increased HSPA1A correlated with expanded multiorgan dysfunction, severe NE and female sex.. MMP9, PPARG and CCR5 mRNA expression within first days of life correlates with the severity of NE. At 6-12 h, IL8 and HSPA1A are good reporters of clinical variables in NE patients. HSPA1A may have a role in the sexual dimorphism observed in NE. CCR5 is potentially involved in the link between severe NE and chorioamnionitis.

Topics: Chorioamnionitis; Female; Gene Expression Profiling; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Interleukin-8; Male; Matrix Metalloproteinase 9; PPAR gamma; Pregnancy; Prospective Studies; Receptors, CCR5; RNA, Messenger; Sex Factors; Toll-Like Receptor 8

Microbial invasion of the amniotic cavity, a clinical condition present in approximately 50% of patients with preterm prelabor rupture of membranes, is often associated with intraamniotic inflammation, a risk factor for a short admission-to-delivery interval, early preterm delivery, and neonatal complications. We previously developed a transcervical amniotic fluid collector, the device that allows the collection of fluid noninvasively from the cervical canal when membrane rupture occurs.. This study was designed to determine whether rapid analysis of an interleukin-8 concentration in fluid obtained noninvasively by the transcervical amniotic fluid collector can be used to assess the risk of intraamniotic inflammation. We also compared the diagnostic performance of this point-of-care test for interleukin-8 in transcervically obtained fluid to that of a white blood cell count determined in amniotic fluid retrieved by transabdominal amniocentesis.. This prospective cohort study was conducted between October 2011 and April 2017. Fluid was retrieved through both transabdominal amniocentesis and the use of a transcervical amniotic fluid collector within 24 hours of amniocentesis in patients with a singleton pregnancy and preterm prelabor rupture of the membranes (16-35 weeks of gestation). Amniotic fluid obtained via amniocentesis was cultured for aerobic and anaerobic bacteria and genital mycoplasmas; a white blood cell count was also measured in amniotic fluid. Intraamniotic infection was diagnosed when microorganisms were identified by the cultivation of amniotic fluid. Intraamniotic inflammation was defined as an elevated amniotic fluid matrix metalloproteinase-8 concentration (>23 ng/mL) assayed by enzyme-linked immunosorbent assay. Interleukin-8 in cervical fluid obtained by the collector was measured by the point-of-care test that used a test strip and scanner based on the fluorescence immunochromatographic analysis in 2019. The diagnostic indices, predictive values, and likelihood ratios of the 2 different tests were calculated.. The point-of-care test was predictive of intraamniotic inflammation, based on the determination of interleukin-8 in fluid retrieved by a transcervical amniotic fluid collector. Therefore, the analysis of cervically obtained fluid by such point-of-care test may be used to noninvasively monitor intraamniotic inflammation in patients with preterm prelabor rupture of membranes.

Topics: Adult; Amniotic Fluid; Chorioamnionitis; Cohort Studies; Female; Humans; Interleukin-8; Obstetric Labor, Premature; Point-of-Care Testing; Pregnancy; Prenatal Diagnosis; Prospective Studies; Sensitivity and Specificity

To investigate whether amniotic fluid (AF) "sludge" in patients with preterm labor (PTL) with intact membranes is related to intra-amniotic infection or inflammation.. 105 PTL patients before 29 weeks' gestation were enrolled. AF "sludge" was evaluated by transvaginal sonography. Microorganisms were identified in AF by our newly established PCR method using a eukaryote-made thermostable DNA polymerase.. AF "sludge" was present in 18.1% (19/105) of patients. The results obtained in the AF "sludge" group vs the no "sludge" group were as follows: (i) a similar positive rate of microorganisms in AF by PCR, 31.6% (6/19) vs 38.4% (33/86); (ii) a higher level of AF interleukin-8, 15.2 (0.2-381.5) ng/mL vs 5.8 (0.1-413.7) ng/mL; P = .005); and (3) a higher frequency of histological chorioamnionitis, 52.6% (10/19) vs 23.3% (20/86); P = .010.. The presence of AF "sludge" is related to intra-amniotic inflammation with or without microorganisms.

Topics: Amniotic Fluid; Chorioamnionitis; Female; Gestational Age; Humans; Infections; Interleukin-8; Mycoplasma; Obstetric Labor, Premature; Particulate Matter; Polymerase Chain Reaction; Pregnancy; Retrospective Studies; Ultrasonography; Ureaplasma

The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression.. Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR.. Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01).. Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Chorioamnionitis; Female; Gene Expression Profiling; Gestational Age; Humans; Immunohistochemistry; Infant, Newborn; Interleukin-8; Male; MicroRNAs; Multidrug Resistance-Associated Protein 2; Neoplasm Proteins; Placenta; Pregnancy; Premature Birth; Real-Time Polymerase Chain Reaction; Severity of Illness Index; Up-Regulation; Young Adult

Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease.. The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development.. We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum.. Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included several with known functions in cardiac injury, morphogenesis, angiogenesis, and tissue remodeling (eg, angiotensin I converting enzyme 2, STEAP family member 4, natriuretic peptide A, and secreted frizzled-related protein 4; all P<.05). Multiple gene sets and pathways that are involved in cardiac morphogenesis and vasculogenesis were downregulated significantly by gene set and Ingenuity Pathway Analysis (hallmark transforming growth factor beta signaling, cellular morphogenesis during differentiation, morphology of cardiovascular system; all P<.05).. Disruption of gene networks for cardiac morphogenesis and vasculogenesis occurred in the preterm fetal heart of nonhuman primates with preterm labor, intraamniotic infection, and severe fetal inflammation. Inflammatory injury to the fetal heart in utero may contribute to the development of heart disease later in life. Development of preterm labor therapeutics must also target fetal inflammation to lessen organ injury and potential long-term effects on cardiac function.

Topics: Angiotensin-Converting Enzyme 2; Animals; Atrial Natriuretic Factor; Biomarkers; Chorioamnionitis; Down-Regulation; Female; Fetal Diseases; Heart; Interleukin-6; Interleukin-8; Macaca nemestrina; Membrane Proteins; Microarray Analysis; Models, Animal; Myocardium; Obstetric Labor, Premature; Oxidoreductases; Peptidyl-Dipeptidase A; Pregnancy; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; Systemic Inflammatory Response Syndrome; Up-Regulation

Neutrophil infiltration of the chorioamnion-decidua tissue at the maternal-fetal interface (chorioamnionitis) is a leading cause of prematurity, fetal inflammation, and perinatal mortality. We induced chorioamnionitis in preterm rhesus macaques by intraamniotic injection of LPS. Here, we show that, during chorioamnionitis, the amnion upregulated phospho-IRAK1-expressed neutrophil chemoattractants CXCL8 and CSF3 in an IL-1-dependent manner. IL-1R blockade decreased chorio-decidua neutrophil accumulation, neutrophil activation, and IL-6 and prostaglandin E2 concentrations in the amniotic fluid. Neutrophils accumulating in the chorio-decidua had increased survival mediated by BCL2A1, and IL-1R blockade also decreased BCL2A1+ chorio-decidua neutrophils. Readouts for inflammation in a cohort of women with preterm delivery and chorioamnionitis were similar to findings in the rhesus macaques. IL-1 is a potential therapeutic target for chorioamnionitis and associated morbidities.

Topics: Amnion; Animals; Apoptosis; Chorioamnionitis; Chorion; Cytokines; Decidua; Female; Humans; Infant, Newborn; Inflammation; Interleukin-1; Interleukin-1 Receptor-Associated Kinases; Interleukin-8; Lipopolysaccharides; Macaca mulatta; Minor Histocompatibility Antigens; Neutrophil Infiltration; Neutrophils; Pregnancy; Proto-Oncogene Proteins c-bcl-2; Receptors, Interleukin-1; Signal Transduction

Preterm birth is the primary cause of perinatal morbidity and mortality worldwide. Inflammation induces a cascade of events leading to preterm birth by activating nuclear factor-

Topics: Amnion; Chemokine CCL2; Chorioamnionitis; Extraembryonic Membranes; Female; Flagellin; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Interleukin-8; Kv Channel-Interacting Proteins; Matrix Metalloproteinase 9; Myometrium; NF-kappa B; Pregnancy; Premature Birth; RNA, Messenger; RNA, Small Interfering; Term Birth

Does proviral integration site for Moloney murine leukaemic virus (PIM)1 kinase play a role in regulating the inflammatory processes of human labour and delivery?. PIM1 kinase plays a critical role in foetal membranes in regulating pro-inflammatory and pro-labour mediators.. Infection and inflammation have strong causal links to preterm delivery by stimulating pro-inflammatory cytokines and collagen degrading enzymes, which can lead to rupture of membranes. PIM1 has been shown to have a role in immune regulation and inflammation in non-gestational tissues; however, its role has not been explored in the field of human labour.. PIM1 expression was analysed in myometrium and/or foetal membranes obtained at term and preterm (n = 8-9 patients per group). Foetal membranes, freshly isolated amnion cells and primary myometrial cells were used to investigate the effect of PIM1 inhibition on pro-labour mediators (n = 5 patients per treatment group).. Foetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and from preterm pre-labour rupture of membranes (PPROM) (n = 9 per group). Amnion was collected from women with and without preterm chorioamnionitis (n = 8 per group). Expression of PIM1 kinase was determined by qRT-PCR and western blotting. To determine the effect of PIM1 kinase inhibition on the expression of pro-inflammatory and pro-labour mediators induced by bacterial products lipopolysaccharide (LPS) (10 μg/ml) and flagellin (1 μg/ml) and pro-inflammatory cytokine tumour necrosis factor (TNF) (10 ng/ml), chemical inhibitors SMI-4a (20 μM) and AZD1208 (50 μM) were used in foetal membrane explants and siRNA against PIM1 was used in primary amnion cells. Statistical significance was set at P < 0.05.. PIM1 expression was significantly increased in foetal membranes after spontaneous term labour compared to no labour at term and in amnion with preterm chorioamnionitis compared to preterm with no chorioamnionitis. There was no change in PIM1 expression with preterm labour or PPROM compared to preterm with no labour or PPROM. In human foetal membranes, PIM1 inhibitors SMI-4a and AZD1208 significantly decreased the expression of pro-inflammatory cytokine interleukin-6 (IL6) and chemokines CXCL8 and CCL2 mRNA and release, prostaglandin prostaglandin F2α (PGF2α) release, adhesion molecule intercellular adhesion molecule 1 mRNA expression and release, and oxidative stress marker 8-isoprostane release after stimulation with either LPS or flagellin. Primary amnion cells transfected with PIM1 siRNA also showed decreased expression of IL6, CXCL8 and CCL2, PTGS2 mRNA and PGF2α release, and matrix metalloproteinase-9 (MMP9) expression, when stimulated with TNF.. None.. The conclusions were drawn from in vitro experiments using foetal membrane explants and primary cells isolated from amnion. Animal models are necessary to determine whether PIM1 kinase inhibitors can prevent spontaneous preterm birth in vivo.. PIM1 kinase inhibitors may provide a novel therapeutic approach for preventing spontaneous preterm birth.. Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Funding for this study was provided by the NHMRC (grant no. 1058786), Norman Beischer Medical Research Foundation and the Mercy Research Foundation. The authors have no conflict of interest.

Topics: Benzylidene Compounds; Biphenyl Compounds; Chemokine CCL2; Chorioamnionitis; Cyclooxygenase 2; Extraembryonic Membranes; Female; Fetal Membranes, Premature Rupture; Flagellin; Gene Expression Regulation; Humans; Interleukin-6; Interleukin-8; Labor, Obstetric; Lipopolysaccharides; Matrix Metalloproteinase 9; Myometrium; Obstetric Labor, Premature; Pregnancy; Proto-Oncogene Proteins c-pim-1; RNA, Small Interfering; Thiazolidinediones; Thiazolidines; Tissue Culture Techniques; Tumor Necrosis Factor-alpha

Intrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response.. Rhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1β or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days' gestational age.. Intraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1β,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1β alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation.. Intraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response.

Topics: Animals; Chorioamnionitis; Disease Models, Animal; Female; Fetus; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-8; Keratins; Lipopolysaccharides; Macaca mulatta; Male; Polymerase Chain Reaction; Pregnancy; RNA, Messenger; Skin; Ureaplasma

To determine whether the presence of intra-amniotic infection and elevated proinflammatory cytokine levels in amniotic fluid (AF) are associated with failure in the newborn hearing screen (NHS) test in very preterm neonates.. This is a retrospective cohort study of 112 premature singleton neonates born to women with preterm labor or preterm premature rupture of membranes at ≤32 wk. AF obtained through amniocentesis was cultured, and interleukin-6 (IL-6) and IL-8 levels were determined.. Fourteen (12.5%) neonates failed the NHS test. The prevalence of a positive AF culture was 40% (45/112). Multiple logistic regression analyses indicated that intra-amniotic infection was significantly associated with failure in the NHS test after adjusting for baseline covariates such as maternal white blood cell count (WBC) and periventricular leukomalacia. However, the IL-6 and IL-8 levels in AF were not significantly associated with hearing screen failure. Moreover, neither gestational age at birth nor birth weight was associated with NHS failure.. The presence of intra-amniotic infection, but not elevated levels of AF IL-6 and IL-8, may contribute to the risk for failure in the NHS test in very preterm neonates. This finding suggests that intra-amniotic infection in utero might contribute to the development of congenital sensorineural hearing loss.

Topics: Amniocentesis; Amniotic Fluid; Chorioamnionitis; Female; Gestational Age; Hearing; Hearing Tests; Humans; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-6; Interleukin-8; Leukomalacia, Periventricular; Neonatal Screening; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Infectious; Regression Analysis; Retrospective Studies; Risk Factors

To what extent the risks of neonatal morbidities are directly related to premature birth or to biological mechanisms of preterm birth remains uncertain. We aimed to examine the effect of exposure to amniotic fluid (AF) infection and elevated cytokine levels on the mortality and pulmonary, intestinal, and neurologic outcomes of preterm infants, and whether these associations persist after adjustment for gestational age at birth. This retrospective cohort study included 152 premature singleton infants who were born at ≤ 32 weeks. AF obtained by amniocentesis was cultured; and interleukin-6 (IL-6) and IL-8 levels in AF were determined. The primary outcome was adverse perinatal outcome defined as the presence of one or more of the followings: stillbirth, neonatal death, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and periventricular leukomalacia. Logistic regression analysis was adjusted for gestational age at birth and other potential confounders. In bivariate analyses, elevated AF IL-6 and IL-8 levels were significantly associated with adverse perinatal outcome. These results were not changed after adjusting for potential confounders, such as low Apgar scores, mechanical ventilation, and surfactant application. However, the independent effect of elevated cytokine levels in AF disappeared when additionally adjusted for low gestational age at birth; consequently, low gestational age remained strongly associated with the risk of adverse perinatal outcome. In conclusion, elevated levels of pro-inflammatory cytokines in AF are associated with increased risk of adverse perinatal outcomes, but this risk is not independent of low gestational age at birth. Culture-proven AF infection is not associated with this risk.

Topics: Adult; Amniotic Fluid; Area Under Curve; Chorioamnionitis; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Interleukin-6; Interleukin-8; Leukomalacia, Periventricular; Logistic Models; Lung Diseases; Male; Multivariate Analysis; Odds Ratio; Perinatal Mortality; Pregnancy; Premature Birth; Retrospective Studies; Risk Factors; ROC Curve; Young Adult

To evaluate whether levels of interleukin 6 (IL-6), interleukin 8 (IL-8), and vascular cell adhesion molecule-1 (VCAM-1) in women with premature rupture of membranes (PROM) differ from those in women without PROM.. An observational study of full-term primiparous pregnant women with PROM (PROM group) and those undergoing elective cesarean delivery (control group) was performed at a center in Yangzhou, China, between January 2003 and July 2006. IL-6, IL-8, and VCAM-1 levels were measured in maternal blood, cord blood, and amniotic fluid. A pathologic examination of fetal membranes was conducted.. The IL-6, IL-8, and VCAM-1 levels in maternal serum, amniotic fluid, and cord blood were significantly higher in the PROM group (n=58) than in the control group (n=38; P<0.05 for all comparisons). In the PROM group, the levels increased with duration of membrane rupture (P<0.05 for all). Women with chorioamnionitis had significantly higher levels than women without chorioamnionitis (P<0.05 for all), and women with PROM whose newborns had low Apgar score (≤7) had higher levels than those whose newborns had a higher Apgar score (P<0.05 for all).. Combined measurements of IL-6, IL-8, and VCAM-1 might help to improve early diagnosis of PROM and chorioamnionitis, and to evaluate the prognosis of newborns.

Topics: Adult; Amnion; Amniotic Fluid; Biomarkers; Cesarean Section; China; Chorioamnionitis; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Pregnancy; Prognosis; Vascular Cell Adhesion Molecule-1

To study the relationship between perinatal prognosis in cases of preterm labor (PTL) and polymicrobial infection in amniotic fluid (AF) and intra-amniotic (IA) inflammation using a highly sensitive and reliable PCR-based method.. To detect prokaryotes using a nested PCR-based method, eukaryote-made thermostable DNA polymerase without bacterial DNA contamination was used in combination with bacterial universal primers. We collected AF aseptically from 118 PTL cases and 50 term subjects.. The prevalence of microorganisms was 33% (39/118) by PCR and only 7.6% (9/118) by culture. PTL caused by a combination of positive Mycoplasma/Ureaplasma and other bacteria had significantly higher AF IL-8 levels and a significantly shorter amniocentesis-to-delivery interval.. Our newly established PCR method is useful for detecting IA microorganisms. Polymicrobial infection with Mycoplasma/Ureaplasma and other bacteria induces severe IA inflammation associated with poor perinatal prognosis in PTL.

Topics: Adult; Amniotic Fluid; Bacteria; Bacterial Infections; Chorioamnionitis; Coinfection; DNA, Bacterial; DNA, Fungal; Female; Fungi; Humans; Interleukin-8; Leukocyte Count; Mycoses; Obstetric Labor, Premature; Polymerase Chain Reaction; Pregnancy; Prognosis; RNA, Ribosomal, 16S; Young Adult

Fetal exposure to in utero inflammation such as chorioamnionitis is related to central nervous system injury. We hypothesized that chorioamnionitis can provoke inflammatory changes in the perilymph and alter hearing outcome.. Pregnant ewes were randomized into 2 groups: intrauterine injection with lipopolysaccharide (LPS; n = 19) or saline (n = 21). In the first experiment, fetal perilymph samples were taken for cytokine analysis. In the second experiment, consecutive bone-conducted auditory brain stem responses were obtained from 1 to 7 months after birth.. Perilymph samples showed a significant elevation in interleukin 8 in the LPS group. Auditory brain stem response analysis demonstrated higher response thresholds and a prolongation of absolute peak V and interpeak intervals I to V and III to V in the LPS group compared to sham treatment.. Our study confirms the hypothesis that an intrauterine inflammation by LPS can result in a fetal perilymphatic inflammatory response and functional impaired hearing outcomes after birth in a sheep model.

Topics: Animals; Chorioamnionitis; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Female; Inflammation; Interleukin-8; Lipopolysaccharides; Perilymph; Pregnancy; Sheep

To assess and compare several maternal seric markers for the prediction of histological chorioamnionitis (HCA) after preterm premature rupture of membranes (PPROM). Study design A prospective and multicentric observational study was undertaken, including six French tertiary referral centres. Pregnant women over 18 years, with PPROM between 22+0 and 36+6 WG were enrolled. A blood sample was obtained before delivery and analysed for C-Reactive Protein (CRP), InterCellular Adhesion Molecule-1 (ICAM-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Matrix-Metalloproteinase 8 and 9 (MMP-8, MMP-9), Triggering receptor on myeloid cells (TREM-1), and Human Neutrophile Peptides (HNP). HCA was determined by histological examination distinguishing maternal from fetal inflammatory response. Placental analyses and biological assays were performed in duplicate. Comparison of maternal seric markers levels in women with or vs. without HCA was performed, using a non-parametric Receiver Operating Characteristic.. 295 women were kept for analysis. The prevalence of HCA was 42.7% (126/295). The concentrations of MMP-8, MMP-9, HNP and CRP were higher in HCA vs. the non-HCA group (P<0.05) whereas the concentrations of ICAM- 1, IL-6, IL-8 were not different (P>0.05). The ROC curve with the largest AUC was for CRP (AUC; 0.70; 95% CI; 0.64-0.77) and it was significantly higher than those for MMP-8, MMP-9, or HNP (P<0.03).. CRP was the best maternal marker for predicting HCA in women with PPROM.

Topics: Adult; Biomarkers; C-Reactive Protein; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Membrane Glycoproteins; Placenta; Pregnancy; Prospective Studies; Receptors, Immunologic; Triggering Receptor Expressed on Myeloid Cells-1

Airway inflammation is involved in the pathogenesis of bronchopulmonary dysplasia (BPD). The aim of the study was to evaluate the inflammatory activity in plasma and exhaled air in very low birth weight (VLBW) BPD survivors at school age.. Twenty-one 6-14-year-old former VLBW (birth weight ≤1,500 g) children with severe radiographic BPD (radBPD), 19 without radBPD (nonBPD group) and 19 non-asthmatic term controls underwent measurement of eosinophil cationic protein, IL-6, IL-8, adiponectin, adipsin, leptin, and resistin in plasma, leukotriene B4 and 8-isoprostane in exhaled breath condensate, and NO in exhaled breath. Background data were obtained from patient records, clinical examination and parental questionnaire. Both univariate and multivariate models were applied in the statistical analysis.. There were no significant differences between the groups in any of the inflammatory markers measured. Five (25%) radBPD and 2 (11%) nonBPD children reported asthma (P = 0.058). In logistic regression analysis, exposure to chorioamnionitis was associated with low IL-8 (OR 29.0, 95% CI 3.27-258) and postnatal corticosteroid therapy with high adiponectin (OR 32.0, 95% CI 1.29-793). High body mass index standard deviation score (BMI-SDS) was associated with high plasma adipsin (OR 2.47, 95% CI 1.07-5.75) and leptin (OR 5.76, 95%CI 1.83-18.2) levels.. The inflammatory activity seems to decrease by school age in VLBW BPD survivors. Chorioamnionitis and postnatal corticosteroid treatment may modulate the inflammatory responsiveness in VLBW subjects even up to school age. The respiratory outcome in VLBW infants might be improved by preventing excessive weight gain.

Topics: Adiponectin; Adolescent; Asthma; Biomarkers; Body Mass Index; Bronchopulmonary Dysplasia; Child; Chorioamnionitis; Complement Factor D; Female; Finland; Glucocorticoids; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Interleukin-6; Interleukin-8; Leptin; Logistic Models; Pregnancy; Survivors

Abstract Objective: To determine the cervical fluid interleukin (IL)-6 and IL-8 levels in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) and the association of these interleukins with microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA).. Sixty women with singleton pregnancies were included in this study. Cervical fluid was sampled at the time of admission using Dacron polyester swabs, which were placed into the endocervical canal for 20 s. IL-6 and IL-8 levels were determined by ELISA. The management of PPROM was active management (except for in pregnancies <28 weeks of gestation) and occurs not later than 72 h after the rupture of membranes.. The women with MIAC had higher IL-6 and IL-8 levels than did the women without MIAC (IL-6: p=0.01; IL-8: p=0.003). There was no difference in IL-6 levels between women with and without HCA (p=0.37). The women with HCA had higher IL-8 levels only in the crude analysis (p=0.01) but not after adjustment for gestational age (p=0.06). The women with both MIAC and HCA had higher levels of IL-6 and IL-8 than did the other women (IL-6: p=0.003; IL-8: p=0.001). IL-8 level of 2653 pg/mL was found to be the best cut-off point in the identification of PPROM pregnancies complicated by both MIAC and HCA with a likelihood ratio of 24.. The presence of MIAC is the most important factor impacting the local cervical inflammatory response, which is determined by IL-6 and IL-8 levels in the cervical fluid. IL-8 levels seem to be a promising non-invasive marker for the prediction of pregnancies complicated by the presence of both MIAC and HCA.

Topics: Adult; Amnion; Amniotic Fluid; Body Fluids; Cervix Uteri; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Interleukin-6; Interleukin-8; Pregnancy; Pregnancy Complications, Infectious; Young Adult

To determine the vaginal fluid interleukin (IL)-6 and IL-8 concentrations in pregnancies complicated by preterm prelabor rupture of membranes and their correlation to microbial invasion of the amniotic cavity (MIAC) as well as histological chorioamnionitis (HCA).. Sixty-eight women with singleton pregnancies were included in this study. Vaginal fluid was collected at the time of admission. IL-6 and IL-8 concentrations in the vaginal fluid were determined using ELISA.. Women with MIAC had higher vaginal fluid IL-6 levels compared to those without MIAC (with MIAC: median 374 pg/mL versus without MIAC: median 174 pg/mL; p = 0.03). IL-8 levels were higher in women with MIAC only in the crude analysis but not after adjustment for gestational age. There was no difference in the IL-6 and IL-8 concentrations between those with and without HCA. Women with both MIAC and HCA had higher IL-6 vaginal fluid levels than those without both MIAC and HCA (with MIAC and HCA: median 466 pg/mL versus without MIAC and HCA: median 178 pg/mL; p = 0.02). IL-8 levels were higher in women with MIAC and HCA only in the crude analysis but not after adjustment for gestational age.. Vaginal fluid IL-6 but not IL-8 levels reflect the presence of MIAC and both MIAC and HCA.

Topics: Adult; Body Fluids; Chorioamnionitis; Cohort Studies; Female; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Pregnancy; Pregnancy Complications, Infectious; Vagina; Young Adult

The maternal-fetal inflammatory response contributes to both preterm premature rupture of membranes (PPROM) and adverse neurological outcomes. Additionally, cytokines associated with fetal placental inflammation can be detrimental to brain development regardless of inciting infection. We investigated whether differential patterns of cytokine markers in maternal and fetal plasma samples reflect subtypes of placental inflammation and neurological outcomes at 6 months in infants born to mothers with PPROM.. Within a prospective cohort study of 25 women with PPROM, plasma cytokines (interleukin [IL]-1β, IL-6, IL-8, and tumor necrosis factor-α) were measured by enzyme-linked immunosorbent assay from maternal blood samples at rupture and delivery, and from fetal umbilical cord blood samples. Patterns of cytokine expression were correlated with specific placenta pathologies. Infants underwent cranial ultrasound after birth and standardized neurological examinations at 6 months' corrected gestational age. Predictors of inflammation and adverse neurological outcome were assessed by logistic regression, adjusting for gestational age at birth.. Inflammation of the fetal side of the placenta was associated with elevated maternal IL-6 and IL-8 at delivery and fetal IL-1β, IL-6, IL-8, and tumor necrosis factor-α. Worse neurological outcome at 6 months was associated with inflammation of the fetal side of the placenta and shorter duration from rupture of membrane to delivery, independent of gestational age at birth or cranial ultrasound results.. Our findings support the connection between fetal inflammation with adverse neurological outcome with PPROM, regardless of cranial ultrasound results. Further longitudinal studies are needed to adequately examine these patterns, and will aid in risk assessment and intervention strategies.

Topics: Adult; Chorioamnionitis; Cohort Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Nervous System Diseases; Placenta; Pregnancy; Prospective Studies; Tumor Necrosis Factor-alpha; Young Adult

To estimate the stage of histological chorioamnionitis (h-CAM) antenatally using clinical data.. Four hundred and twenty-eight singleton mothers were recruited. Clinical data including the levels of white blood cell count (WBC), C-reactive protein (CRP), amniotic fluid interleukin-8 (AF-IL-8) at Cesarean section, and maternal body temperature (MBT) were collected.. Histological chorioamnionitis was present in 45.3% of the cases. Poor neonatal prognosis was highest (59.1%) in cases with h-CAM stage III. AF-IL-8 (odds ratio: 8.5, 95% CI: 5.1-14.8, P < 0.0001) and MBT (odds ratio: 2.3, 95% CI: 1.13-4.1, P = 0.0192) were independent risk factors for h-CAM. The cutoff value of AF-IL-8 for predicting each stage of h-CAM (stage I or higher, stage II or higher, and stage III) were ≥9.9 ng/mL, ≥17.3 ng/mL, and ≥55.9 ng/mL, respectively.. The stage of h-CAM was able to be predicted accurately by the level of AF-IL-8 before delivery.

Topics: Adult; Amniotic Fluid; Body Temperature; C-Reactive Protein; Chorioamnionitis; Female; Humans; Interleukin-8; Leukocyte Count; Parturition; Pregnancy

To explore the relationship between histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) and brain injury in preterm infants.. One hundred and three singleton infants with premature rupture of membranes (PROM) (gestation ages of less than 34 weeks) were enrolled. All the placentas were submitted for pathological evaluation. Umbilical cord blood interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF) levels were measured with liquid chip. All preterm infants accepted brain imaging examinations. Based on the placental pathological examination and umbilical cord blood level of IL-6, the 103 infants were classified into HCA⁻ FIRS⁻, HCA⁺ FIRS⁻, and HCA⁺ FIRS⁺ groups.. The incidences of HCA, FIRS, and brain injury were 53.4%, 20.4% and 38.8% respectively. The prevalence of brain injury in HCA⁻ FIRS⁻, HCA⁺ FIRS⁻, and HCA⁺ FIRS⁺ cases was 21%, 41%, and 76% respectively (P<0.01). The grade 2 and grade 3 of placental inflammation and the inflammation at stage 2 and stage 3 increased the risk of brain injury. The cord blood levels of IL-8, TNF-α, and G-CSF in the HCA⁺ FIRS⁺ group were significantly higher than in the other two groups, and the levels of the above parameters in the HCA⁺ FIRS⁻ were higher than in the HCA⁻ FIRS⁻ group (P<0.05).. Placental inflammation and FIRS are associated with brain injury in preterm infants. Preterm infants exposed to severe placental inflammation have an increased risk of brain injury. Cord blood IL-8, TNF-α and G-CSF may be involved in the process of brain injury in preterm infants with placental inflammation and FIRS.

Topics: Brain Injuries; Chorioamnionitis; Female; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Male; Placenta; Pregnancy; Tumor Necrosis Factor-alpha

The aim of this study was to validate the results of an immunochromatographic bedside test to detect IL6 and IL8 in vaginal secretions after rupture of membranes (ROM) with results obtained by ELISA tests.. A prospective cohort of 60 women with ROM or preterm ROM (PROM) was recruited. An immunochromatographic bedside test was performed with vaginal secretions samplings at admission, every 48 hrs until labor and during labor. Remaining samples were frozen for ELISA analysis. The results of bedside tests were compared to those from ELISA analysis for 114 samples.. With all samples combined, the positive predictive values were 50% for IL6 and 86.8% for IL8 and the negative predictive values were 97.4% for IL6 and 53.3% for IL8. Kappa coefficients were 0.54 for IL6 and 0.41 for IL8.. Our findings show that a bedside test can detect the absence of IL6 in vaginal secretions. This result suggests that bedside test could be used for expectant management after premature PROM to inform the attending physician of the absence of inflammation in vaginal secretions.

Topics: Adult; Chorioamnionitis; Chromatography, Affinity; Enzyme-Linked Immunosorbent Assay; Female; Fetal Membranes, Premature Rupture; Humans; Inflammation; Interleukin-6; Interleukin-8; Predictive Value of Tests; Pregnancy; Sensitivity and Specificity; Vagina; Young Adult

The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response.. Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury.. LPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (p<0.02) and cell death (p<0.05) in the WM, which were equivalent in magnitude between groups.. Ventilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Chorioamnionitis; Female; Gene Expression; Glial Fibrillary Acidic Protein; Hemodynamics; Immunohistochemistry; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung Injury; Pregnancy; Premature Birth; Respiration, Artificial; Reverse Transcriptase Polymerase Chain Reaction; Sheep; Sheep Diseases

The underlying mechanisms of protective immunity of placental trophoblast cells against bacterial infection remain largely unknown. NOD1 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation.. Human extravillous trophoblast cell line HTR8 cells were stimulated with various concentrations of iE-DAP for various periods of time. NOD1 expression was detected by immunofluorescence, and the changes in NOD1 and RICK mRNA and protein in H8 cells were determined by real-time polymerase chain reaction and Western blot analysis. The concentrations of interleukin (IL)-8 and IL-6 secreted by H8 cells were examined by enzyme-linked immunosorbent assay. NF-κB transcription activity and P65 expression were detected by electrophoretic mobility shift assay and Western blot analysis.. H8 cells expressed NOD1, and the effects of iE-DAP on NOD1 were dose- and time-dependent. The concentration of IL-8 increased gradually with increasing concentration of iE-DAP, and the levels of IL-8 and IL-6 were associated with the duration of exposure to iE-DAP. The dose of iE-DAP was significantly associated with expression of RICK and P65, and stimulation of H8 cells by iE-DAP altered NF-κB transcription activity.. NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1-RICK-NF-κB-mediated pathways.

Topics: Cell Line; Chorioamnionitis; Diaminopimelic Acid; Female; Humans; Interleukin-6; Interleukin-8; NF-kappa B; Nod1 Signaling Adaptor Protein; Pregnancy; Pregnancy Trimester, First; Receptor-Interacting Protein Serine-Threonine Kinase 2; Signal Transduction; Trophoblasts

Induced abortion via dilation and evacuation (D&E) typically involves cervical preparation. Some clinicians also induce fetal death in the second trimester. We designed this study to determine if the combination of intra-amniotic digoxin and osmotic dilators induced intrauterine inflammatory changes.. Twenty-two women requesting abortion at 19-23 weeks gestation had amniotic fluid sent for measurement of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), white blood cell (WBC) count and anaerobic and aerobic cultures on day 1, before dilators and digoxin amnioinjection. Sampling was repeated on Day 2, prior to D&E.. All subjects had significantly elevated IL-6, IL-8 and TNF-α in the amniotic fluid on Day 2. The median difference for IL-6 was 19,893.4 pg/mL (p<.0001), 7040.7 pg/mL (p<.0001) for IL-8 and 181.0 pg/mL (p<.0001) for TNF-α. There was no significant difference in WBC count. There were no clinically significant positive cultures and no clinical infections.. The administration of intra-amniotic digoxin and the placement of osmotic dilators prior to D&E create an intrauterine inflammatory response.

Topics: Abortion, Induced; Adult; Amniocentesis; Amniotic Fluid; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Chorioamnionitis; Digoxin; Dilatation and Curettage; Doxycycline; Female; Fetal Death; Humans; Interleukin-1; Interleukin-8; Leukocyte Count; Pilot Projects; Pregnancy; Pregnancy Trimester, Second; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that 2 weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.

Topics: Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokines; Chorioamnionitis; Cytokines; Female; Humans; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-8; Male; Matrix Metalloproteinase 9; Pregnancy; Respiration, Artificial; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To determine whether interleukin (IL)-1β, IL-6, and IL-8 in cervicovaginal fluid, alone or in combination with clinical risk factors, could predict intra-amniotic infection in women with preterm premature rupture of membranes (PPROM).. A prospective cohort study.. University teaching hospital.. Women with singleton pregnancies presenting PPROM between 20 and 35 weeks of gestation (n = 76).. Cervicovaginal fluid samples were collected for IL-1β, IL-6, and IL-8 measurements immediately before amniocentesis. Amniotic fluid obtained by amniocentesis was cultured and the white blood cell count was determined. Clinical risk factors analyzed included demographics and gestational age. Cervicovaginal concentrations of cytokines were measured using a multiplex bead array assay.. A positive amniotic fluid culture.. The prevalence of a positive amniotic fluid culture was 46.1% (35/76). Stepwise multivariate regression analysis yielded a model using cervicovaginal IL-6 and gestational age at sampling with the area under the curve (AUC) of 0.807 for predicting intra-amniotic infection. The AUC for this model was significantly higher than either parameter retained in this model but no differences were observed between the AUC of this model based on non-invasive variables, and amniotic fluid white blood cell count using invasive amniocentesis for the prediction of intra-amniotic infection.. Among measured cytokines, the combination of cervicovaginal IL-6 and gestational age appears to be best in predicting intra-amniotic infection and allows for a considerably better accuracy than the use of either factor alone. Overall, this combination performed as well as amniotic fluid WBC count for predicting intra-amniotic infection.

Topics: Adult; Amniotic Fluid; Cervix Uteri; Chorioamnionitis; Cohort Studies; Cytokines; Female; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocyte Count; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Risk Factors; Vagina

To determine whether the levels of inflammatory mediators in gastric fluid (GF) of a premature newborn are associated with those in amniotic fluid (AF) of the newborn's mother.. Twenty-three pairs of pregnant women and their premature newborns <35 weeks gestation, born by Cesarean sections.. Amniotic fluids and newborn gastric fluids were obtained from women during Cesarean section procedure. The mother-premature newborn dyads were retrospectively assessed to analyze the clinical and laboratory data. Concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and mannose-binding lectin (MBL) were compared between amniotic and newborn gastric fluids in each dyad.. Premature newborns and their mothers with funisitis had significantly higher median AF IL-6, TNF-α and GF IL-8 concentrations than those without funisitis (p = 0.022 for AF IL-6; p = 0.023 for AF TNF-α; p = 0.022 for GF IL-8). The concentrations of IL-6, IL-8, TNF-α and MBL in newborn GF were significantly correlated with those in AF in each dyad (p < 0.001, r = 0.872 for IL-6; p < 0.001, r = 0.851 for IL-8; p < 0.001, r = 0.768 for TNF-α; p < 0.001, r = 0.845 for MBL, respectively).. The levels of inflammatory mediators in GF of a premature newborn immediately after birth are strongly associated with those in AF of the newborn's mother.

Topics: Adult; Amniotic Fluid; Chorioamnionitis; Female; Gastric Juice; Humans; Infant, Newborn; Infant, Premature; Inflammation Mediators; Interleukin-6; Interleukin-8; Pregnancy; Prenatal Exposure Delayed Effects; Retrospective Studies; Tumor Necrosis Factor-alpha

The aim of this study was to determine whether amniotic fluid levels of annexin A2, a phospholipid-binding protein that is abundant in amnion and regulates fibrin homeostasis, are associated with histological chorioamnionitis, preterm premature rupture of the membranes, and subsequent preterm delivery.. Amniotic fluid was obtained from 55 pregnant women with preterm labor and/or preterm premature rupture of the membranes before 32weeks of gestation, and amniotic fluid levels of annexin A2 were measured with a sandwich enzyme-linked immunosorbent assay.. Amniotic fluid levels of annexin A2 in patients with histological chorioamnionitis was higher than that in the remainder (P=0.053), whereas amniotic fluid levels of annexin A2 in patients with preterm premature rupture of the membranes was significantly higher than that in the remainder (P=0.002). Amniotic levels of annexin A2 was a fair test (area under receiver-operator characteristic curve=0.679), and amniotic fluid levels of annexin A2>878.2ng/mL had a sensitivity of 68.8%, a specificity of 65.2%, a positive predictive value of 73.3%, and a negative predictive value of 60.0% for predicting delivery within 2weeks after amniotic fluid sampling. Furthermore, the combined use of amniotic fluid cut-off levels of 878.2ng/mL for annexin A2 and 13.3ng/mL for interleukin-8 improved the specificity (91.3%) and the positive predictive value (89.5%).. We identified amniotic fluid levels of annexin A2, especially in combination with amniotic fluid levels of interleukin-8, as a novel predictive marker for preterm delivery.

Topics: Adult; Amniotic Fluid; Annexin A2; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Interleukin-8; Predictive Value of Tests; Pregnancy; Premature Birth

Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE(2) has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE(2) concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE(2) receptors. Our second study aimed to block LPS-induced increases in PGE(2) with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE(2) concentrations increased (P < 0.05) 12 h and 3-6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 (P = 0.0084) and 7 (P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE(2) and decreased fetal lung IL-1β and IL-8 mRNA (P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A (P = 0.05), -B (P = 0.05), and -D (P = 0.0015) but increased SP-C mRNA (P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.

Topics: Amniotic Fluid; Animals; Chorioamnionitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Lung; Lung Compliance; Pneumonia; Pregnancy; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Random Allocation; RNA, Messenger; Sheep; Sulfonamides; Uterus

To assess the influence of maternal chorioamnionitis on early exhaled nitric oxide (NO) and levels of nitrites-nitrates and interleukin (IL)-8 in endotracheal aspirate fluid in mechanically ventilated preterm neonates.. Cross-sectional study. PATIENT-SUBJECT SELECTION: Between September 2007 and August 2009, 54 mechanically ventilated preterm neonates were included. Patients were divided into two groups according to the presence or absence of maternal chorioamnionitis, and those without chorioamnionitis (controls) were further stratified into two subgroups by birth weight < or ≥ 2,000 g.. The ventilator used was a Babylog 8000. The NO level assessed was the plateau value given by the software of the Sievers NOA apparatus. Collection of endotracheal aspirate fluid samples was performed coinciding with routine aspirations and using the dry technique.. The two groups of control neonates showed statistically significant differences in exhaled NO expressed as nl/min and normalized exhaled NO expressed as either nl/min or nl/min/kg, so they are not homogeneous and cannot be used in clinical practice. Serum C-reactive protein and endotracheal aspirate levels of nitrites-nitrates were significantly higher in the chorioamnionitis group than in controls (3.6 vs. 1.07 µmol/L; P = 0.035). Nitrites-nitrates levels were positively correlated with exhaled NO in ppb (ρ = 0.367; P = 0.006). Minute exhaled endogenous NO was significantly higher in the chorioamnionitis group (0.48 vs. 0.27 nl/min/kg; P = 0.021).. In mechanically ventilated preterm infants weighing <2,000 g, maternal chorioamnionitis was associated with an increase of early exhaled NO (nl/min/kg) and serum levels of C-reactive protein and levels of nitrites-nitrates in endotracheal aspirate fluid.

Topics: Adult; C-Reactive Protein; Case-Control Studies; Chorioamnionitis; Cross-Sectional Studies; Exhalation; Female; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Intubation, Intratracheal; Nitrates; Nitric Oxide; Nitrites; Pregnancy; Pregnancy Complications; Respiration, Artificial; Respiratory Aspiration

Acute chorioamnionitis of infectious origin and chronic chorioamnionitis of immunological origin are two major placental lesions of spontaneous preterm birth with elevated amniotic fluid interleukin-6 and CXCL10 concentrations, respectively. The changes in the amniotic fluid proteome associated with intra-amniotic infection and acute chorioamnionitis are well defined, yet alterations unique to chronic chorioamnionitis remain to be elucidated. This study was conducted to determine those amniotic fluid proteins changing specifically in the presence of chronic chorioamnionitis. Amniotic fluid obtained from acute chorioamnionitis, chronic chorioamnionitis and gestational age-matched controls were analysed by two-dimensional (2D) difference in gel electrophoresis and MALDI-TOF analyses. The type of histological inflammation was used to define each condition in preterm labour cases (n = 125) and term not in labour cases (n = 22), and the amniotic fluid concentrations of interleukin-6, CXCL8, CXCL10 and prostaglandin F(2α) were also measured by specific immunoassays. Among preterm labour cases, 31 differentially expressed proteins were identified in chronic chorioamnionitis cases as compared to both acute chorioamnionitis and control cases. Importantly, glycodelin-A, which maintains maternal tolerance against an allogeneic fetus, was decreased in chronic chorioamnionitis, while haptoglobin was increased. We report the amniotic fluid proteome of chronic chorioamnionitis for the first time, and the findings herein strongly suggest that there is a pathophysiological association between the changes of immunomodulatory proteins in the amniotic fluid and chronic chorioamnionitis, a histological manifestation of maternal anti-fetal allograft rejection.

Topics: Acute Disease; Adolescent; Adult; Amniotic Fluid; Chemokine CXCL10; Chorioamnionitis; Chronic Disease; Cross-Sectional Studies; Dinoprost; Electrophoresis, Gel, Two-Dimensional; Extraembryonic Membranes; Female; Glycodelin; Glycoproteins; Haptoglobins; Humans; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Parity; Pregnancy; Pregnancy Proteins; Proteome; Young Adult

Chorioamnionitis (CAM) is a major cause of preterm delivery. Inflammatory cytokines and chemokines play important roles in the pathogenesis of preterm delivery. Interleukin (IL)-17 is a key cytokine which induces inflammation and is critical to host defense. In this study, we examined the role of IL-17 in the pathogenesis of preterm delivery. The levels of cytokines including IL-17, IL-8 and tumor necrosis factor (TNF) alpha were measured by ELISA in amniotic fluid from 154 cases of preterm labor. Flow cytometry and immunohistochemical staining were performed to determine the distribution of IL-17-producing cells. IL-8 secretion was evaluated in primary cultured human amniotic mesenchymal (HAM) cells and human amniotic epithelial (HAE) cells stimulated with IL-17, TNFalpha or IL-1beta. We also studied the signaling pathway of IL-17 and TNFalpha in HAM cells. Levels of inflammatory cytokines in amniotic fluid were higher in preterm delivery cases than in term delivery cases. Furthermore, IL-8, IL-17 and TNFalpha levels were significantly higher in the preterm cases with CAM stage II or III than those without CAM. Flow cytometry and immunohistochemical staining revealed that CD3(+)CD4(+) T cells were the main source of IL-17 in the chorioamniotic membrane. Interestingly, TNFalpha-induced IL-8 secretion was enhanced by IL-17 in a dose-dependent manner in HAM cells. The IKK inhibitor BMS-345541 and mitogen-activated protein kinase (MAPK) inhibitors p38, JNK and p42/44 (ERK1/2 pathway) reduced IL-8 secretion by IL-17-stimulated and TNFalpha-stimulated HAM cells. These results indicate that IL-17, produced by T cells, promotes inflammation at the fetomaternal interface in preterm delivery.

Topics: Adult; Amniotic Fluid; CD3 Complex; CD4-Positive T-Lymphocytes; Chorioamnionitis; Epithelial Cells; Female; Humans; I-kappa B Kinase; Imidazoles; Interleukin-17; Interleukin-8; Maternal-Fetal Exchange; Mitogen-Activated Protein Kinases; Obstetric Labor, Premature; Pregnancy; Quinoxalines; Tumor Necrosis Factor-alpha

Ureaplasma spp. are the most frequently isolated microorganisms inside the amniotic cavity and have been associated with spontaneous abortion, chorioamnionitis, premature rupture of the membranes (PROM), and preterm labor (PL). We analyzed 118 samples from amniotic fluid of preterm infants before 34 weeks of gestation by quantitative polymerase chain reaction (qPCR). Bacterial load, Ureaplasma biovar discrimination (Ureaplasma urealyticum and Ureaplasma parvum), and the level of inflammation were correlated with short-term clinical outcome. U. parvum was the predominant biovar, and increased bacterial load was significantly linked to histologic chorioamnionitis, PROM + PL, early-onset sepsis, and bronchopulmonary dysplasia. Furthermore, there was a positive correlation between the amount of U. parvum and the magnitude of inflammatory response inside the amniotic cavity observed by elevated interleukin 8 levels. We postulate that the bacterial load of Ureaplasma spp. measured by qPCR should be determined in studies investigating the potential clinical impact of intrauterine Ureaplasma spp. on the outcome of preterm infants.

Topics: Amniotic Fluid; Chorioamnionitis; Colony Count, Microbial; DNA, Bacterial; Female; Histocytochemistry; Humans; Infant, Newborn; Interleukin-8; Male; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious; Ureaplasma; Ureaplasma Infections; Ureaplasma urealyticum

Chorioamnionitis frequently induces a fetal inflammatory response syndrome (FIRS), characterized by an elevation of proinflammatory mediators and systemic inflammation. Although there is increasing evidence that inflammation and lipid metabolism influence each other, the effects of chorioamnionitis-induced FIRS on fetal lipid homeostasis are currently not known. Accordingly, we hypothesize that chorioamnionitis induces an inflammatory response in the fetal liver, consequently leading to metabolic disturbances. Chorioamnionitis was induced by intra-amniotic injection of 10 mg endotoxin (control) for 2 d or 2 wk before delivery. Saline injections were given to controls. The effect of chorioamnionitis on hepatic inflammation and metabolic parameters was analyzed in ovine fetuses at the GA of 125 d (normal GA = 150 d). We found that 2 d after the endotoxin injections, inflammatory markers were significantly higher compared with controls. In addition, lipid and glucose metabolism were disturbed in response to endotoxin. Moreover, the antioxidant state capacity was reduced, and hepatic damage was apparent. Two weeks after the endotoxin injections, the fetal livers were still inflamed and had higher glucose concentrations in the blood. In addition, the levels of markers for hepatic damage (alanine aminotransferase and aspartate aminotransferase) were increased. In conclusion, chorioamnionitis induces liver inflammation leading to metabolic disturbances in the fetus.

Topics: Animals; Chorioamnionitis; Endotoxins; Female; Fetus; Hematopoiesis; Inflammation; Interleukin-8; Lipid Metabolism; Liver; Pregnancy; Sheep

To determine whether umbilical cord blood concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), and matrix metalloproteinase-8 (MMP-8) are of value in the diagnosis of histological chorioamnionitis (HCA) and funisitis in patients with preterm premature rupture of membranes (PPROM).. Department of Obstetrics and Gynaecology, Charles University in Prague, Faculty of Medicine Hradec Kralove, University Hospital Hradec Kralove, Czech Republic.. We compared umbilical cord blood IL-6, IL-8, and MMP-8 concentrations in 83 women with PPROM between 24th and 36th gestational weeks with the presence and the absence of HCA/funisitis using nonparametric tests (Mann-Whitney U test), given the non-normal distribution of analyte. Comparisons of proportions were performed the D'Agostino and Pearson omnibus normality test and the Shapiro-Wilk test.. Patients with HCA had a significantly higher median umbilical cord blood IL-6 concentration than patients without histological signs of inflammation (12.0 pg/mL [2.1-138.3] versus 2.7 pg/mL [0.1-12.4]; p=0.004) but did not have significantly higher median umbilical cord IL-8 (29.9 pg/mL [14.0-186.3]; versus 18.9 pg/mL [7.9-89.4]; p=0.13) and MMP-8 (2.9 pg/mL [0.5-25.2] versus 0.5 ng/mL [0.5-7.9]; p=0.18). Patients with HCA and funisitis had a significantly higher median umbilical cord blood IL-6 (222 pg/mL [95.3-411.7] versus 6.1 pg/mL [1.3-18.5]; p<0.0001) and IL-8 (20.9 pg/mL [8.4-37.7] versus 190.7 pg/mL [83.8-554.2]; p=0.0004) concentration than patients with HCA alone. Differences were not found in MMP-8 concentrations (3.7 ng/mL [0.5-21.4] versus 2.4 ng/mL [0.5-88.1]; p=0.7).. HCA was associated with a significant increase in umbilical cord blood IL-6 concentration. In patients with HCA and funisitis, umbilical cord blood IL-6 and IL-8 were significantly higher than those without histological signs of inflammation.

Topics: Adult; Biomarkers; Chorioamnionitis; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Fetus; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 8; Pregnancy

To evaluate the influence of chorioamnionitis (CA) on plasma cytokines and the cytokine-associated risk of bronchopulmonary dysplasia (BPD) during the perinatal period.. Eleven cytokines from 128 very low gestational age infants were analyzed from cord blood and from plasma at ages 1 day and 7 days after birth. The diagnosis of CA was based on histology of the placenta, fetal membranes, and umbilical cord. Neonatal risk factors were recorded.. In the 48 infants born with CA, high concentrations of inflammatory cytokines in cord blood decreased during the first postnatal day. Inflammatory cytokines in cord blood was associated with the severity of CA. At 1 day after birth, the concentration of interleukin (IL)-8 predicted the risk of BPD. For the 75 infants born without CA, cytokine concentrations increased after birth. For the 128 infants born with or without CA, at 1 day after birth, the concentrations of IL-8, granulocyte colony-stimulating factor, and anti-inflammatory IL-10 were associated with the risk of BPD, after adjustment for the duration of gestation and severity of respiratory distress during the first day.. In infants exposed to CA, insufficient inhibition of high fetal inflammatory cytokine response shortly after birth may increase the risk of BPD.

Topics: Adult; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Male; Pregnancy; Prospective Studies; Risk Factors; ROC Curve; Sensitivity and Specificity

To quantify the expression of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) in chorioamniotic membranes of PPROM pregnant women with chorioamnionits.. The study included 25 PPROM women in labor, 15 PPROM without labor, and 25 pregnant women in preterm labor (PTL). Chorioamniotic membranes were collected for histopathological analyses and cytokine mRNA expression quantification by real time PCR. Comparisons were performed using the Mann-Whitney, Kruskal-Wallis, Fisher's exact test or z test with significance set at p<0.05. The software employed was the SigmaStat version 3.1.. During the study PPROM incidence was 4.6% and chorioamnionits was present in 75% of the samples. IL-1beta, IL-6, and IL-8 mRNA expression did not statistically differ among study groups. TNF-alpha mRNA expression was statistically higher in PTL. No difference in the mRNA concentration of the cytokines studied in the presence of chorioamnionitis was observed.. Chorioamniotic membranes are sources of IL-1beta, IL-6, IL-8, and TNF-alpha and their mRNA concentrations in PPROM are not related to the presence of chorioamnionitis.

Topics: Adult; Amnion; Case-Control Studies; Chorioamnionitis; Chorion; Extraembryonic Membranes; Female; Fetal Membranes, Premature Rupture; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Labor Stage, First; Obstetric Labor, Premature; Pregnancy; RNA, Messenger; Tumor Necrosis Factor-alpha

The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days.. For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21.. Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1beta, 6, 8, and 10 and interferon gamma and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor beta. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.. The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

Topics: Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Humans; Immunity, Cellular; Immunity, Innate; Infant, Extremely Low Birth Weight; Infant, Newborn; Interferon-gamma; Interleukin-1beta; Interleukin-6; Interleukin-8; Logistic Models; Male; Multivariate Analysis; Pregnancy

To determine whether amniotic fluid levels of interleukin-8 (IL-8) are of value in the antenatal diagnosis of acute histological chorioamnionitis (HCA) in preterm premature rupture of membranes (PPROM).. Department of Obstetrics and Gynaecology, Charles University, Medical School and University Hradec Kralove, Czech Republic.. We compared amniotic fluid IL-8 levels in twenty-nine pregnant women with preterm premature rupture of membranes between 24th and 36th gestational weeks with presence and absence acute histological chorioamnionitis or/and microbial invasion in the amniotic cavity using nonparametric tests (Mann-Whitney test), given the non-normal distribution of analyte. Comparisons of proportions were performed with Shapiro-Wilk normality test.. Patients with HCA had a significantly higher median amniotic fluid IL-8 concentration than patients without the histological signs of chorioamnionitis (1867 pg/mL, 826-5577 versus 1045 pg/mL, 60-4133, p=0.013). Patients with MIAC had a significantly higher median amniotic fluid level than patients without invasion (1888 pg/mL, 519-5577 versus 1225 pg/mL, 60-2766, p= 0.017). Women with HCA and MIAC had a significantly higher median amniotic fluid IL-8 level than women without histological signs of chorioamnionitis and microbial invasion (3117 pg/mL, 826-5577 versus 1468 pg/mL, 394-2766, p=0.034).. HCA or/and MIAC are associated with a significant increase of amniotic fluid interleukin-8 levels. Amniotic fluid IL-8 seems to be a marker of intraamniotic inflammation.

Topics: Adult; Amniotic Fluid; Biomarkers; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Predictive Value of Tests; Pregnancy; Prospective Studies; Ureaplasma; Ureaplasma Infections

All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:B5) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 +/- 3 mL/kg), lung volume increased similarly with endotoxin (22 +/- 4 mL/kg) or RA plus endotoxin (20 +/- 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 +/- 0.3 mum after endotoxin-induced chorioamnionitis, 6.0 +/- 0.4 mum in controls (P < 0.05 versus endotoxin) and 5.5 +/- 0.2 mum after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 +/- 0.3 in endotoxin-induced chorioamnionitis, 2.1 +/- 0.3 in controls and 4.1 +/- 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.

Topics: Animals; Bronchopulmonary Dysplasia; Chorioamnionitis; Disease Models, Animal; Elastin; Endotoxins; Female; Fetus; Humans; Infant, Newborn; Interleukin-8; Lung; Pregnancy; Pulmonary Alveoli; Sheep; Tretinoin

Chorioamnionitis is a risk factor for the development of bronchopulmonary dysplasia. Endotoxin-induced oxidative stress to the fetus in the uniquely hypoxic intrauterine environment has not been reported. Using a model of chorioamnionitis, we measured markers of pulmonary and systemic oxidant exposures in fetal lambs at 124 d gestation (term = 150 d) exposed to 10 mg intra-amniotic endotoxin 2 d (n = 6) or 7 d (n = 6) before delivery, or saline as controls (n = 9). The 7 d endotoxin-exposed animals had 3-fold higher protein carbonyls (0.66 +/- 0.46 versus 0.23 +/- 0.14 nmol/mg protein) and 10-fold greater myeloperoxidase activity (2.38 +/- 1.87 versus 0.27 +/- 0.18 nM) in the bronchoalveolar lavage fluid (BALF), suggestive of neutrophil-derived oxidant activity. However, in the lung tissue, protein carbonyls, superoxide dismutase, and peroxiredoxin 1 were not different between groups. The expression of peroxiredoxin 1 was prominent, primarily in the peri-bronchiolar epithelium. Notably, evidence of oxidant exposure was minimal at 2 d when BALF inflammatory cells, lung IL-1beta, and IL-8 were highest. Intra-amniotic endotoxin induced systemic oxidative stress as plasma protein carbonyl was elevated at 7 d (0.14 +/- 0.04 nmol/mg protein; p = 0.005). Surfactant protein A and B mRNAs were highest at 2 d, suggesting that oxidative stress did not contribute to the lung maturation response. A modest lung oxidative stress in chorioamnionitis could contribute to bronchopulmonary dysplasia.

Topics: Amniotic Fluid; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chorioamnionitis; Disease Models, Animal; Female; Fetal Organ Maturity; Gestational Age; Humans; Infant, Newborn; Injections; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Lung; Oxidative Stress; Peroxidase; Peroxiredoxins; Pregnancy; Protein Carbonylation; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; RNA, Messenger; Sheep; Superoxide Dismutase; Time Factors

The mechanisms contributing to hypoxic respiratory failure (HRF) in term infants are multifactorial. Recent evidence suggests a potential pathogenetic role for inflammation. Nitric oxide (NO), a pulmonary vasodilator, is inhibited by inflammatory mediators that are upregulated in the presence of placental inflammation.. To examine the relationship between histological chorioamnionitis and/or funisitis, serum concentrations of inflammatory mediators and severity of HRF.. Prospective observational study involving term neonates with HRF and normal controls. Blood samples were taken at birth from mixed cord blood, at 6 h and 30 h for cytokines and CRP, and at 72 h and 96 h for CRP. Placentas were examined for chorioamnionitis. The primary outcome was the administration of inhaled nitric oxide (iNO) therapy. Data were analysed using analysis of variance and chi(2) analysis.. 32 neonates with hypoxic respiratory failure and 25 controls were enrolled. 14/32 (44%) neonates with HRF required iNO, 9/32 (28%) required high-frequency ventilation and 3/32 (9%) required ECMO; 2/32 (6%) died. Neonates with HRF had more than threefold higher cord levels of interleukin 8 (IL8) than the controls (p<0.05). At 6 h and 30 h, serum IL6, IL8 and CRP were > or =2.2-fold higher in neonates who received iNO (p<0.003). 23/32 (72%) infants with HRF had evidence of histological chorioamnionitis and/or funisitis compared with 5/25 (20%) controls (p<0.001).. Severe HRF, as defined by the need for iNO, is associated with raised blood levels of proinflammatory mediators and increased occurrence of histological chorioamnionitis and funisitis, suggesting that inflammation contributes to the severity of hypoxic failure.

Topics: Acute Disease; Biomarkers; Bronchodilator Agents; C-Reactive Protein; Carbon Dioxide; Chorioamnionitis; Female; Humans; Hypoxia; Infant, Newborn; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Nitric Oxide; Oxygen; Partial Pressure; Pregnancy; Prospective Studies; Respiratory Insufficiency

The purpose of this study was to determine cord blood cytokine levels and their relationship with morbidity and mortality in neonates with prolonged, premature rupture of membranes (PPROM). Forty two premature neonates of 29-35 weeks gestational age with PPROM exceeding 24 hours were considered as the PPROM group and simultaneously, 41 premature neonates without PPROM were considered as the control group. All the neonates were admitted to the Neonatology Unit for further evaluation of subsequent complications such as early neonatal sepsis, pneumonia, intraventicular haemorrhage (IVH), respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC) and chronic lung disease (CLD). Cord blood and mothers' blood samples were obtained during delivery in both groups and tested for IL-6, IL-8 and TNF-alpha levels. Twenty one percent of patients with PPROM had histological chorioamnionitis. The risk for developing early neonatal sepsis increased significantly in neonates whose mothers had histological chorioamnionitis (p < 0.05). There was a statistically significant relationship between PPROM and risk of developing NEC (p < 0.05); no significant increase was seen as regards early neonatal sepsis, IVH, RDS, pneumonia, or BPD. The mean IL-8 levels in cord blood and mothers' serum were significantly higher in the PPROM group (p < 0.001, p< 0.005). In addition, IL-6 levels found in mothers' serum were significantly higher than those found in the control group (p < 0.01). However, levels in cord blood were similar (p > 0.05). TNF-alpha levels were similar in both groups (p > 0.05). Neonates who developed NEC had higher IL-8 levels in their cord blood when compared to those without NEC (p < 0.05). In conclusion, the presence of PPROM increases the risk of chorioamnionitis. In addition, PPROM increases the risk of NEC, and patients who developed NEC had significantly higher cord blood IL-8 values. We may conclude that patients with PPROM and higher IL-8 levels in cord blood might be considered as at possible risk of NEC.

Topics: Adult; Chorioamnionitis; Cytokines; Enterocolitis, Necrotizing; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Neonatology; Pregnancy; Risk; Sepsis

Peri-intraventricular hemorrhage (P/IVH) is a common neonatal morbidity among premature infants. The aim of the study was to examine the association between placental and/or fetal inflammation and the onset of P/IVH in premature infants.. A prospective study included 125 infants with gestational age 23-29 weeks. Placentas were examined for the presence of chorioamnionitis and funisitis, cord blood was sampled for the measurement of cytokines (IL-6 and IL-8). Fetal inflammation was defined as levels of IL-6 higher than 7.6 pg/ml. P/IVH was defined as early if diagnosed within the 1st day after birth; thereafter P/IVH was defined as late.. Adjusted for the influence of gestational age, early-onset sepsis (OR 3.2, p = 0.045) and no or incomplete antenatal steroid course (OR 6.0, p = 0.001) significantly predicted early P/IVH. Funisitis (OR 1.6, p = 0.06) and fetal inflammation (OR 2.6, p = 0.06) were only partially associated with early hemorrhage. Contrary to that, respiratory distress syndrome (OR 3.4, p = 0.04), mechanical ventilation (OR 5.9, p = 0.008), low blood pressure (OR 3.5, p = 0.02), and vasopressors (OR 5.7, p = 0.002) were associated with late P/IVH. In multivariate analysis no or incomplete steroid course remained independent predictors for early and use of vasopressors for late P/IVH. The interaction of fetal inflammation and vaginal delivery with no or incomplete steroid course increased the risk of early P/IVH.. These results indicate different risk factors for early and late P/IVH. Neither funisitis nor fetal inflammation independently predicts the onset of P/IVH. However, the interaction of fetal inflammation and vaginal delivery with no or incomplete antenatal steroid course increase the risk of early but not also late P/IVH.

Topics: Cerebral Hemorrhage; Chorioamnionitis; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Inflammation; Interleukin-6; Interleukin-8; Male; Multivariate Analysis; Pregnancy; Prospective Studies; Risk Factors

Chorioamnionitis is associated with intense neutrophil infiltration of the decidua. We therefore determined whether chorioamnionitis enhances decidual interleukin-8 (IL-8) expression and examined cytokine-regulated decidual IL-8 expression. Decidua from chorioamnionitis-complicated pregnancies, but not term controls, displayed marked IL-8 immunohistochemical staining and a dense neutrophil infiltrate. Reverse transcriptase-polymerase chain reaction of microdissected decidual cells identified IL-8 mRNA, confirming decidual synthesis of IL-8. Confluent leukocyte-free term decidual cells were primed with 10(-8) mol/L estradiol (E2) or E2 + 10(-7) mol/L medroxyprogesterone acetate to mimic the steroidal milieu of pregnancy. Compared with cultures maintained in E2 alone, E2 + medroxyprogesterone acetate neither significantly affected IL-8 levels nor altered the response to the cytokines. The addition of 1.0 ng/ml tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1beta) increased IL-8 secretion levels by 236.6 +/- 51.4- and 1062.6 +/- 254.3-fold, respectively (n = 8, mean +/- SEM, P < 0.05), as measured by enzyme-linked immunosorbent assay. Concentration-response studies revealed that 0.01 ng/ml TNF-alpha and IL-1beta elevated IL-8 output by 10- and 100-fold, respectively. Western blotting confirmed these results, and quantitative reverse transcriptase-polymerase chain reaction demonstrated parallel changes in mRNA levels. In conclusion, IL-8 is strongly expressed in term decidua during chorioamnionitis, and TNF-alpha and IL-1beta enhance IL-8 expression in term decidual cells, suggesting that these cytokines are important regulators of chorioamnionitis-related decidual neutrophil infiltration.

Topics: Cells, Cultured; Chorioamnionitis; Decidua; Estradiol; Female; Humans; Interleukin-1beta; Interleukin-8; Medroxyprogesterone Acetate; Pregnancy; Pregnancy Trimester, Third; RNA, Messenger; Tumor Necrosis Factor-alpha

Intra-amniotic infection, diagnosed by microbial invasion of the amniotic cavity (MIAC) and/or the presence of intra-amniotic inflammation (IAI), is related to adverse perinatal outcome in women with preterm labor. Due to the subclinical nature of IAI, a correct diagnosis depends on amniocentesis, which is an invasive method not performed as a clinical routine. The aim of this study was to evaluate if cervical length measured by transvaginal sonography could assist in the identification of women at high risk for IAI.. Cervical length was assessed by transvaginal sonography in 87 women with singleton pregnancies in preterm labor (<34 weeks of gestation). Cervical (n=87) and amniotic (n=55) fluids were collected. Polymerase chain reactions for Ureaplasma urealyticum and Mycoplasma hominis, and culture for aerobic and anaerobic bacteria, were performed. Interleukin (IL)-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay.. IAI was present in 25/55 (45%) of the patients presenting with preterm labor who underwent amniocentesis. Women with IAI had a significantly shorter cervical length (median, 10 (range, 0-34) mm) than had those without IAI (median, 21 (range, 11-43) mm) (P<0.0001). Receiver-operating characteristics curve analysis showed that a cervical length (cut-off of 15 mm) predicted IAI (relative risk, 3.6; CI, 1.9-10.0) with a sensitivity of 72%, specificity of 83%, positive predictive value of 78% and negative predictive value of 78%. Cervical length was also significantly associated with preterm birth up to 7 days from sampling and at

Topics: Adult; Amniocentesis; Cervix Uteri; Chorioamnionitis; Cohort Studies; Female; Humans; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Prospective Studies; Ultrasonography; Uterine Cervicitis

The purpose of this study was to determine the relative contributions of individual proinflammatory cytokines and chemokines to the triggering of preterm labor.. Eighteen chronically instrumented pregnant rhesus monkeys at 135 +/- 3 days gestation (term = 167 days) received 1 of 5 intraamniotic infusions: (1) interleukin-1beta (IL-1beta) (10 microg; n = 5), (2) tumor necrosis factor-alpha (TNF-alpha) (10-100 microg; n = 5), (3) IL-6 (20 microg twice a day; n = 2), (4) IL-8 (20 microg twice a day; n = 2), and (5) saline control (n = 4). Primary study outcomes were the mean uterine hourly contraction area (mm Hg x s/h) in 24 hours during peak response to cytokine infusion (all groups) and the interval from cytokine infusion until labor onset (IL-1beta, IL-6, and IL-8 groups). Secondary outcomes were quantities of amniotic fluid cytokines and chemokines (IL-1beta, TNF-alpha, IL-6, and IL-8), prostaglandins E2 and F2alpha, leukocytes, and matrix metalloproteinase-9 (MMP-9). Histopathology of fetal lungs and placental membranes was assessed.. IL-1beta stimulated the most intense contraction patterns, resulting in preterm labor in all cases. TNF-alpha induced a variable degree of uterine activity among individual animals stimulating either preterm labor (n = 2) or a uterine contraction pattern of moderate intensity (n = 3). Despite prolonged elevations in amniotic fluid levels, neither IL-6 nor IL-8 induced preterm labor or an increase in uterine activity until near term. The mean interval from the initiation of IL-6 and IL-8 infusion to the onset of labor was significantly longer than after IL-1beta (21.9 vs 1.1 days; P < .01), and did not differ from the saline control group (27.6 days; P = NS). Intraamniotic infusion of IL-1beta or TNF-alpha was associated with significant elevations in all tested amniotic fluid cytokines, IL-8, prostaglandins, MMP-9 and leukocytes compared with gestational age-matched saline controls. IL-6 and IL-8 infusions were not associated with increases in IL-1beta or TNF-alpha and only produced a moderate increase in amniotic fluid prostaglandins. All cytokine infusions induced histologic chorioamnionitis and an accumulation of neutrophils in fetal lungs.. Preterm labor was induced by intraamniotic infusions of IL-1beta and TNF-alpha, but not by IL-6 or IL-8 although inflammatory changes in fetal membranes and lungs were uniformly present. Our results indicate a primary role for IL-1beta and TNF-alpha in the triggering of preterm labor associated with inflammation or infection.

Topics: Amniotic Fluid; Animals; Chorioamnionitis; Cytokines; Extraembryonic Membranes; Female; Gestational Age; Inflammation; Injections; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; Macaca mulatta; Matrix Metalloproteinase 9; Neutrophil Infiltration; Obstetric Labor, Premature; Pregnancy; Prostaglandins; Recombinant Proteins; Tumor Necrosis Factor-alpha; Uterine Contraction; Uterus

Chorioamnionitis and funisitis are associated with preterm labor and postnatal morbidity. Activation of endothelium resulting in up-regulation of adhesion molecules seems to be a key mechanism in development of organ damage. We investigated whether chorioamnionitis with or without funisitis in preterm infants induced expression and shedding of adhesion molecules in the umbilical cord and resulted in increased concentrations of E-selectin, intercellular adhesion molecule (ICAM)-1, IL-1beta, IL-6, and IL-8 in the cord blood. Data were obtained by using immunohistochemistry and ELISA. Thirty-two preterm infants were divided into three groups according to histology: chorioamnionitis with funisitis, chorioamnionitis without funisitis, and controls without signs of inflammation. ICAM-1 expression on arterial endothelium was higher with funisitis compared with chorioamnionitis alone or with the control group. Similar results for ICAM-1 expression were found in venous endothelium, vascular walls, Wharton's jelly, and amnion epithelium. Endothelial E-selectin and vascular cell adhesion molecule (VCAM)-1 expression was only induced significantly with funisitis. Serum-concentrations of soluble ICAM-1 were higher with funisitis compared with chorioamnionitis alone or control group. Similarly, concentrations of soluble E-selectin, IL-1beta, IL-6, and IL-8 were increased exclusively with funisitis. In conclusion, only chorioamnionitis with funisitis was associated with systemic inflammation and endothelial activation with up-regulation and shedding of umbilical cord adhesion molecules. We speculate that this activation of endothelium may not be limited to the umbilical cord but may also involve other organs resulting in neonatal morbidity. This underlines the importance of funisitis as a risk factor for adverse outcome.

Topics: Cell Adhesion; Chorioamnionitis; Cytokines; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Immunohistochemistry; Infant, Newborn; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Interleukin-8; Male; Placenta; Pregnancy; Risk Factors; Umbilical Cord; Umbilical Veins; Up-Regulation; Vascular Cell Adhesion Molecule-1

Although antenatal infection is thought to play an important role in the pathogenesis of preterm labor and neonatal diseases, the exact mechanisms are largely unknown. We sought to clarify the relationship between antenatal infection and intrauterine and neonatal inflammation. Samples were obtained from 41 preterm infants of <33 wk gestation delivered to 36 mothers and analyzed for the presence of 16s ribosomal RNA (16s rRNA) genes using PCR and for the proinflammatory cytokines IL-6 and IL-8. In 16 (44%) mother-baby pairings, at least one sample was found to be positive for the presence of 16s rRNA genes. All but one of the positive samples were from mothers presenting with preterm prelabor rupture of membranes (pPROM) or in spontaneous idiopathic preterm labor. A strong association was found between the presence of 16s rRNA genes and chorioamnionitis and with funisitis. A marked increase in IL-6 and IL-8 was noted in all tissues positive for 16s rRNA genes, including placenta, fetal membranes, cord blood serum, and, where samples were available, in bronchoalveolar lavage fluid (BAL) and in amniotic fluid. Interestingly, gastric fluid was always positive for 16s rRNA genes if any other intrauterine or BAL sample was positive, suggesting that this sample may provide an alternative to amniotic fluid to identify antenatal infection. In conclusion, we have found that microbial genes are particularly prevalent in pPROM and spontaneous preterm labor groups and that their presence is strongly associated with a marked intrauterine inflammatory response.

Topics: Amniotic Fluid; Bronchoalveolar Lavage Fluid; Chorioamnionitis; Extraembryonic Membranes; Female; Fetal Blood; Gastric Juice; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Placenta; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious; RNA, Ribosomal, 16S; Ureaplasma Infections; Ureaplasma urealyticum

Unresolved pulmonary inflammation in hyaline membrane disease (HMD) may be a precursor to the development of chronic lung disease of early infancy. We investigated whether nuclear factor kappaB (NF-kappaB), a transcription factor that regulates the inflammatory process, is activated in pulmonary leukocytes in tracheal aspirates from premature infants with HMD. A total of 172 samples were obtained from 59 infants, two thirds of whom showed NF-kappaB activation in lung neutrophils and macrophages on at least one occasion. Infants who had activated NF-kappaB showed elevated tumor necrosis factor-alpha concentrations in their tracheal aspirates. These infants also required a longer period of mechanical ventilation support. Almost half of the infants with HMD had antenatal exposure to chorioamnionitis on the basis of placental histopathologic examination. These infants had evidence of activated NF-kappaB and elevated cytokines and were more likely to have Ureaplasma urealyticum colonization in their airways. Together, these observations suggest that NF-kappaB activation in pulmonary leukocytes may be involved in the lung inflammatory process in infants with HMD.

Topics: Birth Weight; Chorioamnionitis; Cytokines; Female; Humans; Hyaline Membrane Disease; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Leukocytes; Lung; Macrophages; Male; Microscopy, Fluorescence; Neutrophils; NF-kappa B; Odds Ratio; Oxygen; Pregnancy; Time Factors; Trachea; Tumor Necrosis Factor-alpha; Ureaplasma Infections; Ureaplasma urealyticum

The association between elevated interleukin (IL)-8 concentrations in amniotic fluid and preterm delivery is well described. Little consideration has been given to the impact of different groups of microorganisms within the amniotic cavity on IL-8 concentration.. We collected amniotic fluid, placental tissue and amniotic membranes during preterm cesarean sections for bacterial culture. In addition, we determined IL-8 concentrations in maternal serum, amniotic fluid and cord blood and correlated them with the various intra-amniotic pathogens isolated by bacterial culture.. IL-8 concentrations were determined in amniotic fluid in 107 cases, in cord blood in 185 cases and in maternal blood in 158 cases. Women with intra-amniotic Ureaplasma urealyticum infection had significantly higher amniotic fluid concentrations of IL-8 than those without (P< 0.001). In cord blood, we found significantly elevated IL-8 concentrations due to intra-amniotic infection with U. urealyticum (P=0.045) and other pathogens (P=0.04). In maternal sera, we found no significant elevation of maternal IL-8 in any of the groups.. Intrauterine infection with U. urealyticum seems to play a profound role in the cascade of inflammation and increases IL-8 concentrations in amniotic fluid and cord blood.

Topics: Adult; Amniotic Fluid; Chorioamnionitis; Cohort Studies; Female; Fetal Blood; Humans; Interleukin-8; Obstetric Labor, Premature; Pregnancy; Prospective Studies; Ureaplasma Infections; Ureaplasma urealyticum

The clinical or histologic diagnosis of chorioamnionitis has been associated with an increased risk of neuropathology and adverse neurologic outcomes in premature and term infants. Inflammatory cytokines have been implicated in the pathogenesis of these processes. The objective of this study was to determine whether exposure to chorioamnionitis and fetal inflammatory syndrome is associated with elevated concentrations of inflammatory cytokines (TNF-alpha, IL-6, and IL-8) in the CSF of term and preterm infants.. Eighty-four mother/infant pairs were studied, 54 infants were premature. Twenty-eight showed signs of maternal (n = 14), or fetal (n = 14) inflammation based on placental pathology; mothers of 24 infants showed signs of clinical chorioamnionitis not confirmed by placental pathology and 32 infants were considered as 'controls' since they had only transient difficulty adjusting to extra-uterine life warranting evaluation for sepsis. The cytokine concentrations in the CSF were measured within 24 h of birth.. When compared to the control group (IL-8 = 341 +/- 170 pg/ml and IL-6 = 7.4 +/- 1.8 pg/ml) significantly higher concentrations of IL-8 were detected in the CSF of infants exposed to clinical chorioamnionitis (1,854 +/- 878 pg/ml; p = 0.001) and maternal/fetal inflammation (1,754 +/- 787 pg/ml; p = 0.001) and of IL-6 in infants with maternal/fetal inflammation (47.6 +/- 45.1 pg/ml; p = 0.01).. These results indicate that infants exposed to clinical chorioamnionitis, or inflammation in utero, experience at least a transient elevation in inflammatory cytokines in CSF.

Topics: Chorioamnionitis; Female; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; Pregnancy; Term Birth

Intra-amniotic secretion and abundance of epithelial cell-derived neutrophil-activating peptide (ENA)-78, a potent chemoattractant and activator of neutrophils, was studied in the context of term and preterm parturition. Staining of ENA-78 immunoperoxidase was localized predominantly to chorionic trophoblasts and amniotic epithelium in term and preterm gestational membranes, with weaker and less consistent staining in decidual cells. The abundance of ENA-78 in membrane tissue homogenates was significantly increased ( approximately 4-fold) with term labor in amnion (n = 15), and with preterm labor ( approximately 30-fold) in amnion and choriodecidua (n = 31). In amnion tissue homogenate extracts, ENA-78 levels were positively correlated with the degree of leukocyte infiltration (r2 = 0.481). In amniotic fluids, median ENA-78 levels from pregnancies with preterm labor without intra-amniotic infection were significantly lower (P < 0.01 by ANOVA) than those from pregnancies with preterm deliveries with infection; levels in samples derived from term pregnancies were similar before and after labor. Production of ENA-78 by amnion monolayers was stimulated in a concentration-dependent fashion by both interleukin-1beta and tumor necrosis factor alpha. Production of ENA-78 by choriodecidual explants was increased modestly after 2-4 h of exposure to lipopolysaccharide (5 microg/ml). An immunoreactive doublet ( approximately 8 kDa) was detected in choriodecidual explant-conditioned media by immunoblotting. We conclude that ENA-78, derived from the gestational membranes, is present in increased abundance in the amniotic cavity in response to intrauterine infection and, hence, may play a role in the mechanism of infection-driven preterm birth and rupture of membranes secondary to leukocyte recruitment and activation.

Topics: Amniotic Fluid; Cells, Cultured; Chemokine CXCL5; Chemokines, CXC; Chorioamnionitis; Epithelial Cells; Extraembryonic Membranes; Female; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Pregnancy; Pregnancy Complications, Infectious; Uterus

Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. We hypothesized that ventilation of the antenatally inflamed lung would result in amplification of the lung injury. Therefore, we induced fetal lung inflammation with intra-amniotic endotoxin (10 mg of Escherichia coli 055:B5) 4 days before premature delivery at 130 days of gestation. Lung function and lung inflammation after surfactant treatment and 4 h of mechanical ventilation were evaluated. Inflammatory cell numbers in amniotic fluid were increased >10-fold by antenatal endotoxin exposure. Antenatal endotoxin exposure had minimal effects on blood pressure, heart rate, lung compliance, and blood gas values. The endotoxin-exposed lungs required higher ventilation pressures. Ventilation did not increase the number of inflammatory cells or the protein in bronchoalveolar lavage fluid of the endotoxin-exposed animals above that measured in endotoxin-exposed fetuses that were not ventilated. IL-1beta, IL-6, and IL-8 mRNA in cells from bronchoalveolar lavage fluid were increased by antenatal endotoxin exposure but not changed by ventilation. IL-1beta and IL-8 protein was increased in lung tissue by 4 h of ventilation. Very little inflammation was induced by ventilation in this premature lamb model of surfactant treatment and gentle ventilation. After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury.

Topics: Animals; Biomarkers; Birth Weight; Bronchopulmonary Dysplasia; Chorioamnionitis; Endotoxins; Female; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Pneumonia; Pregnancy; Respiration, Artificial; RNA, Messenger; Sheep

Antenatal betamethasone (Beta) is widely used in women with asymptomatic chorioamnionitis at risk for preterm delivery, but its effects on fetal inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation received the following treatments: intra-amniotic (IA) saline (control), 0.5 mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However, compared with Endo 5 days after treatment, Beta + Endo lambs had increased alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had increased lung inflammation but equivalent lung volumes 15 days after treatment. The late increase in inflammation in the Beta + Endo animals suggests that glucocorticoids impair the ability of the preterm lung to downregulate Endo-induced inflammation after fetal clearance of the glucocorticoids. These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids.

Topics: Acute-Phase Reaction; Animals; Betamethasone; Bronchoalveolar Lavage Fluid; Chorioamnionitis; Drug Synergism; Endotoxins; Female; Gene Expression; Glucocorticoids; Hydrocortisone; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Lymphocyte Count; Lymphocytes; Monocytes; Neutrophils; Pneumonia; Pregnancy; Serum Amyloid A Protein; Sheep; Tumor Necrosis Factor-alpha

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation, and a very small increase in inflammatory cells in the fetal lung after 5 h, 2 days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung maturation. TNF-alpha given into the airways at birth increased granulocytes in the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the mRNA for surfactant protein C but did not adversely effect postnatal lung function. An intravascular injection of IL-1alpha caused a systemic inflammatory response in fetal sheep, whereas there was no fetal response to intravascular TNF-alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha. Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals.

Topics: Amniotic Fluid; Animals; Animals, Newborn; Antineoplastic Agents; Chorioamnionitis; Female; Gene Expression; Gestational Age; Injections, Spinal; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Pneumonia; Pregnancy; Recombinant Proteins; Respiration, Artificial; Sheep; Tumor Necrosis Factor-alpha

Previous studies indicate an association between intra-amniotic microbial invasion and/or inflammation and spontaneous preterm birth, but there is a limited amount of data available from Europe. The aim of this study was to investigate the occurrence of intra-amniotic microorganisms and cytokines (interleukin-6 and interleukin-8) in a Swedish population of women in preterm labor and their correlation with preterm birth.. Amniotic fluid was retrieved transabdominally from 61 patients in preterm labor before 34 weeks of gestation. Polymerase chain reaction analyses for Ureaplasma urealyticum and Mycoplasma hominis and culture for aerobic and anaerobic bacteria were performed. Interleukin-6 and interleukin-8 were analyzed with enzyme-linked immunosorbent assay.. Microorganisms in amniotic fluid were detected in 10 patients (16%). Patients with detected bacteria in the amniotic fluid had significantly higher levels of interleukin-6 and interleukin-8. There was also an association between interleukin-6/-8, the amniocentesis-delivery interval (or= 1.5 ng/mL or interleukin-8 >or= 1.3 ng/mL was associated with an increased risk of delivery within 7 days (interleukin-6: relative risk 7.3; 95% confidence interval: 2.8-19; sensitivity 83%, specificity 87%; interleukin-8: relative risk 14, 95% confidence interval: 3.6-55, sensitivity 91%, specificity 87%).. The occurrence of intra-amniotic microbial invasion and inflammation in this population of Swedish women in preterm labor was similar to data reported from populations with a higher incidence of preterm delivery. Amniotic interleukin-6 and interleukin-8 correlated with the presence of microorganisms and with preterm birth.

Topics: Adult; Amniocentesis; Amniotic Fluid; Chorioamnionitis; Female; Humans; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; ROC Curve; Survival Analysis; Sweden

Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses.. Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to 125 days of gestation at time points that ranged from 2 hours to 15 days after treatment.. When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1beta and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection.. These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Topics: Amnion; Amniotic Fluid; Animals; Anti-Inflammatory Agents; Betamethasone; Blood Vessels; Chorioamnionitis; Chorion; Endotoxins; Epithelium; Female; Half-Life; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Count; Pregnancy; Sheep

To determine interleukin (IL)-6 and IL-8 concentrations in the lower uterine segment in patients with chorioamnionitis compared to those without.. Biopsy specimens from the lower uterine segment of 33 patients with chorioamnionitis were matched to specimens of 33 patients without. The biopsies had been taken during cesarean section. The concentrations of IL-6 and IL-8 in protein extracts of these specimens were determined by enzyme linked immunosorbent assays.. Compared to the controls patients with chorioamnionitis showed significantly lower gestational age and higher parity, and were more likely to receive fenoterol or betamethasone. In the chorioamnionitis group the median IL-6 concentrations were higher than in the controls (61.5 and 19.4 pg/mg protein, respectively [p < 0.01]). The same applies to the median IL-8 concentrations (162.3 and 13.4 pg/mg protein, respectively [p < 0.001]).. To our knowledge this is the first study which could clearly demonstrate significantly increased IL-6 and IL-8 levels in the lower uterine segment of patients with chorioamnionitis. Increased concentrations of pro-inflammatory cytokines may play a pivotal role in cervical softening and dilatation during chorioamniotic infection.

Topics: Adult; Case-Control Studies; Chorioamnionitis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Pregnancy; Pregnancy Trimester, Third; Uterus

Inflammatory mediators that are induced by gram-negative bacteria in the course of intrauterine infections threaten successful pregnancy. To compare the effect of two different routes of cytokine induction, bacterial lipopolysaccharide (LPS) was administered in vivo either into the cord vein or into the amniotic cavity of pig fetuses in the second half of gestation for 20 h and cytokines were detected in the amnion.Tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were induced in the amniotic epithelium after intra-amniotic but not after intra-venous administration of LPS. The presence of IL-8 was confirmed by RT-PCR. In contrast, transforming growth factor-beta1 (TGF-beta1) was expressed constitutively and was found in all samples of the amniotic epithelium. Amniotic fluid contained only minute levels of TNF-alpha. IL-8 levels in amniotic fluid increased after the treatment with LPS and the highest IL-8 levels were found in dead LPS-treated fetuses.

Topics: Amnion; Animals; Chorioamnionitis; Female; Fetus; Immunohistochemistry; Interleukin-8; Lipopolysaccharides; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Swine Diseases; Swine, Miniature; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

To determine whether vaginal interleukin-6, interleukin-8, neutrophils, bacterial vaginosis, and selected vaginal bacteria are predictors of amniotic fluid (AF) infection among women in preterm labor.. One hundred ninety-seven afebrile women in preterm labor with intact membranes had vaginal and AF samples collected for Gram stain, culture, and interleukin-8 and interleukin-6 determinations. Vaginal interleukin-6, interleukin-8, neutrophils, and vaginal flora were compared in women with positive and negative AF cultures. The negative AF culture group was subdivided according to AF interleukin-6 concentration. Logistic regression was used to examine the associations between vaginal cytokines and flora and AF infection or elevated AF interleukin-6.. The vaginal interleukin-8 concentration and neutrophil count were significantly higher with both AF infection and elevated concentrations of AF interleukin-6 and interleukin-8. The vaginal interleukin-6 concentration was not associated with AF infection or high concentration of AF cytokines. Amniotic fluid infection was associated with bacterial vaginosis or intermediate vaginal flora by Gram stain, absence of hydrogen peroxide-producing Lactobacillus, and presence of vaginal Bacteroides ureolyticus and Fusobacterium. Vaginal interleukin-8 levels greater than 30 ng/mL had 80% sensitivity and a positive predictive value of 35%, and an abnormal vaginal Gram stain (more than five neutrophils per 400x field, bacterial vaginosis species, or intermediate flora) had 90% sensitivity and a positive predictive value of 27% to detect AF infection or elevated AF interleukin-6.. A high vaginal interleukin-8 concentration, abnormal vaginal Gram stain, absent hydrogen peroxide-producing Lactobacillus, and anaerobic vaginal flora were strongly associated with AF infection among women in preterm labor.

Topics: Adult; Bacteriological Techniques; Chorioamnionitis; Female; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Neutrophils; Obstetric Labor, Premature; Pregnancy; Vagina; Vaginosis, Bacterial

Fetal intrauterine exposure to proinflammatory cytokines present in amniotic fluid has been associated with an increased risk of chronic lung disease. However, the impact of histologically confirmed chorioamnionitis on the fetal lung has not yet been elucidated. We therefore investigated cellular immune response, cell proliferation, and messenger ribonucleic acid cytokine expression in fetal pulmonary tissue in the presence or absence of chorioamnionitis.. Serial tissue sections were obtained from 27 fetuses at the time of autopsy. Three mothers had received antibiotics for treatment of clinical chorioamnionitis before abortion. Immunohistochemical staining of lung tissue comprised lineage-specific markers (CD68(+), CD3(+), neutrophil elastase). Positively stained cells were evaluated with a graticule, and cells per 5 mm(2) were counted. We undertook in situ hybridization to assess the expression of interleukin 8 messenger ribonucleic acid in the fetal lung.. Seven of 27 fetuses had been exposed to chorioamnionitis. Fetal lungs showed a marked increase in the presence of histologically confirmed chorioamnionitis in densities of CD68(+) macrophages (68 vs 9.5 cells/5 mm(2), median group vs control group; P =.02) and lymphocytes (7 vs 2.5 cells/5 mm(2), median chorioamnionitis vs control group; P =.05) and a similar but lesser increase in neutrophil density (16 vs 4 cells/5 mm(2); difference not significant). Interleukin 8 messenger ribonucleic acid was expressed in 4 of 6 tissue specimens investigated in the chorioamnionitis group. Exposure to chorioamnionitis resulted in interleukin 8 messenger ribonucleic acid expression 7-fold higher than in the nonchorioamnionitis group; however, this difference did not achieve statistical significance.. Chorioamnionitis was associated with an intrauterine inflammatory response of the fetal lung characterized by a severe infiltration of macrophages, neutrophils, and lymphocytes and also by an increased expression of interleukin 8 messenger ribonucleic acid.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; CD3 Complex; Chorioamnionitis; Female; Fetal Death; Fetal Diseases; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-8; Leukocyte Elastase; Lung; Lung Diseases; Lymphocytes; Macrophages; Neutrophils; Placenta; Pregnancy; RNA, Messenger

Intraamniotic endotoxin causes chorioamnionitis, which is followed by improved fetal lung function after 4 d in fetal sheep. We evaluated 0.1 mg, 1 mg, 4 mg, and 10 mg endotoxin for inflammation and lung maturation effects after 7 d. Four and 10 mg endotoxin caused similar lung maturation and inflammation in the lung and chorioamnion. The number of neutrophils in cord blood and the inflammatory cells in alveolar lavage and fetal lung tissue increased in a dose-dependent manner. Lower endotoxin doses induced indicators of chorioamnionitis, lung and systemic inflammation without inducing lung maturation. Therefore, some degree of inflammation can occur without subsequent lung maturation. The inflammatory changes caused by 4 mg endotoxin were assessed after 5 h, 24 h, 72 h, and 7 d to discern local versus systemic inflammation after intraamniotic endotoxin. At 5 h active inflammatory cells were in the airways producing hydrogen peroxide, and interleukin-6 and -8 were increased in the cord blood indicating both lung and systemic responses. Cells recruited into the amniotic fluid produced proinflammatory cytokine mRNA for 7 d with no cytokine mRNA in chorioamnion, lung, or spleen after 72 h. The cells in the amniotic fluid may be a source of prolonged fetal exposure to proinflammatory cytokines.

Topics: Amniotic Fluid; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Data Interpretation, Statistical; Disease Models, Animal; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Male; Neutrophils; Pregnancy; Pulmonary Surfactants; Random Allocation; Respiratory Distress Syndrome, Newborn; RNA, Messenger; Sheep; Time Factors

The purpose of our study was to compare maternal serum levels of interleukin-6, interleukin-8, tumor necrosis factor-alpha and interferon-gamma in gravidities, during spontaneous term and preterm labor and their relation to histologic chorioamnionitis.. We investigated 61 women: 10 in preterm labor, 36 in term labor and 15 healthy pregnant nonlabouring controls. Venous bloods for cytokines determinations were obtained during the first stage of labor and during routine screening tests. Titers of cytokines were measured by means of ELISA technique. All births after preterm deliveries were examined to establish histologic chorioamnionitis.. Serum levels of IL-6 and IL-8 were significantly elevated both in term (mean: IL-6: 17.5 +/- 58 pg/ml; IL-8: 148 +/- 215 pg/ml) and preterm labor (IL-6: 23 +/- 44 pg/ml; IL-8: 332 +/- 389 pg/ml) when compared to nonlabouring gravidities (IL-6: 5 +/- 7 pg/ml; IL-8: 14 +/- 11 pg/ml). IL-6 and IL-8 titers were statistically similar in term and preterm labors and in patients with and without histologic chorioamnionitis. TNF-alpha and IFN-gamma were not statistically analyzed because only a few patients had detectable serum levels of these cytokines.. Serum levels of IL-6 and IL-8 in both: term and preterm labor are elevated in comparison to nonlabouring gravidities. The elevated levels of these cytokines are not connected with coexisting chorioamnionitis.

Topics: Adult; Case-Control Studies; Chorioamnionitis; Cytokines; Female; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Labor, Obstetric; Obstetric Labor, Premature; Placenta; Pregnancy; Tumor Necrosis Factor-alpha

The aim of this study was to determine whether fetal exposure to intra-amniotic inflammation and a systemic fetal inflammatory response (funisitis) are associated with the development of cerebral palsy at the age of 3 years.. This cohort study included 123 preterm singleton newborns (gestational age at birth, /=3 years. The presence of intra-amniotic inflammation was determined by elevated amniotic fluid concentrations of proinflammatory cytokines such as interleukins 6 and 8 and by amniotic fluid white blood cell count. Cytokine concentrations were measured with sensitive and specific immunoassays. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton jelly. Cerebral palsy was diagnosed by neurologic examination at the age of 3 years.. Newborns with subsequent development of cerebral palsy had a higher rate of funisitis and were born to mothers with higher median concentrations of interleukins 6 and 8 and higher white blood cell counts in the amniotic fluid compared with newborns without subsequent development of cerebral palsy (funisitis: 75% [9/12] vs 23% [24/105]; interleukin 6: median, 18.9 ng/mL; range, 0. 02-92.5 ng/mL; vs median, 1.0 ng/mL; range, 0.01-115.2 ng/mL; interleukin 8: median, 13.0 ng/mL; range, 0.1-294.5 ng/mL; vs median, 1.2 ng/mL; range, 0.05-285.0 ng/mL; white blood cell count: median, 198 cells/mm(3); range, 0->1000 cells/mm(3); vs median, 3 cells/mm(3); range, 0-19,764 cells/mm(3); P <.01 for each). After adjustment for the gestational age at birth, the presence of funisitis and elevated concentrations of interleukins 6 and 8 in amniotic fluid significantly increased the odds of development of cerebral palsy (funisitis: odds ratio, 5.5; 95% confidence interval, 1.2-24.5; interleukin 6: odds ratio, 6.4; 95% confidence interval, 1. 3-33.0; interleukin 8: odds ratio, 5.9; 95% confidence interval, 1. 1-30.7; P <.05 for each).. Antenatal exposure to intra-amniotic inflammation and evidence of a systemic fetal inflammatory response (funisitis) are strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years.

Topics: Amniotic Fluid; Cerebral Palsy; Child, Preschool; Chorioamnionitis; Female; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Multivariate Analysis; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects

To determine whether inflammatory cytokine concentrations (Il-1 beta, Il-6, Il-8 and G-CSF) in umbilical cord blood are useful predictors of an early-onset neonatal infection.. 240 women and their newborns were enrolled in our study and umbilical cord blood samples collected from neonates (n = 240) were subjected to ELISA for Il-1 beta, Il-6, Il-8 and G-CSF. Clinical outcome of the neonates was followed and documented. Placenta histology was also available in majority of the cases (n = 195).. Early-onset neonatal infection was diagnosed in 5.4% of neonates (13/240) and placental examination showed histologic chorioamnionitis in 17.9% (35/195). Both Il-1 beta and Il-6 cord blood concentrations were elevated in association with histologic chorioamnionitis (Il-1 beta-2.7 vs. 2.1 pg/ml, p < 0.05 and Il-6 15.6 vs. 12.8 pg/ml, p < 0.005). Only Il-6 was elevated (16.0 vs. 13.2 pg/ml, p < 0.05) in neonates with early-onset bacterial infections. ROC analysis showed acceptable diagnostic performance of Il-6 in the identification of acute histologic chorioamnionitis and clinical neonatal infection.. Il-6 in umbilical cord blood seems to be a promising predictor for early-onset neonatal infections.

Topics: Chorioamnionitis; Female; Fetal Blood; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Infections; Interleukin-1; Interleukin-6; Interleukin-8; Pregnancy; ROC Curve; Sensitivity and Specificity

The number and percentage of viable vaginal polymorphonuclear leukocytes (vPMNs) are known to be increased in women who experience preterm labor. Whether those parameters may be associated with the presence of histologic chorioamnionitis (CAM) is not known.. We investigated prospectively 39 women at 26.3 +/- 6.2 weeks of gestation. The following were determined in vaginal washings: total number of vPMNs and the percent that were viable, the pH, and the concentrations of granulocyte elastase and interleukin-8 (IL-8). In addition, the white blood cell count and the serum level of C-reactive protein were determined in peripheral blood. The placenta and the umbilical cord were examined histologically with special reference to the presence of CAM. The optimal cutoff value for prediction of histologic CAM was obtained for each variable using receiver operating characteristic curves. A multivariate logistic-regression model was used to determine the independent risk factors for this disorder.. Histologic CAM was present in ten women (37.1 +/- 3.8 weeks) and absent in 29 women (38.2 +/- 1.5 weeks). The total number of vPMNs, the percent of viable vPMNs, and the IL-8 level were all significantly increased in the women with CAM, in contrast to those without CAM. When the optimal cutoff value for each of seven covariates was entered into the model, only the percent of viable vPMNs, > or = 11%, demonstrated a significant relationship with histologic CAM (odds ratio 26.9; 95% confidence interval 1.3 to 545; p < 0.05).. Women with a % viability of vPMNs of > or = 11% were at a significantly higher risk for histologic CAM. Data suggest that an influx of PMNs into the vagina occurs continuously in patients with histologic CAM.

Topics: Adult; C-Reactive Protein; Cell Survival; Chorioamnionitis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydrogen-Ion Concentration; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Logistic Models; Multivariate Analysis; Neutrophils; Placenta; Pregnancy; Prospective Studies; ROC Curve; Umbilical Cord; Vagina

Interleukin-8 (IL-8) is a chemotactic cytokine that has been implicated in the process of human parturition, including the processes of cervical ripening and rupture of fetal membranes. In this study, the in vitro release of IL-8 from human amnion, choriodecidua, and placenta tissues obtained before and after spontaneous labor onset both at term and preterm, was assessed. The effect of chorioamnionitis on IL-8 release was also established. All tissue explants examined released IL-8; however, IL-8 release from choriodecidual explants was significantly (p < 0.02) greater than that observed from amnion and placenta. Furthermore, choriodecidual IL-8 release was significantly (p < 0.001) greater from term tissues (850 +/- 134.4 ng/mg DNA, n = 18) than from preterm tissues (458 +/- 68.8 ng/mg DNA, n = 17). Spontaneous onset of labor, irrespective of the eventual mode of delivery, was not associated with any significant changes in IL-8 release from human gestational tissues compared to not-in-labor tissues, both at term and preterm. IL-8 release from gestational tissues was not significantly different in the absence or presence of chorioamnionitis. These data are in contrast to the previously reported stimulatory effects of bacterial endotoxin on IL-8 release from human gestational tissues. The data are consistent, however, with the suggestion that IL-8 release is an early event in chorioamnionitis that precedes the appearance of clinically overt symptoms.

Topics: Amnion; Chorioamnionitis; Chorion; Culture Techniques; Decidua; Extraembryonic Membranes; Female; Gestational Age; Humans; Interleukin-8; Labor, Obstetric; Placenta; Pregnancy

Amniochorion is a source of interleukin-8 during infection and inflammation. In this study we investigate the role of 2 immunoinhibitory cytokines, transforming growth factor and interleukin-10, in regulating interleukin-8 production from human fetal membranes and define their mechanism of regulation.. Amniochorion was placed in an organ explant system for 72 hours. Tissues were stimulated with lipopolysaccharide (50 ng/mL), lipopolysaccharide plus transforming growth factor-beta (50/50, 50/100), transforming growth factor-beta (50 and 100 ng/mL), lipopolysaccharide plus interleukin-10 (50/50 and 50/100), and interleukin-10 (50 and 100 ng/mL) in culture. Tissue and media samples were frozen until quantitation of interleukin-8 messenger ribonucleic acid and protein. Quantitation of messenger ribonucleic acid was performed by quantitative competitive polymerase chain reaction and protein by enzyme-linked immunoassay, respectively.. Lipopolysaccharide-stimulated tissues produced approximately 6 x 10(6) molecules per microliter of interleukin-8 messenger ribonucleic acid compared with 6 x 10(3) molecules per microliter in controls. Transforming growth factor-beta alone and lipopolysaccharide plus transforming growth factor-beta stimulation produced 6 x 10(5) and 6 x 10(4) molecules of interleukin-8 messenger ribonucleic acid per microliter, respectively. Tissues stimulated with lipopolysaccharide plus 50 ng/mL interleukin-10 produced approximately 600 molecules per microliter of interleukin-8 messenger ribonucleic acid, whereas no amplifiable messenger ribonucleic acid was detected in tissues treated with lipopolysaccharide plus 100 ng/mL interleukin-10. Tissues treated with interleukin-10 alone produced 6 x 10(3) molecules of messenger ribonucleic acid, similar to control levels. Enzyme-linked immunosorbent assay data showed similar levels of interleukin-8 peptide release from lipopolysaccharide and lipopolysaccharide plus transforming growth factor-beta-treated fetal membranes. A dose-dependent decrease in interleukin-8 peptide release was seen in tissues treated with lipopolysaccharide plus interleukin-10, whereas stimulation with transforming growth factor or interleukin-10 alone resulted in interleukin-8 peptide release similar to that of control levels.. Transforming growth factor-beta seems to have no effect on interleukin-8 protein production in the presence of an infectious agent; however, a drop in messenger ribonucleic acid levels was observed. Interleukin-10 in the presence of lipopolysaccharide showed down-regulation of interleukin-8 messenger ribonucleic acid expression and peptide production. These data suggest that fetal membrane interleukin-8 production can be controlled by interleukin-10 during an infectious process.

Topics: Amnion; Chorioamnionitis; Chorion; Dose-Response Relationship, Drug; Female; Humans; Interleukin-10; Interleukin-8; Lipopolysaccharides; Organ Culture Techniques; Polymerase Chain Reaction; Pregnancy; Transcription, Genetic; Transforming Growth Factors

To study the relationship of maternal blood and amniotic fluid cytokine levels in patients with preterm premature rupture of membrane and chorioamnionitis.. IL8 and TNF alpha levels of maternal blood and amniotic fluid were determined by 125I radioimmunoassay (RIA) and an enzyme-labeled immunosorbent assay (ELISA). Chorioamnionitis was diagnosed by fetal membrane histology.. The maternal serum IL8 levels and amniotic fluid IL8, TNF alpha levels were higher than those of controls (P < 0.05). There was significant relationship between maternal serum and amniotic fluid IL8, TNF alpha with the time of the premature rupture of membanes. The longer the time the higher the maternal serum IL8 and amniotic fluid IL8, TNF alpha; There were 13 patients with chorioamnionitis, and their maternal serum and amniotic fluid IL8, TNF alpha were higher than those of patients with non-chorioamnionitis (P < 0.01-0.05).. IL8, TNF alpha levels of maternal serum and amniotic fluid are valuable clinical indexes in identification of chorioamnionitis in patients with preterm premature rupture of membranes.

Topics: Adult; Amniotic Fluid; Chorioamnionitis; Female; Fetal Membranes, Premature Rupture; Humans; Interleukin-8; Pregnancy; Tumor Necrosis Factor-alpha

The present study examined whether maternal serum cytokine levels are useful for the diagnosis of histologic chorioamnionitis. The blood samples of 29 women who delivered preterm between 22 and 34 weeks of gestation were collected at delivery, and placentas were histopathologically examined for chorioamnionitis. The interleukin (IL) 6 titer was higher in 18 mothers with histologic chorioamnionitis (median 12.0 pg/ml, range 4.9-63.5 pg/ml) than that in 11 mothers without histologic chorioamnionitis (median 3.5 pg/ml, range 1.7-14.9 pg/ml; p < 0.0001). The C-reactive protein (CRP) titer also differed significantly between these two groups (chorioamnionitis group: median 5.2 mg/dl, range 0.1-12.3 mg/dl; no chorioamnionitis group: median 0.2 mg/dl, range 0.1-0.5 mg/dl; p = 0.0001). The IL-6 titer showed better clinical diagnostic indices and a higher odds ratio (9.78, 95% confidence interval 1.50-63.82) than did CRP (3.26, 95% confidence interval 1.22-8.67). The levels of IL-8, monocyte chemotactic and activating factor, and soluble IL-6 receptor did not differ between the two groups. These data suggest that the level of maternal serum IL-6 is more useful than other markers, including CRP, for the identification of women at risk of impending preterm labor with histologic chorioamnionitis.

Topics: Adult; Amnion; Biomarkers; C-Reactive Protein; Chorioamnionitis; Chorion; Enzyme-Linked Immunosorbent Assay; Female; Humans; Incidence; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Monocyte Chemoattractant Proteins; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Regression Analysis

The objectives of this study were 1) to evaluate interleukin-8 concentrations in cervical secretions in predicting preterm delivery, microbial invasion of the amniotic cavity and histologic chorioamnionitis in patients with preterm labor and intact membranes and 2) to compare the diagnostic value of interleukin-8 with fetal fibronectin determinations in predicting preterm delivery, microbial invasion of the amniotic cavity and histologic chorioamnionitis in patients with preterm labor and intact membranes. Interleukin-8 and fetal fibronectin were assayed in cervical secretions in 106 patients with singleton pregnancies and intact membranes admitted for preterm labor. Amniotic fluid obtained by amniocentesis was cultured and placentas (No = 43) analyzed for the presence of chorioamnionitis. The prevalence of pregnancies delivered preterm was 46.2% (49/106) and 15.09% (16/106) of amniotic fluid cultures were positive. Interleukin-8 levels in cervical secretions were significantly increased in patients who delivered preterm (p < or = 0.0001), in presence of positive amniotic fluid culture (p = 0.0016) and histological chorioamnionitis (p = 0.008) than in patients with negative findings. Receiver-operator characteristics curve analysis showed that an interleukin-8 value > 450 pg/ml is comparable to that of a fetal fibronectin value > 50 ng/ml in predicting preterm delivery (p = 0.247). Among patients who delivered preterm interleukin-8 concentrations > 860 pg/ml predicted a positive amniotic fluid culture with a sensitivity of 81.2% and a specificity 66.6%. Further, in patients who delivered preterm and had a negative amniotic fluid culture, IL-8 concentrations > 480 pg/ml predicted histological chorioamnionitis with a sensitivity 78.5% and specificity 61.5%. A positive fetal fibronectin > 50 ng/ml was not predictve of either a positive amniotic fluid culture or the presence of histological chorioamnionitis. In conclusion, increased concentrations of interleukin-8 and fetal fibronectin are associated with impending delivery and their diagnostic value seems comparable. However, interleukin-8 concentrations identify patients at risk of a positive amniotic fluid culture and the presence of histological chorioamnionitis. Measurement of interleukin-8 in cervical secretion is a non-invasive method to identify patients at risk for both preterm delivery and intrauterine infection.

Topics: Adult; Amniotic Fluid; Cervix Uteri; Chorioamnionitis; Female; Fetus; Fibronectins; Gestational Age; Humans; Interleukin-8; Obstetric Labor, Premature; Pregnancy

A large array of cytokines show high activity in amniotic fluid. Attempts have been made to quantify the concentrations or to track rising levels for diagnostic purposes when examining disturbances of the feto-maternal unit. However, the kinetics of cytokine production in the amniotic fluid are not well understood, and there is lack of knowledge about concomitant levels in fetal and maternal blood.. The presence of cytokines in fetal and placental cells was demonstrated by immunohistochemistry using mAb. Cytokines were quantified by enzymimmunoassay in amniotic fluid and fetal and maternal blood. This was done with regard to two disease states that quite frequently complicate the course of pregnancy, namely chorioamnionitis and intrauterine growth retardation. The cytokines examined were G-CSF, GM-CSF, TNF-alpha, IL-1, IL-6, and IL-8.. In chorioamnionitis, all cytokines, except GM-CSF, were elevated about 100 times in the amniotic fluid. An accompanying increase in maternal and fetal blood was only found for IL-6 and G-CSF; IL-8 was elevated in fetal blood only. Intrauterine growth retardation was characterized by elevated levels of TNF-alpha in the amniotic fluid, whereas G-CSF, GM-CSF, and IL-1 beta were significantly reduced. Immunohistochemistry showed that under normal conditions the cytokines are to be found in a characteristic distribution in certain cell types in the fetus, the placenta, and the placental bed. With rising concentrations, more cells seemed to be recruited for cytokine production, especially macrophages and decidual cells. In chorioamnionitis, fetal extramedullary granulopoiesis was augmented, and in intrauterine growth retardation, erythropoiesis as well as granulopoiesis were depressed.. Not only inflammatory disease but also intrauterine growth retardation is characterized by a changing cytokine pattern. Alterations in fetal hematopoiesis observed at postmortem examination of perinatal deaths can be correlated to changes in cytokine production within the feto-maternal unit.

Topics: Amniotic Fluid; Chorioamnionitis; Cytokines; Embryonic and Fetal Development; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Concentrations of five cytokines, GM-CSF, G-CSF, IL-1, IL-6 and IL-8, were determined within five compartments under four different conditions: at the time of a Caesarean section performed between 25 and 38 weeks' gestational age in normal pregnancy without uterine contraction (n = 12), in normal pregnancy with labour already established (n = 8), in pregnancy complicated by amniotic infection (n = 11), or under the conditions of preeclampsia with fetal intrauterine dystrophy (n = 13), cytokine concentrations were determined in fetal arterial and venous blood, in amniotic fluid, and in retroplacentally obtained maternal blood and peripheral maternal blood. With dystrophy, the concentrations of GM-CSF, G-CSF and IL-1 were about 20-50% lower (P < 0.01) in the amniotic fluid, and IL-6 and IL-8 were elevated in maternal peripheral blood (P < 0.01) but not within maternal retroplacental blood. Thus, preeclampsia/intrauterine dystrophy is characterized by reduction of some cytokines within the amniotic fluid compartment and concomitant reactive augmentations of other cytokines within the maternal and fetal organism. With amniotic fluid infection, concentrations of G-CSF, IL-6 and IL-8 were elevated in all compartments (P < 0.001) but GM-CSF and IL-1 showed a significant rise only within amniotic fluid and retroplacental maternal blood (P < 0.001), a rise that was apparently not transmitted to peripheral maternal or fetal blood. Care was taken to exclude the presence of uterine contractions in the group of controls, because this condition by itself causes severe elevation of cytokine concentrations, which are pronounced within amniotic fluid.

Topics: Amniotic Fluid; Chorioamnionitis; Cytokines; Female; Fetal Blood; Fetal Growth Retardation; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Labor, Obstetric; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Topics: Amniocentesis; Amniotic Fluid; Chorioamnionitis; Female; Gestational Age; Humans; Infant, Newborn; Interleukin-8; Obstetric Labor, Premature; Pregnancy

The goals of this study were (1) to determine immunoreactive neutrophil attractant/activating peptide-1/interleukin-8 levels in amniotic fluid from patients with preterm labor and (2) to compare neutrophil attractant/activating peptide-1/interleukin-8 levels, amniotic fluid culture, Gram stain, and the leukotaxis bioassay for their ability to predict histologic chorioamnionitis and clinical outcome.. Amniotic fluid was collected by amniocentesis from 55 patients with idiopathic preterm labor and three patients with preterm labor and clinical chorioamnionitis. Gram stain, culture (aerobic, anaerobic, and Mycoplasma species), leukotaxis bioassay, and a commercially available neutrophil attractant/activating peptide-1/interleukin-8 enzyme-linked immunosorbent assay (sensitivity 1 ng/ml) were performed on the amniotic fluid samples. Placentas and chorionic membranes were evaluated for evidence of histologic chorioamnionitis in patients delivered preterm.. All patients with detectable leukoattractants by the leukotaxis bioassay had neutrophil attractant/activating peptide-1/interleukin-8 levels above the threshold of the assay. The presence of amniotic fluid neutrophil attractant/activating peptide-1/interleukin-8 is a more sensitive marker for histologic chorioamnionitis and delivery before 34 weeks than is amniotic fluid culture (100% vs 59%, p < 0.01; and 95% vs 56%, p < 0.01, respectively). Also, of patients in idiopathic preterm labor those without amniotic fluid leukoattractants (group 1) had the lowest amniotic fluid levels, followed by patients with amniotic fluid leukoattractants and a negative culture (group 2) and patients with amniotic fluid leukoattractants and a positive culture (group 3) who had the highest levels (group 1 vs group 2, p < 0.001; group 2 vs group 3, p < 0.01).. Amniotic fluid neutrophil attractant/activating peptide-1/interleukin-8, like the leukotaxis assay, is an accurate antepartum predictor of histologic chorioamnionitis and subsequent early delivery in patients with preterm onset of labor. This study supports the role of neutrophil attractant/activating peptide-1/interleukin-8 in the recruitment of neutrophils into chorionic membranes and placenta during developing intrauterine infection.

Topics: Amniocentesis; Amniotic Fluid; Biological Assay; Chemotactic Factors; Chemotaxis, Leukocyte; Chorioamnionitis; Female; Humans; Interleukin-8; Obstetric Labor, Premature; Predictive Value of Tests; Pregnancy; Ureaplasma urealyticum

We measured the amniotic fluid Interleukin-8 (AF IL-8) levels of 80 women to see whether or not AF IL-8 levels were of value in the diagnosis of intraamniotic infection. Of twelve patients developing conventional signs of infection, 9 had an AF IL-8 concentration above 10,000 pg/ml serum. In two patients, whose baby had a serious neonatal infection, AF IL-8 concentration also exceeded 10,000 pg/ml. Only one out of 66 apparently uninfected patients had an AF IL-8 level above 10,000 pg/ml. We therefore suggest that measuring the AF IL-8 levels is of value in cases of suspected intraamniotic infection.

Topics: Amniocentesis; Amniotic Fluid; C-Reactive Protein; Cesarean Section; Chorioamnionitis; Diagnosis, Differential; Female; Gestational Age; Humans; Infant, Newborn; Interleukin-8; Obstetric Labor, Premature; Pregnancy; Reference Values

IL-8 is a chemotactic and activating cytokine for neutrophils which eliminate invading bacteria by releasing bactericidal metabolites. Cord blood mononuclear cells (CBMCs) obtained from neonates born to mothers with chorioamnionitis actively produced a significantly higher amount of IL-8 than those of neonates without chorioamnionitis, suggesting that the mononuclear cells of fetuses with chorioamnionitis had been activated in utero. As lipopolysaccharide (LPS) can often be detected in the uteroplacental space in chorioamnionitis, the LPS-mediated activation mechanism of neonatal mononuclear cells was analyzed in vitro to produce IL-8. Neonatal mononuclear cells stimulated with LPS increased IL-8 production in a time- and dose-dependent manner. The ability of term or preterm neonatal mononuclear cells to produce IL-8 was comparable with that of adult (maternal) mononuclear cells, suggesting functional maturity of the neonatal or fetal mononuclear cells to produce IL-8. However, IL-8 production by neonatal CBMCs was down-regulated by dexamethasone, a glucocorticoid which is clinically administered to mothers to promote fetal lung maturity in preterm delivery. Our present study revealed a regulatory mechanism of fetal IL-8 production, suggesting that functionally mature fetal mononuclear cells produce IL-8 in response to LPS in chorioamnionitis and activate the fetal defense mechanism against infection.

Topics: Cells, Cultured; Chorioamnionitis; Dexamethasone; Dose-Response Relationship, Immunologic; Female; Fetal Blood; Gene Expression Regulation; Humans; Infant, Newborn; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Pregnancy; Time Factors

Interleukin-8 (IL-8) exerts unique chemotactic and activating activity on neutrophils. To address the significance of IL-8 in the fetoplacental unit during pregnancy, we cultured human placental explants that had been obtained by vaginal delivery, Caesarean section, or artificial abortion and then measured the IL-8 titer in the culture supernatants by enzyme immunoassay (EIA). Chorionic tissue from the first trimester produced a significant amount of IL-8 (2.2 +/- 0.4 ng/ml/10 mg, n = 5), while placentae in the second trimester (8.3 +/- 1.6 ng/ml/10 mg, n = 7) or at term (9.2 +/- 0.7 ng/ml/10 mg, n = 29) produced significantly higher amounts of IL-8. The presence or absence of labor did not affect the amount of placental IL-8 production. However, placentae with chorioamnionitis (25.2 +/- 1.6 ng/ml/10 mg, n = 9) showed significantly higher IL-8 production than those without chorioamnionitis (p less than 0.0001). Northern blot analysis of IL-8 mRNA expression demonstrated a constant level during pregnancy with or without chorioamnionitis, indicating the possibility that the major site of regulation of IL-8 synthesis in the placenta is posttranscriptional. Immunohistochemical analysis of first and third trimester placental tissues with rabbit anti-IL-8 antibody revealed the IL-8 producing cells to be trophoblasts and macrophage-like cells. IL-8 produced by the placental cells might contribute to potentiation of the immunocompetence of placental cells against bacteria invading the fetoplacental unit.

Topics: Blotting, Northern; Cells, Cultured; Chorioamnionitis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Interleukin-8; Placenta; Pregnancy; RNA, Messenger; Trophoblasts

Interleukin-8 (IL-8) exerts chemotactic activity on neutrophils at inflammatory sites to eliminate invading bacteria. To investigate whether the preterm fetus with chorioamnionitis produces IL-8, the titers of IL-8 were examined in sera of babies with (n = 38) and without chorioamnionitis (n = 34) using an EIA kit specific for IL-8. The infected babies had a significantly higher IL-8 titer than those not infected at 22-36 gestational weeks. The IL-8 titer was increased even in the mild histologic stage of chorioamnionitis and became much higher in the more severe stage. The IL-8 elevation, however, was remarkably suppressed by infusion of a steroid into the mother to promote fetal lung maturation. This retrospective study demonstrated that titration of IL-8 in cord serum is a more useful marker for the early detection of chorioamnionitis, because of its higher sensitivity and specificity, than conventional markers such as C-reactive protein.

Topics: Anti-Bacterial Agents; Betamethasone; Chorioamnionitis; Female; Fetal Blood; Fetal Membranes, Premature Rupture; Fetal Organ Maturity; Humans; Infant, Newborn; Interleukin-8; Lung; Obstetric Labor, Premature; Pregnancy; Retrospective Studies; Sensitivity and Specificity