RESUMO
In indicated preterm births such a Gestational Diabetes Mellitus (GDM), little is known about the role of the amnion membranes. Investigating the role of amnion membrane inflammation in response GDM may suggest novel pathophysiologic mechanisms. We hypothesize that increased GDM inflammatory mediators may weaken the amnion membrane predisposing them to infection. Maternal and fetal serum and amnion membrane biopsies were collected from 20 GDM and 38 normoglycemic subjects (control) who underwent elective cesarean sections. Cytokines and adipokines were evaluated in serum and amnion culture supernatant samples. Amnion membrane biopsies from GDM and control subjects were studied: fresh frozen for RNA analysis for Toll-like receptor expression; cultured with LPS to test membrane permeability, and inflammation LPS + anti-TLR4 for testing mechanism. GDM was associated with higher fetal serum leptin (p = 0.004) and IL-10 (p = 0.04) compared to controls. Amnion membrane explants from GDM had higher levels of IL-6 (p = 0.019), and lower expression of Claudin-4 (p = 0.007) and increased permeability (p = 0.046) compared to controls. GDM membranes treated with LPS showed an increased expression of IL-10 (p = 0.013); IL-6 (p = 0.004) and TNF-α (p = 0.0005) but did not affect membrane permeability. LPS and anti-TLR4 antibody treatment reduced the production of TNF-α in controls (p = 0.03) and GDM (p = 0.007) compared to LPS alone. Fetal inflammatory response seems more balanced in GDM and does not impact membrane permeability function even with an infectious stimulus. Light fetal membrane inflammatory response may explain lack of preterm labor in GDM. Concluding, benign inflammation in the membranes may not be harmful for pregnancy maintenance.
Assuntos
Diabetes Gestacional/imunologia , Membranas Extraembrionárias/imunologia , Trabalho de Parto Prematuro/epidemiologia , Adulto , Biomarcadores/sangue , Glicemia/análise , Estudos de Casos e Controles , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/patologia , Membranas Extraembrionárias/patologia , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/diagnóstico , Inflamação/imunologia , Mediadores da Inflamação/sangue , Trabalho de Parto Prematuro/imunologia , Placenta/imunologia , Placenta/patologia , Gravidez , Índice de Gravidade de Doença , Adulto JovemRESUMO
Preterm labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) impose substantial morbimortality on mothers and newborns. Exosomes act in intercellular communication carrying molecules involved in physiopathological processes. Little is known about exosomal proteins in prematurity. Our aim was to evaluate the protein expression of hemopexin, C1 inhibitor (C1INH) and alpha-2-macroglobulin (A2M) from circulating exosomes of women with PTL and PPROM. Plasma was obtained from PTL, PPROM, Term in labor and Term out of labor (T) patients, exosomes were isolated by ultracentrifugation, then lysed and the proteins quantified. Western Blot (WB) and Nanoparticle Tracking Analysis (NTA) were performed. Data were compared by Kruskal-Wallis, unpaired T-test and one-way ANOVA. WB and NTA confirmed exosome isolation (concentration: 4.3 × 1010 particles/ml ± 1.9 × 1010). There was no difference regarding hemopexin or C1INH expression between the groups. For A2M, the fold change was significantly higher on preterm groups when compared to term groups (1.07 ± 0.30 vs. 0.42 ± 0.17, p < 0.0001). Higher levels of A2M in circulating exosomes are linked to preterm pregnancies. sEV are strong candidates to intermediate maternal-fetal communication, carrying preterm labor-related immunomodulatory proteins.
Assuntos
Exossomos/metabolismo , Ruptura Prematura de Membranas Fetais/imunologia , Ruptura Prematura de Membranas Fetais/metabolismo , Trabalho de Parto Prematuro/imunologia , Trabalho de Parto Prematuro/metabolismo , alfa 2-Macroglobulinas Associadas à Gravidez/metabolismo , Gestantes , Adulto , Proteína Inibidora do Complemento C1/metabolismo , Feminino , Ruptura Prematura de Membranas Fetais/sangue , Hemopexina/metabolismo , Humanos , Troca Materno-Fetal/imunologia , Troca Materno-Fetal/fisiologia , Trabalho de Parto Prematuro/sangue , Gravidez , Adulto JovemRESUMO
Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters' expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Malária/complicações , Trabalho de Parto Prematuro/imunologia , Placenta/patologia , Plasmodium berghei/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Malária/imunologia , Malária/parasitologia , Troca Materno-Fetal/imunologia , Camundongos , Nutrientes/metabolismo , Trabalho de Parto Prematuro/parasitologia , Trabalho de Parto Prematuro/patologia , Placenta/metabolismo , Gravidez , Xenobióticos/metabolismoRESUMO
PROBLEM: We compared the frequency of intra-amniotic infection in preterm labor (PL) with women not in labor, and correlated infection with amniotic fluid (AF) cytokines. Detailed identification of species, especially mycoplasmata, was tried to improve our understanding of the pathogenesis of PL. METHOD OF STUDY: AF from 20 women with PL and 20 controls were evaluated. Infection was detected by PCR for Mycoplasma hominis, Ureaplasma urealyticum and 16S rRNA bacterial gene, which was cloned and sequenced for bacterial identification. Interleukin (IL)-1ß, IL-6, IL-8 and tumor necrosis factor (TNF)-α levels were measured by ELISA. RESULTS: Frequency of intra-amniotic infection is higher in PL (40.0%). Sequencing-based method identified Bacteroides fragilis, Prevotella bivia and Leptotrichia amnionii, in addition to Mycoplasma species detected by PCR. AF infection correlated with increased IL-1ß and IL-6 levels. CONCLUSION: The frequency of intra-amniotic infection, especially M. hominis, in PL women who delivered with 7 days, is high and correlates with high IL-1ß and IL-6 levels, but not IL-8.
Assuntos
Líquido Amniótico/metabolismo , Bactérias Anaeróbias Gram-Negativas/fisiologia , Infecções por Bactérias Gram-Negativas/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Infecções por Mycoplasma/imunologia , Mycoplasma hominis/fisiologia , Trabalho de Parto Prematuro/imunologia , Infecções por Ureaplasma/imunologia , Ureaplasma urealyticum/fisiologia , Líquido Amniótico/imunologia , Líquido Amniótico/microbiologia , Feminino , Bactérias Anaeróbias Gram-Negativas/patogenicidade , Infecções por Bactérias Gram-Negativas/epidemiologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Interleucina-8/metabolismo , Infecções por Mycoplasma/epidemiologia , Mycoplasma hominis/patogenicidade , Trabalho de Parto Prematuro/epidemiologia , Trabalho de Parto Prematuro/microbiologia , Gravidez , Prevalência , RNA Ribossômico 16S/análise , Análise de Sequência de RNA , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Infecções por Ureaplasma/epidemiologia , Ureaplasma urealyticum/patogenicidadeRESUMO
PURPOSE: To evaluate vaginal microflora and interleukin-1ß (IL-ß), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) concentrations in the cervicovaginal fluid of a group of pregnant women in preterm labor when compared with a group of full-term pregnant women not yet in labor. METHOD: Case-control study performed in a University tertiary referral maternity in Campinas, Brazil with 45 pregnant women in preterm labor and 45 full-term pregnant women not in labor. All patients underwent speculum examination for the collection of cervicovaginal fluid. Bacterial vaginosis (BV) was diagnosed according to the criteria of Amsel and Nugent. Culture was performed for group B streptococcus (GBS) and lactobacilli, and hybrid capture assay for screening for chlamydial and gonococcal infection. Cytokine concentrations were measured using ELISA technique. Statistical analysis was performed using χ(2), Fisher's exact, and crude and adjusted odds ratios. Significance level was defined at 5%. The main outcome measures were cervicovaginal cytokines in preterm labor. RESULTS: IL-6 and IL-8 were significantly associated with preterm labor. The changes in vaginal microflora, as well as BV and GBS, were more frequent in women in preterm labor, although BV and GBS showed no statistical significance. The presence of Candida sp., absence of lactobacilli, positive screening for chlamydial and gonococcal infection and the presence of IL-1ß and TNF-α were not associated with preterm labor. CONCLUSIONS: IL-6 and IL-8 and the presence of any type of vaginal infection were the factors that were significantly associated with preterm labor.
Assuntos
Líquidos Corporais/imunologia , Citocinas/imunologia , Trabalho de Parto Prematuro/imunologia , Trabalho de Parto Prematuro/microbiologia , Complicações Infecciosas na Gravidez/microbiologia , Vagina/imunologia , Vagina/microbiologia , Adolescente , Adulto , Líquidos Corporais/química , Brasil , Estudos de Casos e Controles , Citocinas/análise , Feminino , Humanos , Inflamação/microbiologia , Interleucina-1beta/análise , Interleucina-1beta/imunologia , Interleucina-6/análise , Interleucina-6/imunologia , Interleucina-8/análise , Interleucina-8/imunologia , Gravidez , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/imunologia , Vaginose Bacteriana/diagnóstico , Adulto JovemRESUMO
Increased risk of preterm labor has been linked to cervicovaginal infection with Ureaplasma urealyticum and group B streptococci. Although various experimental models have been developed to study the role of amniochorion infection in preterm labor, they typically exclude the initial interaction between intrauterine leukocytes (recruited from decidual vessels into the avascular fetal membranes) and infecting bacteria. In this work, we ascertained whether inflammatory molecules secreted by bacterium-activated intrauterine leukocytes stimulate the amniochorion production of mediators involved in human labor. Using a two-step process beginning with placental circulating leukocytes as a proxy for intrauterine leukocytes, we found that coincubation of amniochorion explants with plasma from placental whole blood preincubated with group B streptococci resulted in a significant increase in tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 9 (MMP-9) levels in tissue. Extensive changes in the connective tissue arrangement and a decrease in collagen content demonstrated the degradation of the extracellular matrix following this treatment. In contrast, plasma from blood preconditioned with U. urealyticum induced a highly significant secretion of interleukin-1ß (IL-1ß) and prostaglandin E(2) (PGE(2)) by the amniochorion without changes in the extracellular matrix organization or content. These data demonstrate that group B streptococci induce degradation of the amniochorion as a result of MMP-9 production, probably via TNF-α, whereas U. urealyticum stimulates the secretion of PGE(2), probably via IL-1ß, potentially stimulating myometrial contraction. Our study provides novel evidence that the immunological cells circulating within the uterine microenvironment respond differentially to an infectious agent, triggering alternative molecular signaling pathways leading to human labor.
Assuntos
Âmnio/imunologia , Córion/imunologia , Leucócitos/imunologia , Trabalho de Parto Prematuro/imunologia , Streptococcus agalactiae/fisiologia , Ureaplasma urealyticum/fisiologia , Âmnio/metabolismo , Córion/metabolismo , Dinoprostona/metabolismo , Feminino , Humanos , Inflamação/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Técnicas de Cultura de Órgãos , Placenta/citologia , Placenta/imunologia , Gravidez , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
O parto pré-termo é uma das grandes intercorrências obstétricas, sendo a maior causa de morbidade e mortalidade perinatal. Dentre os diferentes fatores envolvidos no seu desencadeamento, a infecção intra-amniótica parece representar um papel central. As infecções desencadeiam resposta inflamatória nos tecidos materno e fetal, mediada pela produção de citocinas inflamatórias. As citocinas induzem a liberação de prostaglandinas, aumentando a contratilidade uterina, favorecendo a rotura das membranas fetais, a modificação e dilatação da cérvice e, finalmente, o parto pré-termo. A síntese de citocinas depende de controle genético. Diversos polimorfismos relacionados a genes humanos codificadores de citocinas são reconhecidos e associados a fenótipos de alta, média e baixa produção desses fatores. Assim sendo, a relação entre determinados genótipos e a ocorrência e/ou características de diferentes patologias tem sido investigada. Este tipo de abordagem pode contribuir para o conhecimento da patogenia, permitindo o reconhecimento de parâmetros preditivos e a definição de novas estratégias terapêuticas.
Preterm birth is a major obstetric incident and one of the main causes of perinatal mortality and morbidity. Among the different factors involved in its unleashing, intra-amniotic infection seems to play a central role. The infections unleash inflammatory response in both maternal and fetal tissues, mediated by the production of inflammatory cytokines. They also lead to liberation of prostaglandin, which increases myometrial contractility, favoring the rupture of fetal membrane, alteration and dilation of the cervix and, finally, preterm birth. The production of cytokines depends on genetic control. Many polymorphisms related to human genes that codify cytokines are recognized and associated with phenotypes of high, medium and low production of such factors. Thus, the relation between certain genotypes and the occurrence and/or characteristics of several pathologies has been the focus of investigations. This approach may contribute with a better understanding of the pathogenesis, allowing the identification of predictive parameters and the establishment of new intervention strategies.
Assuntos
Feminino , Gravidez , Citocinas/genética , Complicações Infecciosas na Gravidez/metabolismo , Líquido Amniótico/metabolismo , Líquido Amniótico/microbiologia , Nascimento Prematuro/genética , Nascimento Prematuro/imunologia , Nascimento Prematuro/metabolismo , Trabalho de Parto Prematuro/genética , Trabalho de Parto Prematuro/imunologia , Trabalho de Parto Prematuro/metabolismo , Componentes do Gene , Polimorfismo GenéticoRESUMO
OBJECTIVE: To investigate the association of preterm delivery with polymorphisms of IL-6, IL-10, IFN-gamma, TGFbeta1 and TNF-alpha genes. STUDY DESIGN: The study group consisted of 45 Caucasian, 81 mixed race and 13 black women with a history of preterm labor, consecutively referred. All of them had delivered before 37 weeks' gestation. The control group was composed of 56 Caucasian, 48 mixed race and 15 black women with successful pregnancy. DNA was extracted from whole blood, and cytokine genotyping was performed using the Cytokine Genotyping Tray (One-Lambda, Canoba Park, California). The polymorphisms analyzed were: TNF-alpha (-08 G --> A), IL-10 (-1082 G --> A), IL-6 (-174 G --> C), TGFbeta1 (+10 T --> C e 25 C --> G) and IFN-gamma (+874 A --> T). RESULTS: There were no differences in genotype frequencies of IL-10, TGF-beta, TNF-alpha or IL-6 polymorphisms between the groups. In the Caucasian group there was a trend toward increased frequencies of the TT genotype of IFN-gamma in controls. CONCLUSION: Preterm delivery is not associated with TNF-alpha (-308), IL-10 (-1082), IL-6 (-174), TGFbeta1 (+10 e 25) or IFN-gamma (+874) polymorphisms.
Assuntos
Citocinas/genética , Trabalho de Parto Prematuro/genética , Trabalho de Parto Prematuro/imunologia , Polimorfismo Genético/genética , Adolescente , Adulto , Feminino , Genótipo , Humanos , Interferon gama/genética , Interleucina-10/genética , Pessoa de Meia-Idade , Trabalho de Parto Prematuro/etnologia , Gravidez , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Sendo o peso da criança, ao nascer, o determinante mais importante das chances que o recém-nascido tem de sobreviver, crescer e se desenvolver saudavelmente, a prevenção do parto prematuro toma-se um importante fator de saúde pública. Evidências apontam que as infecções crônicas podem ter um papel fundamental no estabelecimento do trabalho de parto prematuro. A doença periodontal é uma reação imuno-inflamatória decorrente de uma infecção crônica causada por microrganismos gram-positivos e gram-negativos. Ela é capaz de elevar os níveis séricos de mediadores inflamatórios que, em conjunto com bacteremias e endotoxinemias transitórias, poderiam afetar o período gestacional. Assim, vários estudos têm sido dirigidos a fim de verificar o possível papel da doença periodontal como fator de risco ao parto prematuro de neonatos de baixo peso. Este artigo vem mostrar, através de uma revisão analítica da literatura, a associação entre infecção e trabalho de parto prematuro e as evidências encontradas sobre uma possível relação causal entre doença periodontal e nascimento prematuro de baixo peso. Concluiu-se que a doença periodontal é capaz de aumentar os níveis de mediadores inflamatórios associados ao trabalho de parto; que maiores níveis de periodontopatógenos podem estar relacionados ao nascimento prematuro de baixo peso; que o tratamento da doença periodontal nas mulheres grávidas, no início da gestação, parece diminuir o risco de ocorrência de nascimento prematuro de baixo peso; quanto maior a severidade da doença periodontal, maiores são as chances de NPBP