RESUMO
Preterm birth is the major cause of neonatal mortality and morbidity, and bacterial infections that ascend from the lower female reproductive tract are the most common route of uterine infection leading to preterm birth. The uterus and growing fetus are protected from ascending infection by the cervix, which controls and limits microbial access by the production of mucus, cytokines, and antimicrobial peptides. If this barrier is compromised, bacteria may enter the uterine cavity, leading to preterm birth. Using a mouse model, we demonstrate, to our knowledge for the first time, that viral infection of the cervix during pregnancy reduces the capacity of the female reproductive tract to prevent bacterial infection of the uterus. This is due to differences in susceptibility of the cervix to infection by virus during pregnancy and the associated changes in TLR and antimicrobial peptide expression and function. We suggest that preterm labor is a polymicrobial disease, which requires a multifactorial approach for its prevention and treatment.
Assuntos
Infecções Bacterianas/imunologia , Colo do Útero/imunologia , Infecções por Herpesviridae/imunologia , Doenças do Colo do Útero/virologia , Doenças Uterinas/imunologia , Animais , Infecções Bacterianas/microbiologia , Células Cultivadas , Colo do Útero/microbiologia , Colo do Útero/virologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Hormônios Esteroides Gonadais/fisiologia , Infecções por Herpesviridae/virologia , Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Nascimento Prematuro/etiologia , Receptores Toll-Like/metabolismo , Infecções por Ureaplasma/imunologia , Infecções por Ureaplasma/microbiologia , Doenças do Colo do Útero/imunologia , Doenças Uterinas/microbiologia , Doenças Uterinas/virologiaRESUMO
The reported prevalence of antiphospholipid antibodies in women with a chief complaint of pregnancy loss varies, as does the risk of adverse outcomes in subsequent pregnancies. Our objectives were to assess the prevalence of antiphospholipid antibodies meeting revised Sapporo thresholds among women presenting with a chief complaint of pregnancy loss and risks in subsequent pregnancies for these women. We examined a retrospective cohort of patients presenting with a chief complaint of pregnancy loss between 2003 and 2012. Antiphospholipid antibodies were assessed at the providers' discretion, and patients were considered positive if they met the revised Sapporo criteria. Patient data were obtained by review of the medical records. 338/390 women (86.7%) presented with a chief complaint of pregnancy loss and had testing for antiphospholipid antibodies. 19/338 women (5.6%) persistently tested positive for at least one antiphospholipid antibody. Seven women who tested positive had isolated recurrent early pregnancy loss ≤10 weeks, and 12 women who tested positive had venous thromboembolism (VTE), systemic lupus erythematosus (SLE), delivery <34 weeks for pre-eclampsia, and/or placental insufficiency, or fetal demise >10 weeks. Subsequent pregnancy outcomes were available for 13 patients. Compared with women with recurrent early pregnancy loss alone, subsequent obstetric morbidity was significantly more likely in those patients with a history of SLE and/or VTE (p=0.048). We conclude that the prevalence of positive antiphospholipid antibodies in women with a chief complaint of pregnancy loss and without autoimmune disease or prior thrombosis is low and that among these women, subsequent pregnancy outcomes are largely favorable.
Assuntos
Aborto Espontâneo/sangue , Anticorpos Antifosfolipídeos/sangue , Aborto Espontâneo/imunologia , Adulto , Anticorpos Antifosfolipídeos/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Gravidez , Prevalência , Estudos Retrospectivos , Tromboembolia Venosa/sangue , Tromboembolia Venosa/imunologiaRESUMO
Embryo implantation, which is an absolute requirement for reproduction, starts with blastocyst apposition to the uterine endometrium, followed by attachment to the endometrial surface epithelium. Recent clinical studies reported an increase in implantation and pregnancy rates among women receiving intrauterine human chorionic gonadotropin (hCG) prior to embryo transfer suggesting that, at least in some cases, female infertility is a result of inadequate secretion of hCG. In this study, we characterized the effect of hCG on trophoblast-epithelial interaction by further developing our recently described in vitro model of implantation. Here, we confirmed hCG increased attachment of trophoblast to epithelial cells, using a single-cell trophoblast-epithelial coculture system in addition to a blastocyst-like spheroid-epithelial coculture system. Furthermore, we discovered that the source and concentration was pivotal; the first preparation of hCG affected 2 molecules related to implantation, MUC16 and osteopontin, while the second preparation required additional cytokines to mimic the effects. Using this system, we can develop a comprehensive knowledge of the cellular and gene targets of hCG and other factors involved in embryo apposition and implantation and potentially increase the number of therapeutic targets for subfertile patients.
Assuntos
Gonadotropina Coriônica/farmacologia , Implantação do Embrião/fisiologia , Epitélio/metabolismo , Trofoblastos/metabolismo , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Técnicas de Cocultura , Implantação do Embrião/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Feminino , Humanos , Trofoblastos/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
PROBLEM: Implantation remains the rate-limiting step for the success of in vitro fertilization. Appropriate models to study the molecular aspects of human implantation are necessary in order to improve fertility. METHODS: First trimester trophoblast cells are differentiated into blastocyst-like spheroids (BLS) by culturing them in low attachment plates. Immortalized human endometrial stromal cells and epithelial cells (ECC-1) were stably transfected with GFP or tdTomato. Co-culture experiments were monitored using Volocity imaging analysis system. RESULTS: This method demonstrates attachment and invasion of BLS, formed by trophoblast cells, into stromal cells, but not to uterine epithelial cells. CONCLUSION: We have developed an in vitro model of uterine implantation. The manipulation of this system allows for dual color monitoring of the cells over time. Additionally, specific compounds can be added to the culture media to test how this may affect implantation and invasion. This model is a helpful tool in understanding the complexity of human implantation.