Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro
Ano de defesa: | 2015 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
|
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Farmacologia
|
Departamento: |
Farmacologia
|
País: |
BR
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/3854 |
Resumo: | The mechanisms involved in human parturition, and the molecular changes that occur during the transition from pregnancy and birth are not completely elucidated. Endogenous or administered prostaglandins, including the PGE1 and PGE2, are related to contractile activity and cervical ripening, playing an important role on labor. Due to maternal or fetal causes, some pregnancies require labor induction. In many cases, prostaglandins, including Dinoprostone (PGE2) and Misoprostol (PGE1 analog), are used for labor induction. However, the response to labor induction is variable, and the reasons why this occurs are unknown. Once delivery also involves modulation of oxidative metabolism, that can be potentially affected by administered drugs, in the present study, we analyzed prostaglandin E2 receptor (EP1, EP2, EP3 and EP4) gene expression of myometrial and cervical cells, in vivo and in vitro, as well as oxidative markers in myometrial cells exposed in vitro to different concentrations of Misoprostol. In both studies, tissue biopsies were obtained from pregnant women at term. In the in vivo study, from women with spontaneous deliveries or Dinoprostone induced labors, responsive or non-responsive to labor induction, and in the in vitro study, from women with spontaneous and non-spontaneous labors, these induced with misoprostol. Gene expression was analyzed by qtRT-PCR and oxidative biomarkers by spectrophotometric and fluorimetric analysis. The results obtained from the in vivo study showed a concurrent and antagonic regulation of EP1 and EP3 mRNA expression in cervical and myometrial tissues in pregnant women at term in Dinoprostone induced labors. EP1 mRNA was upregulated in the cervical tissue of women who did not respond to Dinoprostone induction. In addition, in the myometrium, significantly higher levels of EP3 mRNA were observed in women treated with Dinoprostone, independent of their responsiveness, indicating a possible regulation of the EP3 gene at a transcriptional level. In vitro analysis revealed that myometrial cells derived from women with spontaneous labors showed greater capacity for misoprostol genomic response, since an overexpression of genes associated with muscle contraction (EP1 and EP3) was observed. In addition, Misoprostol was able to differentially modulate two important oxidative metabolism markers (protein carbonylation and lipid peroxidation). However, this effect was dependent on cells source (whether obtained from spontaneous or non-spontaneous labors) and drug concentration. The results suggest that, in term pregnant women, there is modulation of the PGE2 receptors genes in myometrial and cervical tissues in Dinoprostone or Misoprostol-induced labors, and that the EPs have an important role in the success of spontaneous delivery and in the pharmacological response to PGE1 analog administration. Addicionally, oxidative metabolism also seems to play an important role in the parturition process, requiring further studies to define its real function in this process. |
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2016-03-312016-03-312015-09-18KONOPKA, Cristine Kolling. PROSTAGLANDIN E2 RECEPTORS GENE MODULATION IN MYOMETRIAL AND CERVICAL CELLS OF PROSTAGLANDIN INDUCED LABOR: AN IN VIVO AND IN VITRO STUDY. 2015. 109 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015.http://repositorio.ufsm.br/handle/1/3854The mechanisms involved in human parturition, and the molecular changes that occur during the transition from pregnancy and birth are not completely elucidated. Endogenous or administered prostaglandins, including the PGE1 and PGE2, are related to contractile activity and cervical ripening, playing an important role on labor. Due to maternal or fetal causes, some pregnancies require labor induction. In many cases, prostaglandins, including Dinoprostone (PGE2) and Misoprostol (PGE1 analog), are used for labor induction. However, the response to labor induction is variable, and the reasons why this occurs are unknown. Once delivery also involves modulation of oxidative metabolism, that can be potentially affected by administered drugs, in the present study, we analyzed prostaglandin E2 receptor (EP1, EP2, EP3 and EP4) gene expression of myometrial and cervical cells, in vivo and in vitro, as well as oxidative markers in myometrial cells exposed in vitro to different concentrations of Misoprostol. In both studies, tissue biopsies were obtained from pregnant women at term. In the in vivo study, from women with spontaneous deliveries or Dinoprostone induced labors, responsive or non-responsive to labor induction, and in the in vitro study, from women with spontaneous and non-spontaneous labors, these induced with misoprostol. Gene expression was analyzed by qtRT-PCR and oxidative biomarkers by spectrophotometric and fluorimetric analysis. The results obtained from the in vivo study showed a concurrent and antagonic regulation of EP1 and EP3 mRNA expression in cervical and myometrial tissues in pregnant women at term in Dinoprostone induced labors. EP1 mRNA was upregulated in the cervical tissue of women who did not respond to Dinoprostone induction. In addition, in the myometrium, significantly higher levels of EP3 mRNA were observed in women treated with Dinoprostone, independent of their responsiveness, indicating a possible regulation of the EP3 gene at a transcriptional level. In vitro analysis revealed that myometrial cells derived from women with spontaneous labors showed greater capacity for misoprostol genomic response, since an overexpression of genes associated with muscle contraction (EP1 and EP3) was observed. In addition, Misoprostol was able to differentially modulate two important oxidative metabolism markers (protein carbonylation and lipid peroxidation). However, this effect was dependent on cells source (whether obtained from spontaneous or non-spontaneous labors) and drug concentration. The results suggest that, in term pregnant women, there is modulation of the PGE2 receptors genes in myometrial and cervical tissues in Dinoprostone or Misoprostol-induced labors, and that the EPs have an important role in the success of spontaneous delivery and in the pharmacological response to PGE1 analog administration. Addicionally, oxidative metabolism also seems to play an important role in the parturition process, requiring further studies to define its real function in this process.Os mecanismos pelo qual a parturição humana é iniciada espontaneamente e as mudanças moleculares que ocorrem durante a transição entre a gestação e o parto não são completamente elucidados. Um dos principais fatores envolvidos são as prostaglandinas, endógenas ou administradas, entre elas a PGE1 e PGE2, que estão relacionadas à atividade contrátil e ao amadurecimento cervical. Em casos de necessidade de antecipação do nascimento, as prostaglandinas, entre elas a Dinoprostona (PGE2) e o Misoprostol (análogo da PGE1), são utilizadas para indução do parto. Entretanto, a resposta à indução do parto é variável e os motivos pelos quais isto ocorre é desconhecido. Uma vez que o parto também envolve modulação do metabolismo oxidativo, que pode ser potencialmente afetado por ação de fármacos, no presente estudo analisamos a expressão dos genes dos receptores de prostaglandina E2 (EP1, EP2, EP3 e EP4) em células miometriais e cervicais, in vivo e in vitro, bem como marcadores oxidativos em células miometriais expostas in vitro a diferentes concentrações de Misoprostol. Para a realização dos dois estudos, foram obtidas biópsias teciduais em parturientes a termo; no estudo in vivo, em mulheres com parto espontâneo, responsivas e não responsivas à indução do parto com Dinoprostona e no estudo in vitro, em mulheres com partos espontâneos e não espontâneos, estes induzidos com Misoprostol. A expressão gênica foi analisada através de qtRT-PCR e no estudo in vitro, além das análises da modulação gênica, foram conduzidas análises complementares de biomarcadores oxidativos, através de ensaios espectrofotométricos e fluorimétricos. Nos resultados obtidos a partir do estudo in vivo, observou-se regulação concomitante e antagônica da expressão do mRNA de EP1 e EP3 nos tecidos cervical e miometrial em gestantes a termo com partos induzidos com Dinoprostona. O mRNA do EP1 foi superexpresso no tecido cervical de mulheres que não responderam à indução com Dinoprostona. Além disso, no miométrio, níveis significativamente mais elevados de mRNA do EP3 foram observados em mulheres tratadas com Dinoprostona, independente da sua capacidade de resposta, indicando uma possível regulação da expressão do gene EP3 a nível transcricional. A análise in vitro evidenciou que as células miometriais oriundas de mulheres com parto espontâneo apresentaram maior capacidade de resposta genômica ao Misoprostol, uma vez que uma superexpressão dos genes relacionados com a contração muscular (EP1 e EP3) foi observada. Adicionalmente, o Misoprostol foi capaz de modular diferencialmente dois importantes marcadores do metabolismo oxidativo (lipoperoxidação e carbonilação de proteínas). Porém, este efeito foi dependente da origem das células (se obtida de partos espontâneos ou não espontâneos) e da concentração do fármaco. Os resultados obtidos sugerem que, em gestantes a termo, existe modulação dos genes dos receptores de PGE2 no miométrio e colo em partos induzidos com Dinopostona ou Misoprostrol, e que os EPs possuem um papel relevante no sucesso do parto espontâneo e na resposta farmacológica aos análogos a prostaglandina E1. Adicionalmente, o metabolismo oxidativo também parece desempenhar um papel importante no processo da parturição, necessitando de estudos complementares para esclarecimento da sua real função neste processo.application/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em FarmacologiaUFSMBRFarmacologiaProstaglandinaDinoprostonaMisoprostolReceptor de PGE2ÚteroGestaçãoPartoMiométrioCérviceProstaglandinDinoprostoneMisoprostolPGE2 receptorUterusPregnancyLaborMyometriumCervixCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAModulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitroProstaglandin E2 receptors gene modulation in myometrial and cervical cells of prostaglandin induced labor: an in vivo and in vitro studyinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisCruz, Ivana Beatrice Mânica dahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4790333D6Goncalves, Paulo Bayard Diashttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4781845H4Santos, Roberto Christ Viannahttp://lattes.cnpq.br/9176719594431835Premaor, Melissa Orlandinhttp://lattes.cnpq.br/1919693261808995Gasperin, Bernardo Garzierahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757171E8http://lattes.cnpq.br/0307121790616384Konopka, Cristine Kolling2010000000004003003003005003003000b5fcfe0-b017-4163-80e2-17c110fbcf01cbb1c311-1aeb-4a7e-a1b0-2acd98be0fe7702c6e56-abeb-4325-95c4-604f84047af6d8266a15-f797-4b1b-820c-51f0bf7957874edbaa05-7afc-4d42-811a-e81695fe99cf337179da-fa11-4436-a3c1-f4c9016278edinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALKONOPKA, CRISTINE KOLLING.pdfapplication/pdf1654024http://repositorio.ufsm.br/bitstream/1/3854/1/KONOPKA%2c%20CRISTINE%20KOLLING.pdf90518d1e4ac4ee23fd5c20718525802aMD51TEXTKONOPKA, CRISTINE KOLLING.pdf.txtKONOPKA, CRISTINE KOLLING.pdf.txtExtracted texttext/plain226146http://repositorio.ufsm.br/bitstream/1/3854/2/KONOPKA%2c%20CRISTINE%20KOLLING.pdf.txt4c6c7c588e413915b3953a36eb307787MD52THUMBNAILKONOPKA, CRISTINE KOLLING.pdf.jpgKONOPKA, CRISTINE KOLLING.pdf.jpgIM Thumbnailimage/jpeg5691http://repositorio.ufsm.br/bitstream/1/3854/3/KONOPKA%2c%20CRISTINE%20KOLLING.pdf.jpg8052746c890663de02f1047d3001abd1MD531/38542022-01-06 15:27:40.053oai:repositorio.ufsm.br:1/3854Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-01-06T18:27:40Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
dc.title.alternative.eng.fl_str_mv |
Prostaglandin E2 receptors gene modulation in myometrial and cervical cells of prostaglandin induced labor: an in vivo and in vitro study |
title |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
spellingShingle |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro Konopka, Cristine Kolling Prostaglandina Dinoprostona Misoprostol Receptor de PGE2 Útero Gestação Parto Miométrio Cérvice Prostaglandin Dinoprostone Misoprostol PGE2 receptor Uterus Pregnancy Labor Myometrium Cervix CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
title_full |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
title_fullStr |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
title_full_unstemmed |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
title_sort |
Modulação gênica dos receptores de prostaglandina E2 em células miometriais e cervicais em partos induzidos com prostaglandinas: estudo in vivo e in vitro |
author |
Konopka, Cristine Kolling |
author_facet |
Konopka, Cristine Kolling |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Cruz, Ivana Beatrice Mânica da |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4790333D6 |
dc.contributor.referee1.fl_str_mv |
Goncalves, Paulo Bayard Dias |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4781845H4 |
dc.contributor.referee2.fl_str_mv |
Santos, Roberto Christ Vianna |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/9176719594431835 |
dc.contributor.referee3.fl_str_mv |
Premaor, Melissa Orlandin |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/1919693261808995 |
dc.contributor.referee4.fl_str_mv |
Gasperin, Bernardo Garziera |
dc.contributor.referee4Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757171E8 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/0307121790616384 |
dc.contributor.author.fl_str_mv |
Konopka, Cristine Kolling |
contributor_str_mv |
Cruz, Ivana Beatrice Mânica da Goncalves, Paulo Bayard Dias Santos, Roberto Christ Vianna Premaor, Melissa Orlandin Gasperin, Bernardo Garziera |
dc.subject.por.fl_str_mv |
Prostaglandina Dinoprostona Misoprostol Receptor de PGE2 Útero Gestação Parto Miométrio Cérvice |
topic |
Prostaglandina Dinoprostona Misoprostol Receptor de PGE2 Útero Gestação Parto Miométrio Cérvice Prostaglandin Dinoprostone Misoprostol PGE2 receptor Uterus Pregnancy Labor Myometrium Cervix CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Prostaglandin Dinoprostone Misoprostol PGE2 receptor Uterus Pregnancy Labor Myometrium Cervix |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
The mechanisms involved in human parturition, and the molecular changes that occur during the transition from pregnancy and birth are not completely elucidated. Endogenous or administered prostaglandins, including the PGE1 and PGE2, are related to contractile activity and cervical ripening, playing an important role on labor. Due to maternal or fetal causes, some pregnancies require labor induction. In many cases, prostaglandins, including Dinoprostone (PGE2) and Misoprostol (PGE1 analog), are used for labor induction. However, the response to labor induction is variable, and the reasons why this occurs are unknown. Once delivery also involves modulation of oxidative metabolism, that can be potentially affected by administered drugs, in the present study, we analyzed prostaglandin E2 receptor (EP1, EP2, EP3 and EP4) gene expression of myometrial and cervical cells, in vivo and in vitro, as well as oxidative markers in myometrial cells exposed in vitro to different concentrations of Misoprostol. In both studies, tissue biopsies were obtained from pregnant women at term. In the in vivo study, from women with spontaneous deliveries or Dinoprostone induced labors, responsive or non-responsive to labor induction, and in the in vitro study, from women with spontaneous and non-spontaneous labors, these induced with misoprostol. Gene expression was analyzed by qtRT-PCR and oxidative biomarkers by spectrophotometric and fluorimetric analysis. The results obtained from the in vivo study showed a concurrent and antagonic regulation of EP1 and EP3 mRNA expression in cervical and myometrial tissues in pregnant women at term in Dinoprostone induced labors. EP1 mRNA was upregulated in the cervical tissue of women who did not respond to Dinoprostone induction. In addition, in the myometrium, significantly higher levels of EP3 mRNA were observed in women treated with Dinoprostone, independent of their responsiveness, indicating a possible regulation of the EP3 gene at a transcriptional level. In vitro analysis revealed that myometrial cells derived from women with spontaneous labors showed greater capacity for misoprostol genomic response, since an overexpression of genes associated with muscle contraction (EP1 and EP3) was observed. In addition, Misoprostol was able to differentially modulate two important oxidative metabolism markers (protein carbonylation and lipid peroxidation). However, this effect was dependent on cells source (whether obtained from spontaneous or non-spontaneous labors) and drug concentration. The results suggest that, in term pregnant women, there is modulation of the PGE2 receptors genes in myometrial and cervical tissues in Dinoprostone or Misoprostol-induced labors, and that the EPs have an important role in the success of spontaneous delivery and in the pharmacological response to PGE1 analog administration. Addicionally, oxidative metabolism also seems to play an important role in the parturition process, requiring further studies to define its real function in this process. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-09-18 |
dc.date.accessioned.fl_str_mv |
2016-03-31 |
dc.date.available.fl_str_mv |
2016-03-31 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
KONOPKA, Cristine Kolling. PROSTAGLANDIN E2 RECEPTORS GENE MODULATION IN MYOMETRIAL AND CERVICAL CELLS OF PROSTAGLANDIN INDUCED LABOR: AN IN VIVO AND IN VITRO STUDY. 2015. 109 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/3854 |
identifier_str_mv |
KONOPKA, Cristine Kolling. PROSTAGLANDIN E2 RECEPTORS GENE MODULATION IN MYOMETRIAL AND CERVICAL CELLS OF PROSTAGLANDIN INDUCED LABOR: AN IN VIVO AND IN VITRO STUDY. 2015. 109 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
url |
http://repositorio.ufsm.br/handle/1/3854 |
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Programa de Pós-Graduação em Farmacologia |
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UFSM |
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Farmacologia |
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Universidade Federal de Santa Maria |
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