Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina
Autor(a) principal: | |
---|---|
Data de Publicação: | 2023 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/30172 |
Resumo: | The are innumerous hepatotoxic agents that can cause liver injury, but when this damage extends for long periods, it can characterize a chronic profile that makes the patient’s treatment and recuperation difficult. Chronic hepatic diseases (CHD) are a serious worldwide public health problem, which leads to high indices of morbidity and mortality. Due to the difficulties in studying CHD in human beings, experimental injury models are developed in rodents. Thioacetamide (TAA) is a hepatotoxic substance used for this purpose. Each rat, however, demonstrates individual tolerances for the TAA toxicity, as such there is no study in literature that administrates TAA by oral gavage to induce chronic hepatic injury. The nucleotide ATP and its derivatives are released during hepatic injury, acting as cellular signals for lymphocyte response. Ectonucleotidases anchored in its membrane regulate this purinergic signalization, modulating the immune response, so that therapies that affect this purinergic signalization may act as possible therapeutical targets. Besides, pentoxifylline (PTX), is an anti-inflammatory hemorheological drug that may act as a possible antifibrotic agent. In this study an in vivo experiment was made, using 30 Wistar rats, divided into four groups: Group I – Control, Group II – PTX (100mg/kg), Group III – TAA (125mg/kg) and Group IV – TAA (125mg/kg) + PTX (100mg/kg). The chronic hepatic injury occurred by the oral gavage of TAA three times a week for 12 weeks. Groups II and IV animals received PTX orally every day during the 4 last weeks. After this period, the animals were euthanized, and liver and blood were collected for lymphocyte isolation, for hemogram evaluation and serum damage markers as well. In group III animals we observed an increase in AST and a decrease in triglycerides levels in the serum. There was an increase in the total leukocyte cell count in the blood, majorly in neutrophil numbers. There was also a decrease in E-NTPDase activity in liver lymphocytes, a pro-inflammatory profile, while liver membrane ENTPDase we observed an increase in this activity, possibly due to increased ATP signalization released due to cell damage. In blood lymphocytes the ectoenzymes demonstrate increased activities for a regulated immune profile. PTX treatment did not demonstrate alterations in the serum damage markers, suggesting some level of damage reversion. Additionally, the treatment reverted the ectoenzymes activities in liver lymphocytes to physiological levels, differing from those observed in non-treated animals, while in liver membranes the E-NTPDase kept elevated for nucleotides regulation. However, PTX was inefficient to revert the low triglycerides levels in the serum but was able to modulate purinergic signalization during the chronic hepatic injury, which was efficiently induced by our proposed method. |
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2023-09-04T17:37:08Z2023-09-04T17:37:08Z2023-07-17http://repositorio.ufsm.br/handle/1/30172The are innumerous hepatotoxic agents that can cause liver injury, but when this damage extends for long periods, it can characterize a chronic profile that makes the patient’s treatment and recuperation difficult. Chronic hepatic diseases (CHD) are a serious worldwide public health problem, which leads to high indices of morbidity and mortality. Due to the difficulties in studying CHD in human beings, experimental injury models are developed in rodents. Thioacetamide (TAA) is a hepatotoxic substance used for this purpose. Each rat, however, demonstrates individual tolerances for the TAA toxicity, as such there is no study in literature that administrates TAA by oral gavage to induce chronic hepatic injury. The nucleotide ATP and its derivatives are released during hepatic injury, acting as cellular signals for lymphocyte response. Ectonucleotidases anchored in its membrane regulate this purinergic signalization, modulating the immune response, so that therapies that affect this purinergic signalization may act as possible therapeutical targets. Besides, pentoxifylline (PTX), is an anti-inflammatory hemorheological drug that may act as a possible antifibrotic agent. In this study an in vivo experiment was made, using 30 Wistar rats, divided into four groups: Group I – Control, Group II – PTX (100mg/kg), Group III – TAA (125mg/kg) and Group IV – TAA (125mg/kg) + PTX (100mg/kg). The chronic hepatic injury occurred by the oral gavage of TAA three times a week for 12 weeks. Groups II and IV animals received PTX orally every day during the 4 last weeks. After this period, the animals were euthanized, and liver and blood were collected for lymphocyte isolation, for hemogram evaluation and serum damage markers as well. In group III animals we observed an increase in AST and a decrease in triglycerides levels in the serum. There was an increase in the total leukocyte cell count in the blood, majorly in neutrophil numbers. There was also a decrease in E-NTPDase activity in liver lymphocytes, a pro-inflammatory profile, while liver membrane ENTPDase we observed an increase in this activity, possibly due to increased ATP signalization released due to cell damage. In blood lymphocytes the ectoenzymes demonstrate increased activities for a regulated immune profile. PTX treatment did not demonstrate alterations in the serum damage markers, suggesting some level of damage reversion. Additionally, the treatment reverted the ectoenzymes activities in liver lymphocytes to physiological levels, differing from those observed in non-treated animals, while in liver membranes the E-NTPDase kept elevated for nucleotides regulation. However, PTX was inefficient to revert the low triglycerides levels in the serum but was able to modulate purinergic signalization during the chronic hepatic injury, which was efficiently induced by our proposed method.Os agentes causadores de intoxicações hepáticas são inúmeros, e quando as lesões ocasionadas por eles perduram por longos períodos podem caracterizar um perfil crônico, dificultando o tratamento e recuperação do paciente. Doenças hepáticas crônicas (DHC) são um grave problema de saúde pública no Brasil e no mundo, levando a altos índices de morbidade e mortalidade. Em razão da dificuldade de se estudar as DHC em humanos, modelos de dano experimental em fígado de roedores foram desenvolvidos. A tioacetamida (TAA) é uma substância hepatotóxica utilizada para este fim. Contudo, cada rato demonstra tolerâncias individuais mediante a toxicidade do composto, não havendo na literatura uma administração da TAA pela via oral individualmente em cada rato para indução de dano hepático crônico. O nucleotídeo purínico ATP e seus derivados são liberados durante o dano hepático, atuando como sinalizadores celulares na resposta linfocitária. As ectonucleotidases ancoradas nas membranas celulares regulam essa sinalização purinérgica, modulando a resposta imune, de modo que terapias que afetem essa sinalização possam atuar como um alvo terapêutico. Além disso, a pentoxifilina (PTX) é uma droga anti-inflamatória hemorreológica que pode atuar como um possível agente antifibrótico. O objetivo deste estudo é avaliar os efeitos da indução de dano hepático crônico pela administração oral de TAA em ratos Wistar e alterações nas ectoenzimas do sistema purinérgico. Para isso, foi realizado um experimento in vivo, no qual 30 ratos Wistar foram divididos em quatro grupos: Grupo I – Controle, Grupo II – PTX (100mg/kg), Grupo III – TAA (125mg/kg) e Grupo IV – TAA (125mg/kg) + PTX (100mg/kg). A indução de dano hepático crônico ocorreu pela administração oral de TAA três vezes por semana durante 12 semanas. Os animais dos grupos II e IV receberam PTX por via oral diariamente durante as 4 últimas semanas. Após esse período, os animais foram eutanasiados e o sangue e fígado coletados para isolamento de linfócitos, como também avaliação de hemograma e marcadores de dano séricos. Nos animais do grupo III foi observado aumento de AST e diminuição dos triglicerídeos no soro. Houve aumento na contagem de leucócitos totais no sangue, principalmente neutrófilos. Houve ainda diminuição da atividade da E-NTPDase nos linfócitos de fígado, um perfil de característica pró-inflamatória, enquanto na E-NTPDase das membranas de fígado se observou aumento dessa atividade, possivelmente pela elevação da sinalização de eATP liberado em razão do dano celular. Nos linfócitos de sangue as ectoenzimas se encontram aumentadas, demonstrando um perfil imune regulado. O tratamento com PTX não demonstrou alteração nos níveis séricos de marcadores de dano hepático, sugerindo certo grau de reversão do dano. Além disso, o tratamento reverteu a atividade das ectoenzimas dos linfócitos hepáticos a níveis basais,Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessFígadoTioacetamidaPentoxifilinaSistema purinérgicoLiverThioacetamidePentoxifyllinePurinergic systemCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAAtividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilinaPurinergic enzymes activities in chronic hepatic injury induced by oral thioacetamide and pentoxifyline treatment in ratsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisLeal, Daniela Bitencourt Rosahttp://lattes.cnpq.br/3639683273462361Rosemberg, Denis BroockSpanevello, Roselia Mariahttp://lattes.cnpq.br/2451026932744977Ebone, Renan da Silva200800000002600600600600600ebd6d0bc-4e14-43fd-8d4e-ad9ebe640af2ac8e3240-756e-4b3f-9239-d4b3e5564a89b34b71bb-e2fd-4032-b32f-9f2b2d9914b2da7d65ae-3939-4ddc-8509-095f11925052reponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGBT_2023_EBONE_RENAN.pdfDIS_PPGBT_2023_EBONE_RENAN.pdfDissertação de mestradoapplication/pdf1737543http://repositorio.ufsm.br/bitstream/1/30172/1/DIS_PPGBT_2023_EBONE_RENAN.pdf3cd06f5b3495118533a9992a2a3fd190MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.ufsm.br/bitstream/1/30172/2/license_rdf4460e5956bc1d1639be9ae6146a50347MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81956http://repositorio.ufsm.br/bitstream/1/30172/3/license.txt2f0571ecee68693bd5cd3f17c1e075dfMD531/301722023-09-04 14:37:09.084oai:repositorio.ufsm.br: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 Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-09-04T17:37:09Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
dc.title.alternative.eng.fl_str_mv |
Purinergic enzymes activities in chronic hepatic injury induced by oral thioacetamide and pentoxifyline treatment in rats |
title |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
spellingShingle |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina Ebone, Renan da Silva Fígado Tioacetamida Pentoxifilina Sistema purinérgico Liver Thioacetamide Pentoxifylline Purinergic system CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
title_full |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
title_fullStr |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
title_full_unstemmed |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
title_sort |
Atividade de ectoenzimas purinérgicas após dano hepático crônico induzido por tioacetamida em ratos wistar e tratados com pentoxifilina |
author |
Ebone, Renan da Silva |
author_facet |
Ebone, Renan da Silva |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Leal, Daniela Bitencourt Rosa |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3639683273462361 |
dc.contributor.referee1.fl_str_mv |
Rosemberg, Denis Broock |
dc.contributor.referee2.fl_str_mv |
Spanevello, Roselia Maria |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2451026932744977 |
dc.contributor.author.fl_str_mv |
Ebone, Renan da Silva |
contributor_str_mv |
Leal, Daniela Bitencourt Rosa Rosemberg, Denis Broock Spanevello, Roselia Maria |
dc.subject.por.fl_str_mv |
Fígado Tioacetamida Pentoxifilina Sistema purinérgico |
topic |
Fígado Tioacetamida Pentoxifilina Sistema purinérgico Liver Thioacetamide Pentoxifylline Purinergic system CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Liver Thioacetamide Pentoxifylline Purinergic system |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
The are innumerous hepatotoxic agents that can cause liver injury, but when this damage extends for long periods, it can characterize a chronic profile that makes the patient’s treatment and recuperation difficult. Chronic hepatic diseases (CHD) are a serious worldwide public health problem, which leads to high indices of morbidity and mortality. Due to the difficulties in studying CHD in human beings, experimental injury models are developed in rodents. Thioacetamide (TAA) is a hepatotoxic substance used for this purpose. Each rat, however, demonstrates individual tolerances for the TAA toxicity, as such there is no study in literature that administrates TAA by oral gavage to induce chronic hepatic injury. The nucleotide ATP and its derivatives are released during hepatic injury, acting as cellular signals for lymphocyte response. Ectonucleotidases anchored in its membrane regulate this purinergic signalization, modulating the immune response, so that therapies that affect this purinergic signalization may act as possible therapeutical targets. Besides, pentoxifylline (PTX), is an anti-inflammatory hemorheological drug that may act as a possible antifibrotic agent. In this study an in vivo experiment was made, using 30 Wistar rats, divided into four groups: Group I – Control, Group II – PTX (100mg/kg), Group III – TAA (125mg/kg) and Group IV – TAA (125mg/kg) + PTX (100mg/kg). The chronic hepatic injury occurred by the oral gavage of TAA three times a week for 12 weeks. Groups II and IV animals received PTX orally every day during the 4 last weeks. After this period, the animals were euthanized, and liver and blood were collected for lymphocyte isolation, for hemogram evaluation and serum damage markers as well. In group III animals we observed an increase in AST and a decrease in triglycerides levels in the serum. There was an increase in the total leukocyte cell count in the blood, majorly in neutrophil numbers. There was also a decrease in E-NTPDase activity in liver lymphocytes, a pro-inflammatory profile, while liver membrane ENTPDase we observed an increase in this activity, possibly due to increased ATP signalization released due to cell damage. In blood lymphocytes the ectoenzymes demonstrate increased activities for a regulated immune profile. PTX treatment did not demonstrate alterations in the serum damage markers, suggesting some level of damage reversion. Additionally, the treatment reverted the ectoenzymes activities in liver lymphocytes to physiological levels, differing from those observed in non-treated animals, while in liver membranes the E-NTPDase kept elevated for nucleotides regulation. However, PTX was inefficient to revert the low triglycerides levels in the serum but was able to modulate purinergic signalization during the chronic hepatic injury, which was efficiently induced by our proposed method. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-09-04T17:37:08Z |
dc.date.available.fl_str_mv |
2023-09-04T17:37:08Z |
dc.date.issued.fl_str_mv |
2023-07-17 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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http://repositorio.ufsm.br/handle/1/30172 |
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http://repositorio.ufsm.br/handle/1/30172 |
dc.language.iso.fl_str_mv |
por |
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por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
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600 600 600 600 600 |
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Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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