Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/11099 |
Resumo: | Acute lung injury is a critical illness syndrome consisting of acute respiratory failure with cellular infiltrate and is characterized by alveolar capillary barrier injury, neutrophil accumulation and induction of proinflammatory cytokines, followed by pulmonary fibrosis. Due to the complexity of the physiological and immunological events involving acute lung injury, there is still no fully established pharmacotherapy. MHTP (2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol) is an unprecedented synthesized alkaloid that has chemical similarity to the cryptostolins and alkaloids CKD712 ((S)-1-(a-naphthylmethyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline) and THI52 (1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline). The purpose of this study was to investigate the pharmacological potential of MHTP in the treatment of experimental acute lung injury in two moments: 72 hours (acute phase) and 10 days (chronic phase). In order to perform this, the model of acute lung injury induced by LPS in male BALB / c mice was used. Three treatments were performed by nasal instillation with MHTP, the first one occurred one hour after challenge with LPS, the second with 24 hours and the third with 48 hours. To select the dose of the substance, a pilot experiment was carried out at doses of 1.25mg / kg; 2.5mg / kg; 5mg / kg; 10mg / kg and 20mg/ kg. The treatment with MHTP (2.5mg / kg, 5mg / kg, 10mg / kg and 20mg / kg) significantly decreased (p <0.05) the migration of total cells, neutrophils and lymphocytes. Based on this experiment, the dose of 2.5mg / kg was chosen because it presented better results. Therefore, this dose was used in the other experiments. This dose also significantly decreased (p <0.05) the production of the cytokines TNF-α and IL-6 and the histological parameters such as: hemorrhage, edema, cellular infiltration and fibrosis deposition. In the 10-day period, treatment with MHTP significantly decreased (p <0.05) the migration of total cells, neutrophils, macrophages and lymphocytes with increased weight and normal return to activities in the animals. The survival rate of the MHTP treated animals was significantly (p <0.05) higher when compared to that of the LPS (sick) animals. Therefore, the results obtained in this study indicate that MHTP exerts a protective effect on acute lung injury, both in the acute phase (72h) and in the chronic phase (10 days), protecting the alveolar epithelial cells and regulating pulmonary inflammation, suggesting that MHTP is a promising therapeutic agent for the management of this disease. . |
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Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar agudaLesão pulmonar agudaAcute lung injury ,MHTPLPSagudocrônicoacutechronicCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAAcute lung injury is a critical illness syndrome consisting of acute respiratory failure with cellular infiltrate and is characterized by alveolar capillary barrier injury, neutrophil accumulation and induction of proinflammatory cytokines, followed by pulmonary fibrosis. Due to the complexity of the physiological and immunological events involving acute lung injury, there is still no fully established pharmacotherapy. MHTP (2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol) is an unprecedented synthesized alkaloid that has chemical similarity to the cryptostolins and alkaloids CKD712 ((S)-1-(a-naphthylmethyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline) and THI52 (1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline). The purpose of this study was to investigate the pharmacological potential of MHTP in the treatment of experimental acute lung injury in two moments: 72 hours (acute phase) and 10 days (chronic phase). In order to perform this, the model of acute lung injury induced by LPS in male BALB / c mice was used. Three treatments were performed by nasal instillation with MHTP, the first one occurred one hour after challenge with LPS, the second with 24 hours and the third with 48 hours. To select the dose of the substance, a pilot experiment was carried out at doses of 1.25mg / kg; 2.5mg / kg; 5mg / kg; 10mg / kg and 20mg/ kg. The treatment with MHTP (2.5mg / kg, 5mg / kg, 10mg / kg and 20mg / kg) significantly decreased (p <0.05) the migration of total cells, neutrophils and lymphocytes. Based on this experiment, the dose of 2.5mg / kg was chosen because it presented better results. Therefore, this dose was used in the other experiments. This dose also significantly decreased (p <0.05) the production of the cytokines TNF-α and IL-6 and the histological parameters such as: hemorrhage, edema, cellular infiltration and fibrosis deposition. In the 10-day period, treatment with MHTP significantly decreased (p <0.05) the migration of total cells, neutrophils, macrophages and lymphocytes with increased weight and normal return to activities in the animals. The survival rate of the MHTP treated animals was significantly (p <0.05) higher when compared to that of the LPS (sick) animals. Therefore, the results obtained in this study indicate that MHTP exerts a protective effect on acute lung injury, both in the acute phase (72h) and in the chronic phase (10 days), protecting the alveolar epithelial cells and regulating pulmonary inflammation, suggesting that MHTP is a promising therapeutic agent for the management of this disease. .Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA lesão pulmonar aguda é uma síndrome de doença crítica que consiste em insuficiência respiratória aguda com infiltrado celular e é caracterizada por lesão da barreira capilar alveolar, acumulação de neutrófilos e indução de citocinas pró-inflamatórias, seguido de uma fibrose pulmonar. Devido à complexidade dos eventos fisiológicos e imunológicos que envolvem a lesão pulmonar aguda, ainda não há uma farmacoterapia totalmente estabelecida. O MHTP (2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol) é um alcaloide inédito sintetizado que possui semelhança química com as criptostilinas e com os alcaloides CKD712 ([(S)-1-(α-naftilmetil)-6,7-di-hidroxi-1,2,3,4- tetrahidroisoquinolina]) e THI52(1- naftiletil -6,7- dihidroxi -1,2,3,4- tetrahidroisoquinolina). O objetivo desse estudo foi investigar o potencial farmacológico do MHTP no tratamento da lesão pulmonar aguda experimental em dois momentos: 72 horas (fase aguda) e dez dias (fase crônica). Para tal, foi usado o modelo de lesão pulmonar aguda induzida por LPS em camundongos BALB/c machos. Foram realizados três tratamentos, por instilação nasal, com MHTP, sendo o primeiro uma hora após o desafio com LPS, o segundo com 24 horas e o terceiro com 48 horas. Para escolha da dose da substância, foi realizado experimento piloto com as doses de 1,25mg/kg; 2,5mg/kg; 5mg/kg; 10mg/kg e 20mg/kg. No tempo de 72 h, o tratamento com MHTP (2,5mg/kg; 5mg/kg; 10mg/kg e 20mg/kg) diminuiu significantemente (p<0,05) a migração de células totais, neutrófilos e linfócitos. A partir desse experimento, foi escolhida a dose de 2,5mg/kg por ter apresentado melhores resultados. Portanto, essa dose foi utilizada nos demais experimentos. Tal dose também diminuiu significativamente (p<0,05) a produção das citocinas TNF-α e IL-6 e os parâmetros histológicos tais como: hemorragia, edema, infiltração celular e deposição de fibrose. No período de dez dias, o tratamento com MHTP, diminuiu significantemente (p<0,05) a migração de células totais, neutrófilos, macrófagos e linfócitos com aumento de peso e retorno normal às atividades nos animais. A taxa de sobrevivência dos animais tratados com MHTP foi significantemente (p<0,05) maior quando comparada com a dos animais LPS (doentes). Portanto, os resultados obtidos nesse trabalho indicam que o MHTP exerce um efeito protetor na lesão pulmonar aguda, tanto na fase aguda (72h) como na fase crônica (dez dias) protegendo as células epiteliais alveolares e regulando a inflamação pulmonar, e sugerindo que o MHTP é um agente terapêutico promissor para o manejo dessa doença.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBPiuvezam , Marcia Reginahttp://lattes.cnpq.br/0961955935523938Xavier, Bianka Márcia do Nascimento2018-08-02T16:00:19Z2018-08-022018-08-02T16:00:19Z2018-02-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/11099porinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2018-09-05T22:57:49Zoai:repositorio.ufpb.br:123456789/11099Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2018-09-05T22:57:49Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
title |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
spellingShingle |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda Xavier, Bianka Márcia do Nascimento Lesão pulmonar aguda Acute lung injury , MHTP LPS agudo crônico acute chronic CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
title_full |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
title_fullStr |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
title_full_unstemmed |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
title_sort |
Efeito imunomodulador do 2-metoxi-4-(7-metoxi-1,2,3,4-tetrahidroisoquinolin-1-il)fenol (mhtp) em um modelo de lesão pulmonar aguda |
author |
Xavier, Bianka Márcia do Nascimento |
author_facet |
Xavier, Bianka Márcia do Nascimento |
author_role |
author |
dc.contributor.none.fl_str_mv |
Piuvezam , Marcia Regina http://lattes.cnpq.br/0961955935523938 |
dc.contributor.author.fl_str_mv |
Xavier, Bianka Márcia do Nascimento |
dc.subject.por.fl_str_mv |
Lesão pulmonar aguda Acute lung injury , MHTP LPS agudo crônico acute chronic CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Lesão pulmonar aguda Acute lung injury , MHTP LPS agudo crônico acute chronic CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Acute lung injury is a critical illness syndrome consisting of acute respiratory failure with cellular infiltrate and is characterized by alveolar capillary barrier injury, neutrophil accumulation and induction of proinflammatory cytokines, followed by pulmonary fibrosis. Due to the complexity of the physiological and immunological events involving acute lung injury, there is still no fully established pharmacotherapy. MHTP (2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol) is an unprecedented synthesized alkaloid that has chemical similarity to the cryptostolins and alkaloids CKD712 ((S)-1-(a-naphthylmethyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline) and THI52 (1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline). The purpose of this study was to investigate the pharmacological potential of MHTP in the treatment of experimental acute lung injury in two moments: 72 hours (acute phase) and 10 days (chronic phase). In order to perform this, the model of acute lung injury induced by LPS in male BALB / c mice was used. Three treatments were performed by nasal instillation with MHTP, the first one occurred one hour after challenge with LPS, the second with 24 hours and the third with 48 hours. To select the dose of the substance, a pilot experiment was carried out at doses of 1.25mg / kg; 2.5mg / kg; 5mg / kg; 10mg / kg and 20mg/ kg. The treatment with MHTP (2.5mg / kg, 5mg / kg, 10mg / kg and 20mg / kg) significantly decreased (p <0.05) the migration of total cells, neutrophils and lymphocytes. Based on this experiment, the dose of 2.5mg / kg was chosen because it presented better results. Therefore, this dose was used in the other experiments. This dose also significantly decreased (p <0.05) the production of the cytokines TNF-α and IL-6 and the histological parameters such as: hemorrhage, edema, cellular infiltration and fibrosis deposition. In the 10-day period, treatment with MHTP significantly decreased (p <0.05) the migration of total cells, neutrophils, macrophages and lymphocytes with increased weight and normal return to activities in the animals. The survival rate of the MHTP treated animals was significantly (p <0.05) higher when compared to that of the LPS (sick) animals. Therefore, the results obtained in this study indicate that MHTP exerts a protective effect on acute lung injury, both in the acute phase (72h) and in the chronic phase (10 days), protecting the alveolar epithelial cells and regulating pulmonary inflammation, suggesting that MHTP is a promising therapeutic agent for the management of this disease. . |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-08-02T16:00:19Z 2018-08-02 2018-08-02T16:00:19Z 2018-02-16 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/11099 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/11099 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
instname_str |
Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
collection |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842930576523264 |