Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos

Detalhes bibliográficos
Autor(a) principal: Nobre, Lívia Maria Soares
Data de Publicação: 2017
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
Texto Completo: http://www.repositorio.ufc.br/handle/riufc/22011
Resumo: Intestinal mucositis (MI) is a very recurrent side effect in patients undergoing treatment with irinotecan, a drug used in first-line treatment regimens for the treatment of colorectal cancer. In the last decades many aspects related to the pathogenesis of MI have been elucidated, however, little is known about the lymphocyte cell profile and their role in its development. The objective of this work is, therefore, to investigate the role of lymphocytes in the pathogenesis of MI through immunosuppression with abatacept. Male swab mice, 20-25g, were divided into groups (n = 8) and treated for 4 days with saline (5 mL / kg, ip), irinotecan (75 or 45 mg / kg, ip), abatacept / Kg, ip 1h before irinotecan on the first day) or only abatacept (10 mg / kg, ip on the first day). The animals were evaluated daily for weight, diarrhea score and survival. Euthanasia occurred on day 5 on the first protocol and on day 7 on the second. Blood was collected for the total leukocyte count and after euthanasia, ileum samples were extracted for myeloperoxidase assay, histopathological analysis, and KC dosing in the ileum of the animals. Statistical analysis was used ANOVA / Bonferroni, Kruskal-Wallis / Dunn's or Log-rank (Mantel-Cox) tests, with p <0.05 accepted as significant. Results Abatacept reduced (p <0.05) the survival of the animals in the first protocol, making day 5 the ideal for euthanasia. Irinotecan caused significant weight loss (p <0.05) in relation to the saline group, however abatacept did not aggravate the loss. Pre-treatment with abatacept anticipated the appearance of moderate-grade diarrhea on the fourth day. Abatacept induced a reduction in villi / crypt ratio, villi height and crypt depth significantly in relation to the irinotecan alone (p <0.05) group, in addition to increasing the neutrophil infiltrate in the animals' ileum. Irinotecan increased the level of KC in the ileus of the animals in relation to the saline group, however abatacept did not significantly modify the level of this cytokine. In the second protocol, the subdose of irinotecan did not cause intense intestinal damage, but the treatment with abatacept proved its deleterious effect inducing the onset of diarrhea on the sixth day (p <0.05) in relation to the saline group, besides aggravating the Intestinal architecture. Abatacept increased neutrophil infiltration in the gut of irinotecan treated animals compared to the group injected with this drug alone (p <0.05), which was associated with elevated KC levels in the intestines of these animals. Irinotecan promoted myelotoxicity at all doses, but abatacept did not aggravate this toxicity. Abatacept alone caused no change in any of the evaluated parameters. Conclusion Abatacept aggravated intestinal mucositis induced by irinotecan in mice.
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spelling Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongosAbatacept worsens irinotecan-induced intestinal mucositis in miceMucositeIntestino GrossoAbatacepteIntestinal mucositis (MI) is a very recurrent side effect in patients undergoing treatment with irinotecan, a drug used in first-line treatment regimens for the treatment of colorectal cancer. In the last decades many aspects related to the pathogenesis of MI have been elucidated, however, little is known about the lymphocyte cell profile and their role in its development. The objective of this work is, therefore, to investigate the role of lymphocytes in the pathogenesis of MI through immunosuppression with abatacept. Male swab mice, 20-25g, were divided into groups (n = 8) and treated for 4 days with saline (5 mL / kg, ip), irinotecan (75 or 45 mg / kg, ip), abatacept / Kg, ip 1h before irinotecan on the first day) or only abatacept (10 mg / kg, ip on the first day). The animals were evaluated daily for weight, diarrhea score and survival. Euthanasia occurred on day 5 on the first protocol and on day 7 on the second. Blood was collected for the total leukocyte count and after euthanasia, ileum samples were extracted for myeloperoxidase assay, histopathological analysis, and KC dosing in the ileum of the animals. Statistical analysis was used ANOVA / Bonferroni, Kruskal-Wallis / Dunn's or Log-rank (Mantel-Cox) tests, with p <0.05 accepted as significant. Results Abatacept reduced (p <0.05) the survival of the animals in the first protocol, making day 5 the ideal for euthanasia. Irinotecan caused significant weight loss (p <0.05) in relation to the saline group, however abatacept did not aggravate the loss. Pre-treatment with abatacept anticipated the appearance of moderate-grade diarrhea on the fourth day. Abatacept induced a reduction in villi / crypt ratio, villi height and crypt depth significantly in relation to the irinotecan alone (p <0.05) group, in addition to increasing the neutrophil infiltrate in the animals' ileum. Irinotecan increased the level of KC in the ileus of the animals in relation to the saline group, however abatacept did not significantly modify the level of this cytokine. In the second protocol, the subdose of irinotecan did not cause intense intestinal damage, but the treatment with abatacept proved its deleterious effect inducing the onset of diarrhea on the sixth day (p <0.05) in relation to the saline group, besides aggravating the Intestinal architecture. Abatacept increased neutrophil infiltration in the gut of irinotecan treated animals compared to the group injected with this drug alone (p <0.05), which was associated with elevated KC levels in the intestines of these animals. Irinotecan promoted myelotoxicity at all doses, but abatacept did not aggravate this toxicity. Abatacept alone caused no change in any of the evaluated parameters. Conclusion Abatacept aggravated intestinal mucositis induced by irinotecan in mice.Mucosite intestinal (MI) é um efeito colateral bastante recorrente em pacientes submetidos ao tratamento com irinotecano, fármaco utilizado em esquemas terapêuticos de primeira linha no tratamento do câncer colorretal. Nas últimas décadas muitos aspectos relativos à patogênese da MI têm sido elucidados, entretanto, pouco se sabe sobre o perfil de células linfocitárias e o papel destas no seu desenvolvimento. O objetivo deste trabalho é, portanto, investigar o papel de linfócitos na patogênese da MI através da imunossupressão com abatacept. Metodologia Camundongos swiss machos, 20-25g, foram divididos em grupos (n=8) e tratados durante 4 dias com salina (5 mL/kg, i.p.), irinotecano (75 ou 45 mg/kg, i.p.), abatacept (10 mg/kg, i.p. 1h antes do irinotecano no primeiro dia) ou somente abatacept (10 mg/kg, i.p. no primeiro dia). Os animais foram avaliados diariamente quanto ao peso, escore de diarreia e sobrevida. A eutanásia ocorreu no dia 5 no primeiro protocolo e no dia 7 no segundo. Coletou-se sangue para a contagem total de leucócitos e após a eutanásia amostras de íleo foram extraídas para realização de ensaio de mieloperoxidase, análise histopatológica e dosagem de KC no íleo dos animais. Para análise estatística foram utilizados os testes ANOVA/Bonferroni, Kruskal-Wallis/Dunn’s ou Log-rank (Mantel-Cox), com p<0,05 aceito como significativo. Resultados Abatacept reduziu (p<0,05) a sobrevida dos animais no primeiro protocolo, fazendo do dia 5 o ideal para eutanásia. Irinotecano causou perda ponderal significativa (p<0,05) em relação ao grupo salina, entretanto abatacept não agravou a perda. O pré-tratamento com abatacept antecipou o aparecimento de diarreia de grau moderado para o quarto dia. Abatacept induziu redução na razão vilo/cripta, altura dos vilos e profundidade das criptas de forma significativa em relação ao grupo tratado somente com irinotecano (p<0,05), além de aumentar o infiltrado de neutrófilos no íleo dos animais. Irinotecano aumentou o nível de KC no íleo dos animais em relação ao grupo salina, entretanto abatacept não modificou o nível desta citocina de forma significativa. No segundo protocolo, a subdose de irinotecano não provocou dano intestinal intenso, porém o tratamento com abatacept comprovou seu efeito deletério induzindo o aparecimento de diarréia no sexto dia (p<0,05) em relação ao grupo salina, além de agravar o dano à arquitetura intestinal. Abatacept elevou a infiltração de neutrófilos no intestino dos animais tratados com irinotecano, em comparação ao grupo injetado apenas com esse fármaco (p<0,05), o que foi associado com os níveis elevados de KC no intestino desses animais. Irinotecano promoveu mielotoxicidade em todas as doses, porém abatacept não agravou essa toxicidade. Abatacept isoladamente não causou alteração em nenhum parâmetro avaliado. Conclusão Abatacept agravou a mucosite intestinal induzida por irinotecano em camundongos.Lima Júnior, Roberto César PereiraNobre, Lívia Maria Soares2017-02-14T14:17:21Z2017-02-14T14:17:21Z2017-01-31info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfNOBRE, L. M. S. Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos. 2017. 79 f. Dissertação (Mestrado em Farmacologia) - Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, 2017.http://www.repositorio.ufc.br/handle/riufc/22011porreponame:Repositório Institucional da Universidade Federal do Ceará (UFC)instname:Universidade Federal do Ceará (UFC)instacron:UFCinfo:eu-repo/semantics/openAccess2019-10-18T11:55:44Zoai:repositorio.ufc.br:riufc/22011Repositório InstitucionalPUBhttp://www.repositorio.ufc.br/ri-oai/requestbu@ufc.br || repositorio@ufc.bropendoar:2024-09-11T18:34:52.410798Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC)false
dc.title.none.fl_str_mv Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
Abatacept worsens irinotecan-induced intestinal mucositis in mice
title Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
spellingShingle Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
Nobre, Lívia Maria Soares
Mucosite
Intestino Grosso
Abatacepte
title_short Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
title_full Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
title_fullStr Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
title_full_unstemmed Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
title_sort Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos
author Nobre, Lívia Maria Soares
author_facet Nobre, Lívia Maria Soares
author_role author
dc.contributor.none.fl_str_mv Lima Júnior, Roberto César Pereira
dc.contributor.author.fl_str_mv Nobre, Lívia Maria Soares
dc.subject.por.fl_str_mv Mucosite
Intestino Grosso
Abatacepte
topic Mucosite
Intestino Grosso
Abatacepte
description Intestinal mucositis (MI) is a very recurrent side effect in patients undergoing treatment with irinotecan, a drug used in first-line treatment regimens for the treatment of colorectal cancer. In the last decades many aspects related to the pathogenesis of MI have been elucidated, however, little is known about the lymphocyte cell profile and their role in its development. The objective of this work is, therefore, to investigate the role of lymphocytes in the pathogenesis of MI through immunosuppression with abatacept. Male swab mice, 20-25g, were divided into groups (n = 8) and treated for 4 days with saline (5 mL / kg, ip), irinotecan (75 or 45 mg / kg, ip), abatacept / Kg, ip 1h before irinotecan on the first day) or only abatacept (10 mg / kg, ip on the first day). The animals were evaluated daily for weight, diarrhea score and survival. Euthanasia occurred on day 5 on the first protocol and on day 7 on the second. Blood was collected for the total leukocyte count and after euthanasia, ileum samples were extracted for myeloperoxidase assay, histopathological analysis, and KC dosing in the ileum of the animals. Statistical analysis was used ANOVA / Bonferroni, Kruskal-Wallis / Dunn's or Log-rank (Mantel-Cox) tests, with p <0.05 accepted as significant. Results Abatacept reduced (p <0.05) the survival of the animals in the first protocol, making day 5 the ideal for euthanasia. Irinotecan caused significant weight loss (p <0.05) in relation to the saline group, however abatacept did not aggravate the loss. Pre-treatment with abatacept anticipated the appearance of moderate-grade diarrhea on the fourth day. Abatacept induced a reduction in villi / crypt ratio, villi height and crypt depth significantly in relation to the irinotecan alone (p <0.05) group, in addition to increasing the neutrophil infiltrate in the animals' ileum. Irinotecan increased the level of KC in the ileus of the animals in relation to the saline group, however abatacept did not significantly modify the level of this cytokine. In the second protocol, the subdose of irinotecan did not cause intense intestinal damage, but the treatment with abatacept proved its deleterious effect inducing the onset of diarrhea on the sixth day (p <0.05) in relation to the saline group, besides aggravating the Intestinal architecture. Abatacept increased neutrophil infiltration in the gut of irinotecan treated animals compared to the group injected with this drug alone (p <0.05), which was associated with elevated KC levels in the intestines of these animals. Irinotecan promoted myelotoxicity at all doses, but abatacept did not aggravate this toxicity. Abatacept alone caused no change in any of the evaluated parameters. Conclusion Abatacept aggravated intestinal mucositis induced by irinotecan in mice.
publishDate 2017
dc.date.none.fl_str_mv 2017-02-14T14:17:21Z
2017-02-14T14:17:21Z
2017-01-31
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dc.identifier.uri.fl_str_mv NOBRE, L. M. S. Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos. 2017. 79 f. Dissertação (Mestrado em Farmacologia) - Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, 2017.
http://www.repositorio.ufc.br/handle/riufc/22011
identifier_str_mv NOBRE, L. M. S. Abatacept agrava a mucosite intestinal induzida por irinotecano em camundongos. 2017. 79 f. Dissertação (Mestrado em Farmacologia) - Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, 2017.
url http://www.repositorio.ufc.br/handle/riufc/22011
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