Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2013 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/11719 |
Resumo: | Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil. |
| id |
CRUZ_77f41c81243164a063295ebfc0bde80e |
|---|---|
| oai_identifier_str |
oai:www.arca.fiocruz.br:icict/11719 |
| network_acronym_str |
CRUZ |
| network_name_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| repository_id_str |
2135 |
| spelling |
Amaral, Sylvia S.Oliveira, André G.Marques, Pedro E.Quintão, Jayane L. D.Pires, Daniele A.Resende, Rodrigo R.Sousa, Bruna R.Melgaço, Juliana G.Pinto, Marcelo A.Russo, Remo C.Gomes, Ariane K. C.Andrade, Lidia M.Zanin, Rafael F.Pereira, Rafaela V. S.Bonorino, CristinaSoriani, Frederico M.Lima, Cristiano X.Cara, Denise C.Teixeira, Mauro M.Leite, Maria F.Menezes, Gustavo B.2015-09-21T17:25:28Z2015-09-21T17:25:28Z2013AMARAL, Sylvia S.; et al. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity. Cell Communication and Signaling , v.11. n.10, 14p, 2013.https://www.arca.fiocruz.br/handle/icict/1171910.1186/1478-811X-11-10engBioMed CentralLesão hepáticaLesão remotaLiver injurySterile inflammationAcetaminophenRemote injuryCell deathImmune systemInflammationPurinergic signalingAcetaminofenMorte CelularSistema ImunológicoInflamaçãoReceptores PurinérgicosAltered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicityinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, BrasilUniversidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Pontifícia Universidade Católica. Instituto de Ciências Biomédicas. Porto Alegre, RS, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil.Pontifícia Universidade Católica. Instituto de Ciências Biomédicas. Porto Alegre, RS, Brasil.Universidade Federal de Minas Gerais. Departamento de Biologia Geral. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Faculdade de Medicina. Departamento de Cirurgia. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil / 8Howard Hughes Medical Institute. Chevy Chase, MD, USA,Universidade Federal de Minas Gerais. Instituto de Ciências Biomédicas. Belo Horizonte, MG, Brasil.Background: Adenosine triphosphate (ATP) is secreted from hepatocytes under physiological conditions and plays an important role in liver biology through the activation of P2 receptors. Conversely, higher extracellular ATP concentrations, as observed during necrosis, trigger inflammatory responses that contribute to the progression of liver injury. Impaired calcium (Ca2+) homeostasis is a hallmark of acetaminophen (APAP)-induced hepatotoxicity, and since ATP induces mobilization of the intracellular Ca2+ stocks, we evaluated if the release of ATP during APAP-induced necrosis could directly contribute to hepatocyte death. Results: APAP overdose resulted in liver necrosis, massive neutrophil infiltration and large non-perfused areas, as well as remote lung inflammation. In the liver, these effects were significantly abrogated after ATP metabolism by apyrase or P2X receptors blockage, but none of the treatments prevented remote lung inflammation, suggesting a confined local contribution of purinergic signaling into liver environment. In vitro, APAP administration to primary mouse hepatocytes and also HepG2 cells caused cell death in a dose-dependent manner. Interestingly, exposure of HepG2 cells to APAP elicited significant release of ATP to the supernatant in levels that were high enough to promote direct cytotoxicity to healthy primary hepatocytes or HepG2 cells. In agreement to our in vivo results, apyrase treatment or blockage of P2 receptors reduced APAP cytotoxicity. Likewise, ATP exposure caused significant higher intracellular Ca2+ signal in APAP-treated primary hepatocytes, which was reproduced in HepG2 cells. Quantitative real time PCR showed that APAP-challenged HepG2 cells expressed higher levels of several purinergic receptors, which may explain the hypersensitivity to extracellular ATP. This phenotype was confirmed in humans analyzing liver biopsies from patients diagnosed with acute hepatic failure. Conclusion: We suggest that under pathological conditions, ATP may act not only an immune system activator, but also as a paracrine direct cytotoxic DAMP through the dysregulation of Ca2+ homeostasis.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txttext/plain1914https://www.arca.fiocruz.br/bitstream/icict/11719/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALjuliana_melgaço_etal_IOC_2013.pdfapplication/pdf2030939https://www.arca.fiocruz.br/bitstream/icict/11719/2/juliana_melga%c3%a7o_etal_IOC_2013.pdf9a8aec5077d0cb729be01148fd3a2fc4MD52TEXTjuliana_melgaço_etal_IOC_2013.pdf.txtjuliana_melgaço_etal_IOC_2013.pdf.txtExtracted texttext/plain62385https://www.arca.fiocruz.br/bitstream/icict/11719/3/juliana_melga%c3%a7o_etal_IOC_2013.pdf.txtf969129282b627a80d0822f5342c06bdMD53icict/117192022-06-24 12:17:33.801oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352022-06-24T15:17:33Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| title |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| spellingShingle |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity Amaral, Sylvia S. Lesão hepática Lesão remota Liver injury Sterile inflammation Acetaminophen Remote injury Cell death Immune system Inflammation Purinergic signaling Acetaminofen Morte Celular Sistema Imunológico Inflamação Receptores Purinérgicos |
| title_short |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| title_full |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| title_fullStr |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| title_full_unstemmed |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| title_sort |
Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity |
| author |
Amaral, Sylvia S. |
| author_facet |
Amaral, Sylvia S. Oliveira, André G. Marques, Pedro E. Quintão, Jayane L. D. Pires, Daniele A. Resende, Rodrigo R. Sousa, Bruna R. Melgaço, Juliana G. Pinto, Marcelo A. Russo, Remo C. Gomes, Ariane K. C. Andrade, Lidia M. Zanin, Rafael F. Pereira, Rafaela V. S. Bonorino, Cristina Soriani, Frederico M. Lima, Cristiano X. Cara, Denise C. Teixeira, Mauro M. Leite, Maria F. Menezes, Gustavo B. |
| author_role |
author |
| author2 |
Oliveira, André G. Marques, Pedro E. Quintão, Jayane L. D. Pires, Daniele A. Resende, Rodrigo R. Sousa, Bruna R. Melgaço, Juliana G. Pinto, Marcelo A. Russo, Remo C. Gomes, Ariane K. C. Andrade, Lidia M. Zanin, Rafael F. Pereira, Rafaela V. S. Bonorino, Cristina Soriani, Frederico M. Lima, Cristiano X. Cara, Denise C. Teixeira, Mauro M. Leite, Maria F. Menezes, Gustavo B. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Amaral, Sylvia S. Oliveira, André G. Marques, Pedro E. Quintão, Jayane L. D. Pires, Daniele A. Resende, Rodrigo R. Sousa, Bruna R. Melgaço, Juliana G. Pinto, Marcelo A. Russo, Remo C. Gomes, Ariane K. C. Andrade, Lidia M. Zanin, Rafael F. Pereira, Rafaela V. S. Bonorino, Cristina Soriani, Frederico M. Lima, Cristiano X. Cara, Denise C. Teixeira, Mauro M. Leite, Maria F. Menezes, Gustavo B. |
| dc.subject.other.pt_BR.fl_str_mv |
Lesão hepática Lesão remota |
| topic |
Lesão hepática Lesão remota Liver injury Sterile inflammation Acetaminophen Remote injury Cell death Immune system Inflammation Purinergic signaling Acetaminofen Morte Celular Sistema Imunológico Inflamação Receptores Purinérgicos |
| dc.subject.en.pt_BR.fl_str_mv |
Liver injury Sterile inflammation Acetaminophen Remote injury Cell death Immune system Inflammation Purinergic signaling |
| dc.subject.decs.pt_BR.fl_str_mv |
Acetaminofen Morte Celular Sistema Imunológico Inflamação Receptores Purinérgicos |
| description |
Universidade Federal de Minas Gerais. Departamento de Morfologia. Laboratório de Imunobiofotônica. Belo Horizonte, MG, Brasil. |
| publishDate |
2013 |
| dc.date.issued.fl_str_mv |
2013 |
| dc.date.accessioned.fl_str_mv |
2015-09-21T17:25:28Z |
| dc.date.available.fl_str_mv |
2015-09-21T17:25:28Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.citation.fl_str_mv |
AMARAL, Sylvia S.; et al. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity. Cell Communication and Signaling , v.11. n.10, 14p, 2013. |
| dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/11719 |
| dc.identifier.doi.pt_BR.fl_str_mv |
10.1186/1478-811X-11-10 |
| identifier_str_mv |
AMARAL, Sylvia S.; et al. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity. Cell Communication and Signaling , v.11. n.10, 14p, 2013. 10.1186/1478-811X-11-10 |
| url |
https://www.arca.fiocruz.br/handle/icict/11719 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
BioMed Central |
| publisher.none.fl_str_mv |
BioMed Central |
| dc.source.none.fl_str_mv |
reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ |
| instname_str |
Fundação Oswaldo Cruz (FIOCRUZ) |
| instacron_str |
FIOCRUZ |
| institution |
FIOCRUZ |
| reponame_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| collection |
Repositório Institucional da FIOCRUZ (ARCA) |
| bitstream.url.fl_str_mv |
https://www.arca.fiocruz.br/bitstream/icict/11719/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/11719/2/juliana_melga%c3%a7o_etal_IOC_2013.pdf https://www.arca.fiocruz.br/bitstream/icict/11719/3/juliana_melga%c3%a7o_etal_IOC_2013.pdf.txt |
| bitstream.checksum.fl_str_mv |
7d48279ffeed55da8dfe2f8e81f3b81f 9a8aec5077d0cb729be01148fd3a2fc4 f969129282b627a80d0822f5342c06bd |
| bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
| repository.name.fl_str_mv |
Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ) |
| repository.mail.fl_str_mv |
repositorio.arca@fiocruz.br |
| _version_ |
1813009293879803904 |