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CHEMOKINES AND MITOCHONDRIAL PRODUCTS ACTIVATE NEUTROPHILS TO AMPLIFY ORGAN INJURY DURING MOUSE ACUTE LIVER FAILURE
Melgaço, Juliana G. et al. | Fecha del documento: 2012
Autor
Melgaço, Juliana G.
Pinto, Marcelo Alves
Múltipla autoria - ver em Notas
Afiliación
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Desenvolvimento Tecnológico em Virologia. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Desenvolvimento Tecnológico em Virologia. Rio de Janeiro, RJ. Brasil.
Múltipla Afiliação - ver em Notas
Resumen en ingles
Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti–granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1–signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR92/2 mice). Conclusion: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.
Palabras clave en portugues
Quimiocinas
Neutrófilos
Produtos Mitocondriais
Lesão orgânica
Ratos
Insuficiência Hepática Aguda
 
Palabras clave en ingles
Neutrophils
Chemokines
Mouse
Acute Liver Failure
Mitochondrial Products
Organ Injury
 
Editor
Wiley 12 Months
Referencia
MARQUES, Pedro E. et al. Chemokines and Mitochondrial Products Activate Neutrophils to Amplify Organ Injury During Mouse Acute Liver Failure. Hepatology, v.56, n.5, p.1791-1982, Nov. 2012
ISSN
0270-9139
Notas
AUTHORS - Pedro E. Marques,1,2 Sylvia S. Amaral,1,2 Daniele A. Pires,1,2 Laura L. Nogueira,1,2 Frederico M. Soriani,2,9 Braulio H.F. Lima,2 Gabriel A.O. Lopes,2,3 Remo C. Russo,2,3 Thiago V. A´ vila,2,4 Juliana G. Melgac¸o,5 Andr e G. Oliveira,1 Marcelo A. Pinto,5 Cristiano X. Lima,2,6 Ana Maria De Paula,7 Denise C. Cara,1 Maria F. Leite,3,8 Mauro M. Teixeira,2 and Gustavo Batista Menezes1,2; AFFILIATIONS - Abbreviations: ALF, acute liver failure; ALT, alanine aminotransferase; ANOVA, analysis of variance; APAP, acetaminophen; BAL, bronchoalveolar lavage; CXCR2, CXC chemokine receptor 2; DCF-DA, 2’,7’-dichlorodihydrofluorescein diacetate; DILI, drug-induced liver injury; ELISA, enzyme-linked immunosorbent assay; FPR1, formyl peptide receptor 1; gDNA, genomic DNA; GR1, granulocyte receptor 1; IgG, immunoglobulin G; IL-1b, interleukin-1 beta; I/R, ischemia/ reperfusion; IV, intravenous; IVM, intravital microscopy; LT, liver transplantation; Lysm-eGFP, lysozyme M promoter for enhanced green fluorescent protein; mitDNA, mitochondrial DNA; MPO, myeloperoxidase; nDNA, nuclear DNA; NO, nitric oxide; PCR, polymerase chain reaction; PE, phycoerythrin; PECAM-1, platelet-endothelial cell adhesion molecule-1; ROS, reactive oxygen species; SEM, standard error of the mean; TLR9, Toll-like receptor 9; TNF-a, tumor necrosis factor alpha; UFMG, Universidade Federal de Minas Gerais. From the 1Laborat orio de Imunobiofotoˆnica, Departamento de Morfologia; 2Laborat orio de Imunofarmacologia, Departamento de Bioquı´mica e Imunologia; 3Departamento de Fisiologia e Biofı´sica; 4Departamento de Microbiologia, Instituto de Cieˆncias Biol ogicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 5Laborat orio de Desenvolvimento Tecnol ogico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; 6Departamento de Cirurgia, Faculdade de Medicina; 7Departamento de Fı´sica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 8Howard Hughes Medical Institute, Chevy Chase, MD; and 9Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Brazil.