Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Hepatology ; 61(1): 348-60, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24824608

RESUMO

UNLABELLED: Drug-induced liver injury (DILI) is an important cause of acute liver failure, with limited therapeutic options. During DILI, oncotic necrosis with concomitant release and recognition of intracellular content amplifies liver inflammation and injury. Among these molecules, self-DNA has been widely shown to trigger inflammatory and autoimmune diseases; however, whether DNA released from damaged hepatocytes accumulates into necrotic liver and the impact of its recognition by the immune system remains elusive. Here we show that treatment with two different hepatotoxic compounds (acetaminophen and thioacetamide) caused DNA release into the hepatocyte cytoplasm, which occurred in parallel with cell death in vitro. Administration of these compounds in vivo caused massive DNA deposition within liver necrotic areas, together with an intravascular DNA coating. Using confocal intravital microscopy, we revealed that liver injury due to acetaminophen overdose led to a directional migration of neutrophils to DNA-rich areas, where they exhibit an active patrolling behavior. DNA removal by intravenous DNASE1 injection or ablation of Toll-like receptor 9 (TLR9)-mediated sensing significantly reduced systemic inflammation, liver neutrophil recruitment, and hepatotoxicity. Analysis of liver leukocytes by flow cytometry revealed that emigrated neutrophils up-regulated TLR9 expression during acetaminophen-mediated necrosis, and these cells sensed and reacted to extracellular DNA by activating the TLR9/NF-κB pathway. Likewise, adoptive transfer of wild-type neutrophils to TLR9(-/-) mice reversed the hepatoprotective phenotype otherwise observed in TLR9 absence. CONCLUSION: Hepatic DNA accumulation is a novel feature of DILI pathogenesis. Blockage of DNA recognition by the innate immune system may constitute a promising therapeutic venue.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , DNA/metabolismo , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Animais , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Ativação de Neutrófilo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor Toll-Like 9/metabolismo
2.
Parasitology ; 141(10): 1277-88, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24786243

RESUMO

Aquaporin (SmAQP) is the most abundant transmembrane protein in the tegument of Schistosoma mansoni. This protein is expressed in all developmental stages and seems to be essential in parasite survival since it plays a crucial role in osmoregulation, nutrient transport and drug uptake. In this study, we utilized the murine model to evaluate whether this protein was able to induce protection against challenge infection with S. mansoni cercariae. A chimeric (c) SmAQP was formulated with Freund's adjuvant for vaccination trial and evaluation of the host's immune response was performed. Our results demonstrated that immunization with cSmAQP induced the production of high levels of specific anti-cSmAQP IgG antibodies and a Th1/Th17 type of immune response characterized by IFN-γ, TNF-α and IL-17 cytokines. However, vaccination of mice with cSmAQP failed to reduce S. mansoni worm burden and liver pathology. Finally, we were unable to detect humoral immune response anti-cSmAQP in the sera of S. mansoni-infected human patients. Our results lead us to believe that SmAQP, as formulated in this study, may not be a good target in the search for an anti-schistosomiasis vaccine.


Assuntos
Anticorpos Anti-Helmínticos/imunologia , Aquaporinas/imunologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Adjuvantes Imunológicos , Animais , Aquaporinas/genética , Aquaporinas/isolamento & purificação , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/genética , Proteínas de Helminto/imunologia , Proteínas de Helminto/isolamento & purificação , Imunização , Fígado/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes , Esquistossomose mansoni/parasitologia , Vacinação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA