Tesis doctorales: TESEO

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Ministerio de Educación, Cultura y Deporte - Gobierno de España

Título: ACUTE INFLAMMATORY AND FIBROGENIC RESPONSES INDUCED IN LIVER CELLS BY EFAVIRENZ
Autor: Alegre Guerra, Fernando
Universidad: Universitat de València (Estudi General)
Departamento: Fisiología
Fecha de Lectura: 18/05/2017
Mención Europeo / Mención Internacional: Concedido
Programa de doctorado: Programa Oficial de Doctorado en Fisiología
Dirección:
- ESPLUGUES MOTA, JUAN VICENTE (Director)
- APOSTOLOVA ATANASOVSKA, NADEZDA (Codirector)
- BLAS GARCÍA, ANA (Codirector)
Tribunal:
- Barrachina Sancho, Dolores (presidente)
- hernandez gea, virginia (secretario)
- Bartneck, Matthias (vocal)
Descriptores:
- CIENCIAS MEDICAS
- TOXICOLOGIA
- FARMACOLOGIA
Marcador: https://www.educacion.gob.es/teseo/mostrarRef.do?ref=1417719Añadir a favoritos.
Resumen:
Efavirenz (EFV) is among the most widely employed antiretroviral drug against human immunodeficiency virus (HIV) infection. Despite being considered a safe drug, highly efficient and well tolerated, there is a growing concern about EFV-induced side effects. It has been reported acute hepatic toxicity episodes, and although the mechanisms involved are not completely uncovered, evidence has shown that it induces a pattern of actions in hepatocytes, including endoplasmic reticulum (ER) stress and mitochondrial dysfunction, that could underlie induction of hepatic inflammation. The NLRP3 inflammasome, which is activated by diverse stimuli, is an important regulator of inflammatory and fibrogenic responses in several liver disorders, such as drug-induced liver injury, non-specific hepatitis, and non-alcoholic steatohepatitis. In the present work, we have assessed the implication of the NLRP3 inflammasome in the inflammatory and fibrogenic responses of major liver cell types -hepatocytes, hepatic stellate cells (HSCs) and macrophages- to clinically relevant concentrations of EFV, performing in vitro (human hepatic cell lines and primary cells) and in vivo experiments (liver tissue samples from C57BL/6 mice). EFV triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated HSCs, thereby enhancing expression of pro-inflammatory cytokines (such as IL-1ß, TNF-⍺, IL6), components of the NLRP3 inflammasome and purinergic signaling, and fibrogenic (TGF-ß1, TIMP-1, MMP-2, MMP-9 and collagen 1⍺1) mediators in the latter cell type. The NLRP3 inflammasome was not altered in EFV-treated macrophages, but these cells polarized towards the anti-inflammatory and pro-resolving M2 phenotype and displayed upregulated anti-inflammatory markers (PPAR-𝛄, NLRP12 and IL-10). In contrast, no evidence of liver injury was observed in EFV-treated animals, which did not change in inflammatory and fibrogenic markers, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Additionally, we explored the role of p62 in the EFV-induced hepatocyte damage. SQSTM1/p62 is a stress-inducible scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Alterations in its function have been associated with a long list of human pathologies such as cancer, neurodegenerative diseases and metabolic disorders. Our results show that, despite activation of autophagy, p62 protein content is increased due to enhanced SQSTM1 transcription in hepatocytes. This EFV-induced augmented of p62 levels is mediated through the transcription factor CHOP, but not its traditional regulators, namely, NF-κB and Nrf2. Our data also suggest that p62 exerts a protective function against the mitochondrial reactive oxygen species production induced by EFV, decreasing the expression of pro-inflammatory cytokines and components of the NLRP3 inflammasome. EFV elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract EFV-induced liver injury. There is a specific regulation of p62 exerted by EFV, in order to alleviate the inflammatory response. Our results highlight the dynamic nature of the interaction that takes place among liver cell populations and emphasize the role of the anti-inflammatory M2 phenotype and p62 in the regulation of NLRP3 inflammasome-induced liver injury.

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