• Título:  ANTIRETROVIRAL THERAPY AND ITS ROLE IN THE PROGRESSION OF ACUTE AND CHRONIC LIVER INJURY
• Autor:  MARTÍ RODRIGO, ALBERTO
• Universidad:  Universitat de València (Estudi General)
• Departamento:  Farmacología
• Fecha de Lectura:  28/02/2019
• Mención Europeo / Mención Internacional: concedido
• Programa de doctorado:  Programa de Doctorado en Biomedicina y Farmacia por la Universitat de València (Estudi General)
• Dirección: 
  • ESPLUGUES MOTA, JUAN VICENTE (DIRECTOR)
  • BLAS GARCÍA, ANA (CODIRECTOR)
• Tribunal: 
  • Barrachina Sancho, Dolores (PRESIDENTE)
  • GRACIA SANCHO, JORGE (SECRETARIO)
  • NEVZOROVA, YULIA (VOCAL)
• Descriptores: 
  • FARMACOLOGIA EXPERIMENTAL
  • GASTROENTEROLOGIA
  • BIOLOGIA MOLECULAR
• Localización:  BIBLIOTECA FACULTAD DE FARMACIA, UNIVERSIDAD DE VALENCIA (ESTUDI GENERAL)
• 451938_1166026.pdf
• Resumen:
  In the last decades, the use of combined antiretroviral therapies (cART) has become human immunodeficiency virus (HIV) infection in a chronic disease. Thus, current clinical criteria to select the best antiviral combinations mainly rely on the safety of each drug in for life-therapeutic regimens. In this doctoral thesis, the involvement of several antiretrovirals in the progression of both acute and chronic liver damage was studied. First of all, we assessed the mitochondrial disturbances which lead to the clinical toxicity of the nucleosideanalogue reverse transcriptase inhibitors Abacavir (ABC) and Didanosine (ddI) in hepatocytes. We described how these molecules, at clinical doses, undermined the mitochondrial function by inhibiting complexes I and III of the electron transport chain without affecting cellular viability. However, these drugs became cytotoxic in hepatocytes when they were combined with clinical doses of acetaminophen, whose hepatotoxicity also involves the mitochondria. The second part of this study was aimed to describe the implication of the anti- HIV therapy in the onset and progression of chronic liver disease. After testing several drugs in a mouse model of non-alcoholic fatty liver disease (NAFLD), we focused on Efavirenz (EFV) and Rilpivirine (RPV), both non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), because they exerted an unexpected and surprising anti-adipogenic, anti-inflammatory and anti-fibrogenic effect in the liver. To further analyse this effect, we performed both mouse models of CCl4- induced liver fibrosis and in vitro studies with hepatocytes and hepatic stellate cells (HSC). In this case, we were able to reproduce the RPV-induced hepatoprotective effects observed in the rest of animal models, confirming that this drug exerts a striking anti-inflammatory and anti-fibrotic role in the liver. Additionally, we described that this effect is directly mediated by a selective induction of apoptosis in HSC, which depends on the activation of the transcription factor STAT1 in these cells. At the same time, the secretome of RPV-induced apoptotic HSC activates an intense regenerative response in the liver mediated by STAT3 activation in hepatocytes. Considering that there is no cure for either NALFD or liver fibrosis, the relevance and the clinical applicability of this study is evident. We defend the utilization of RPV in all those HIV-infected patients with special susceptibility to liver disease. Furthermore, we also propose RPV as a potential anti-fibrotic drug, whose effectivity should be tested in patients with chronic liver disease in the next future. Finally, we encourage the scientific community to deeply explore the role of JAKSTAT1 and 3 in the different cell subsets within the liver, as well as in other organs, as key targets to therapeutically manage different fibrotic disorders.