NUEVOS MODELOS EXPERIMENTALES PARA EL ESTUDIO DE MECANISMOS FISIOPATOLÓGICOS EN ENFERMEDAD HEPÁTICA CRÓNICA

Abstract

Chronic liver disease (CLD) is a process of progressive destruction of liver parenchyma that triggers fibrosis and cirrhosis. The progression of the pathology is frequently associated with the occurrence of portal hypertension, hepatic failure and the development of cirrhosis complications. Improving the knowledge of the pathophysiology of CLD and associated complications, as well as the underlying mechanisms, is essential for the development of new diagnostic and therapeutic techniques. This depends to a great extent on the development of robust and reproducible animal models._x000D_ The aim of this doctoral thesis is the development of two new animal models and their application in the investigation of pathophysiological mechanisms associated with chronic liver disease. In the first study we explored the role of the intestinal microbiota (IM) in the development of portal hypertension (PH) in the context of nonalcoholic steatohepatitis (NASH), evaluated by means of faecal transplantation experiments. It is showed for the first time that IM plays a key role in the pathogenesis of PH, regardless of fibrosis. Specifically, we observed that transplantation of a healthy IM in rats with NASH and PH without fibrosis (originated after 8 weeks following a high-fat glucose-fructose diet) restored PH to levels comparable to controls. This reduction of PH was associated with a decrease in intrahepatic vascular resistance probably mediated by an improvement of endothelial dysfunction and intrahepatic insulin resistance._x000D_ In the second study we explored the neurodegenerative process consequence of hepatic encephalopathy (HE), one of the complications of cirrhosis. First, we developed an animal model of episodic HE in which we simulated 10 repeated episodes of HE, one every two weeks, triggered by two of the main precipitating factors: hyperammonemia and / or inflammation. Then, by means of stereological analysis, we showed that these repeated episodes of HE triggered irreversible processes of degeneration and death of Purkinje neurons in the cerebellum. Reduction in the number of Purkinje neurons appeared to be mediated by apoptosis of Bergman glia and activation of astrocytes and microglia in the cerebellum._x000D_ These two new models are tools that have allowed us to investigate factors and mechanisms not very explored so far in CLD and that could become new therapeutic targets in a future.

Date of Award	4 Oct 2017
Original language	Spanish
Supervisor	Salvador Augustin Recio (Director), Juan Genesca Ferrer (Director) & Laia Chavarria Vilarasau (Director)