Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease.
Por:
Maeso-Díaz R, Ortega-Ribera M, Lafoz E, Lozano JJ, Baiges A, Frances R, Albillos A, Peralta C, García-Pagán JC, Bosch J, Cogger VC and Gracia-Sancho J
Publicada:
1 ago 2019
Resumen:
Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.
Filiaciones:
Maeso-Díaz R:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
Ortega-Ribera M:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
Lafoz E:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
Lozano JJ:
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
Baiges A:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
Frances R:
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
Inmunobiologia y traslocación bacteriana. 3Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL -Fundación FISABIO), Alicante, Spain
Albillos A:
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
4 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain
Peralta C:
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
5Protective Strategies Against Hepatic Ischemia-Reperfusion Group, IDIBAPS, Barcelona, Spain
García-Pagán JC:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
Bosch J:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
6Hepatology, Department of Biomedical Research, Inselspital, Bern University, Switzerland
Cogger VC:
7Centre for Education and Research on Ageing ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia
Gracia-Sancho J:
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
6Hepatology, Department of Biomedical Research, Inselspital, Bern University, Switzerland
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