Beatriz Lozano-Ruiz1, Victoria Bachiller1, Irma García-Martínez1, Pedro Zapater2, Isabel Gómez-Hurtado1, Alba Moratalla1, Paula Giménez1, Pablo Bellot1, Rubén Francés3, José Such4, José M González-Navajas5. 1. Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. 2. Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Pharmacology Unit, Hospital General Universitario de Alicante, Spain. 3. Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Medicine, University Miguel Hernández, Elche, Alicante, Spain. 4. Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Medicine, University Miguel Hernández, Elche, Alicante, Spain; Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates. 5. Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: gonzalez_josnav@gva.es.
Abstract
BACKGROUND & AIMS: Inflammation is a common event in the pathogenesis of liver cirrhosis. The inflammasome pathway has acquired significant relevance in the pathogenesis of inflammation, but its role in the inflammatory response in patients with decompensated cirrhosis remains unexplored. METHODS: We performed a prospective study in which 44 patients with decompensated cirrhosis and 12 healthy volunteers were included. We isolated macrophages from blood and ascitic fluid and assessed the expression and activation of the inflammasome, its response to priming by bacterial products, and its association with the degree of liver disease. RESULTS: Macrophages from sterile ascitic fluids showed constitutive activation of caspase-1 and a marked increase in the expression of IL-1β, IL-18, and absent in melanoma 2 (AIM2) when compared to blood macrophages. Pre-stimulation of blood-derived macrophages from cirrhotic patients with bacterial DNA increased the expression of AIM2 and induced a higher AIM2-mediated inflammasome response than priming with other bacterial products such as lipopolysaccharide. By contrast, activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. Last, higher IL-1β and IL-18 production by ascitic fluid macrophages correlated with a more advanced Child-Pugh score. CONCLUSIONS: The inflammasome is highly activated in the ascitic fluid of cirrhotic patients, which may explain the exacerbated inflammatory response observed in these patients under non-infected conditions. Clinically, activation of the inflammasome is associated with a higher degree of liver disease.
BACKGROUND & AIMS:Inflammation is a common event in the pathogenesis of liver cirrhosis. The inflammasome pathway has acquired significant relevance in the pathogenesis of inflammation, but its role in the inflammatory response in patients with decompensated cirrhosis remains unexplored. METHODS: We performed a prospective study in which 44 patients with decompensated cirrhosis and 12 healthy volunteers were included. We isolated macrophages from blood and ascitic fluid and assessed the expression and activation of the inflammasome, its response to priming by bacterial products, and its association with the degree of liver disease. RESULTS: Macrophages from sterile ascitic fluids showed constitutive activation of caspase-1 and a marked increase in the expression of IL-1β, IL-18, and absent in melanoma 2 (AIM2) when compared to blood macrophages. Pre-stimulation of blood-derived macrophages from cirrhotic patients with bacterial DNA increased the expression of AIM2 and induced a higher AIM2-mediated inflammasome response than priming with other bacterial products such as lipopolysaccharide. By contrast, activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. Last, higher IL-1β and IL-18 production by ascitic fluid macrophages correlated with a more advanced Child-Pugh score. CONCLUSIONS: The inflammasome is highly activated in the ascitic fluid of cirrhotic patients, which may explain the exacerbated inflammatory response observed in these patients under non-infected conditions. Clinically, activation of the inflammasome is associated with a higher degree of liver disease.
Authors: María Martínez-Esparza; María Tristán-Manzano; Antonio J Ruiz-Alcaraz; Pilar García-Peñarrubia Journal: World J Gastroenterol Date: 2015-11-07 Impact factor: 5.742