Beta-adrenergic receptor 1 selective antagonism inhibits norepinephrine-mediated TNF-alpha downregulation in experimental liver cirrhosis

• Published in: PloS one Vol. 7; no. 8; p. e43371
• Main Authors: Zapater, Pedro, Gómez-Hurtado, Isabel, Peiró, Gloria, González-Navajas, José Manuel, García, Irma, Giménez, Paula, Moratalla, Alba, Such, José, Francés, Rubén
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.08.2012; Public Library of Science (PLoS)
• Subjects: Adrenergic beta-1 Receptor Antagonists - therapeutic use; Adrenergic receptors; Animals; Bacteria; Benzopyrans - therapeutic use; Beta blockers; Biology; Biomedical research; Butoxamine - therapeutic use; Carbon; Carbon tetrachloride; Carbon Tetrachloride - toxicity; Catecholamines; CCL4 protein; Cirrhosis; Cytokines; Deoxyribonucleic acid; DNA; DNA, Bacterial - metabolism; E coli; Escherichia coli; Ethanolamines - therapeutic use; Female; Fibrosis; Hepatology; Inflammation; Inflammatory response; Interleukin 6; Laboratory animals; Liver; Liver cirrhosis; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Medicine; Mice; Mice, Inbred BALB C; Modulation; Nebivolol; Nervous system; Norepinephrine; Norepinephrine - metabolism; Receptors, Adrenergic, beta - metabolism; Rodents; Translocation; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043371

Bacterial translocation is a frequent event in cirrhosis leading to an increased inflammatory response. Splanchnic adrenergic system hyperactivation has been related with increased bacterial translocation. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA. Forty-six mice were included in a 16-week protocol of CCl(4)-induced cirrhosis. Laparotomies were performed at weeks 6, 10, 13 and 16. A second set of forty mice injected with a single intraperitoneal dose of CCl(4) was treated with saline, 6-hydroxidopamine, Nebivolol or Butoxamine. After 5 days, mice received E. coli-DNA intraperitoneally. Laparotomies were performed 24 hours later. Liver bacterial-DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured. Bacterial-DNA translocation was more frequent in CCl(4)-treated animals compared with controls, and increased as fibrosis progressed. Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with vs without bacterial-DNA (319.7 ± 120.6 vs 120.7 ± 68.6 pg/g for norepinephrine, 38.4 ± 6.1 vs 29.7 ± 4.2 pg/g for TNF-alpha, 41.8 ± 7.4 vs 28.7 ± 4.3 pg/g for IL-6). Only beta-adrenergic receptor-1 was significantly increased in treated vs control animals (34.6 ± 7.3 vs 12.5 ± 5.3, p=0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA. In the second set of mice, cytokine levels were increased in 6-hydroxidopamine and Nebivolol (beta-adrenergic receptor-1 antagonist) treated mice compared with saline. Butoxamine (beta-adrenergic receptor-2 antagonist) didn't inhibit liver norepinephrine modulation of pro-inflammatory cytokines. Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl(4)-treated mice with bacterial-DNA.