Abstract
BackgroundBacterial 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.Animals and MethodsForty-six mice were included in a 16-week protocol of CCl4-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 CCl4 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.ResultsBacterial-DNA translocation was more frequent in CCl4-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.ConclusionsBeta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl4-treated mice with bacterial-DNA.
Highlights
Cirrhosis represents the end-stage of any chronic liver disease, characterized by the most advanced stage of fibrosis, distortion of the liver parenchyma associated with septae and nodule formation, altered blood flow and the potential development of liver failure at long term
Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with vs without bacterial-DNA (319.76120.6 vs 120.7668.6 pg/g for norepinephrine, 38.466.1 vs 29.764.2 pg/g for TNF-alpha, 41.867.4 vs 28.764.3 pg/g for IL-6)
Beta-adrenergic receptor-1 was significantly increased in treated vs control animals (34.667.3 vs 12.565.3, p = 0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA
Summary
Cirrhosis represents the end-stage of any chronic liver disease, characterized by the most advanced stage of fibrosis, distortion of the liver parenchyma associated with septae and nodule formation, altered blood flow and the potential development of liver failure at long term. Our group showed that bacterial DNA (bactDNA) translocation incidence to mesenteric lymph nodes (MLNs) could be correlated with grade of fibrosis in mice treated with weight-controlled CCl4 increasing amounts during a 16-week study [8]. This was associated with changes in gut microbiota content favoring a pro-inflammatory TNF-a and IL-6 up-regulation. These cytokines had already been implicated in fibrosis progression in the past [9,10,11]. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA. Liver bacterial-DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured
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