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

PLoS One. 2012;7(8):e43371. doi: 10.1371/journal.pone.0043371. Epub 2012 Aug 20.

Abstract

Background: 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.

Animals and methods: 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.

Results: 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.

Conclusions: Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl(4)-treated mice with bacterial-DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / therapeutic use*
  • Animals
  • Benzopyrans / therapeutic use
  • Butoxamine / therapeutic use
  • Carbon Tetrachloride / toxicity
  • DNA, Bacterial / metabolism
  • Ethanolamines / therapeutic use
  • Female
  • Liver Cirrhosis, Experimental / chemically induced
  • Liver Cirrhosis, Experimental / drug therapy*
  • Liver Cirrhosis, Experimental / metabolism*
  • Liver Cirrhosis, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Nebivolol
  • Norepinephrine / metabolism*
  • Receptors, Adrenergic, beta / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Benzopyrans
  • DNA, Bacterial
  • Ethanolamines
  • Receptors, Adrenergic, beta
  • Tumor Necrosis Factor-alpha
  • Nebivolol
  • Butoxamine
  • Carbon Tetrachloride
  • Norepinephrine

Grant support

This work has been supported by grants CP05/0005, PI10/0340 and PI11/0962 from Instituto de Salud Carlos III, Madrid, Spain; AP-026/09 and AP-162/11 from Consellería de Sanitat, Generalitat Valenciana, Spain; C-6/11 from Fundación FCVI-HGUA, Alicante, Spain; and Diputación Provincial de Alicante, Alicante, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.