title: Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells.
abstract: OBJECTIVE
  To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury.
  
  
  METHODS
  Liver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed.
  
  
  RESULTS
  CARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group.
  
  
  CONCLUSIONS
  CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines.
authors.affiliation: Postgraduate Program in Health Science, UFRN, Natal, RN, Brazil.|Postgraduate Program in Functional and Structural Biology/Department of Morphology/UFRN, Natal, RN, Brazil.
authors.forename: Raimundo Fernandes de
authors.initials: RF
authors.lastname: Araújo Júnior
authors.affiliation: Postgraduate Program in Health Science, UFRN, Natal, RN, Brazil.
authors.forename: Vinícius Barreto
authors.initials: VB
authors.lastname: Garcia
authors.affiliation: Department of Morphology/Postgraduate Program in Morphology/UFC, Fortaleza, CE, Brazil.
authors.forename: Renata Ferreira de Carvalho
authors.initials: RF
authors.lastname: Leitão
authors.affiliation: Department of Morphology/Postgraduate Program in Morphology/UFC, Fortaleza, CE, Brazil.
authors.forename: Gerly Anne de Castro
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Department of Physical/Analytical Center/UFC, Fortaleza, CE, Brazil.
authors.forename: Emilio de Castro
authors.initials: Ede C
authors.lastname: Miguel
authors.affiliation: Department of Microbiology and Parasitology, UFRN, Natal, RN, Brazil.
authors.forename: Paulo Marcos Matta
authors.initials: PM
authors.lastname: Guedes
authors.affiliation: Department of Biophysics and Pharmacology, UFRN, Postgraduate Programs in Public Health and Pharmaceutical Science, Natal, RN, Brazil.
authors.forename: Aurigena Antunes
authors.initials: AA
authors.lastname: de Araújo
mesh_terms: D000818:Animals; D015415:Biomarkers; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002227:Carbazoles; D016207:Cytokines; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D000431:Ethanol; D008315:Malondialdehyde; D009195:Peroxidase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase