title: Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice.
abstract: Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis, and inflammation. In this article, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology.
  
  
  
  A 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis.
  
  
  
  We found that binge drinking induced significant SYK activation (SYK(Y525/526) ) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-nuclear factor kappa beta (NF-κB) p65, NF-κB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis.
  
  
  
  Our novel observations demonstrate the role of SYK, activation in the pathomechanism of binge drinking-induced liver disease highlighting SYK a potential multifaceted therapeutic target.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Terence N
authors.initials: TN
authors.lastname: Bukong
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Vellve
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Benedek
authors.initials: B
authors.lastname: Gyongyosi
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Aditya
authors.initials: A
authors.lastname: Ambade
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D063425:Binge Drinking / Q000097:blood / Q000473:pathology*; D018932:Chemokine CCL2 / Q000097:blood; D000431:Ethanol / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010078:Oxazines / Q000627:therapeutic use*; D000070780:Perilipin-2 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018932:Chemokine CCL2; D053583:Interleukin-1beta; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D009687:Nuclear Proteins; D010078:Oxazines; D000070780:Perilipin-2; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D064429:Fatty Acid Synthases; D000410:Alanine Transaminase; D000072377:Syk Kinase; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Alcoholic Hepatitis; Binge Drinking; Nonreceptor Tyrosine Kinase