title: Amelioration of hepatic inflammation in a mouse model of NASH using a dithiocarbamate derivative.
abstract: OBJECTIVE
  The process whereby liver inflammation develops in non-alcoholic steatohepatitis (NASH) is not fully understood. While modification of the inflammatory milieu is an attractive target to prevent the development of hepatocellular injury, most antiinflammatory agents have proven ineffective in this setting. Tetraethylthiuram disulfide (TDSF) is able to induce S-glutathionylation of NF-κB along with critical signaling proteins involved with inflammation, especially when complexed with a heavy metal. For this reason, we hypothesized that administration of TDSF would function to ameliorate necroinflammatory activity in a mouse model of NASH.
  
  
  METHODS
  Mice were divided into five groups and received control chow versus a methionine-choline-deficient diet. After 6 weeks of TDSF versus sham gavage, animals were necropsied. Using conventional H&E staining, livers were examined using the Brunt scoring system by a hepatopathologist blinded to treatment groups. Validated mouse primer sets were used for quantitative real-time PCR to evaluate changes in mRNA expression.
  
  
  RESULTS
  Livers treated with TDSF demonstrated a qualitative reduction in lobular inflammation, lipogranuloma formation, and Kupffer cell accumulation, but not steatosis. Significant reductions in inflammatory transcripts for α-1-collagen, TGF-β, Mmp2, MCP-1, and TNF-1α were also observed.
  
  
  CONCLUSIONS
  Animals treated with TDSF exhibit a reduction in lobular inflammation that is independent of lipid accumulation when administered MCD diet. Similar reductions are seen in several inflammatory transcripts associated with NASH. Additional work in this area may reveal a therapeutic role for TDSF or similar agents in curtailing inflammatory signaling within the liver.
authors.affiliation: Division of Transplantation, Department of Surgery, University of Texas, Southwestern, 5323 Harry Hines Blvd, Dallas, TX, USA. jason.schwartz@utsouthwestern.edu.|Department of General Surgery, University of Utah, Salt Lake City, UT, USA. jason.schwartz@utsouthwestern.edu.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Schwartz
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA. lyska.emerson@hsc.utah.edu.
authors.forename: Lyska
authors.initials: L
authors.lastname: Emerson
authors.affiliation: Department of General Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hillas
authors.affiliation: Department of General Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Phan
authors.affiliation: Department of General Surgery, University of Utah, Salt Lake City, UT, USA. heather.thiesset@hsc.utah.edu.
authors.forename: Heather
authors.initials: H
authors.lastname: Thiesset
authors.affiliation: Department of General Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Firpo
authors.affiliation: Department of General Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sorensen
authors.affiliation: Georgia Health Sciences University, Section of Pulmonology, Augusta, GA, USA. TKennedy@georgiahealth.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kennedy
authors.affiliation: Department of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. m-rinella@northwestern.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Rinella
keywords: Animal Models; Disulfiram; Dithiocarbamates; NAFLD; NASH; Therapies