title: A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity.
abstract: OBJECTIVE
  Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity.
  
  
  METHODS
  The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed.
  
  
  RESULTS
  We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP.
  
  
  CONCLUSIONS
  This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role.
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.|Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Suraj J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Luther
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bohr
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Vellve
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Li
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: King
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital and the Shriners Burns Hospital, Boston, MA, USA.|Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush