Notably, hepatocytes from global Nlrp3 mutant mice showed marked hepatocyte pyroptotic cell death with more than a twenty fold increase in active Gasp1-PI double positive cells. Mutant NLRP3 activation restricted to the myeloid lineage resulted in a less severe liver phenotype with an absence of detectable hepatic pyroptotic cell death. Gonclusions: Our data demonstrates that global and to a lesser extent myeloid-specific NLRP3 www.selleckchem.com/products/Rapamycin.html inflammasome activation results in severe liver inflammation and fibrosis, while identifying hepatocyte pyroptotic cell death as a novel mechanism of

NLRP3 mediated liver damage. Disclosures: The following people have nothing to disclose: Alexander Wree, Akiko Eguchi, Matthew D.

McGeough, Casey Johnson, Carla A. Pena, Ali Canbay, Hal M. Hoffman, Ariel E. Feldstein BACKGROUND: Even when sterile, hepatocellular injury is typically followed by a strong inflammatory response. It is commonly believed that this “sterile inflammation” exacerbates liver injury. However, this hypothesis remains to be proven, and ABT-263 datasheet mediators linking injury to sterile inflammation remain to be identified. Several candidates belonging to the group of damage-associated molecular patterns (DAMPs) have been suggested to be involved in this process. AIM: Here we seek to test the hypothesis that high mobility group box 1(HMGB1), a prototypical DAMP, provides a molecular link between hepatocyte death

and sterile inflammation. 上海皓元 METHODS: To investigate the role of HMGB1 in sterile inflammation, we floxed exons 2-4 of the HMGB1 gene and generated mice with targeted deletion of HMGB1 in hepatocytes (using Alb-Gre=HMGB1 ΔHep) or in bone marrow-derived inflammatory cells (using Vav1 Gre=HMGB1 ABM). We tested our hypothesis by investigating inflammation and injury responses in mice with cell-specific deletion of HMGB1 in two clinically relevant models of acute liver injury, warm hepatic ischemia/reperfusion (I/R) and acetaminophen (APAP, 300-500mg/kg i. p.) intoxication. RESULTS: Despite similar degrees of liver injury early (6h) after I/R, HMGB1 ΔHep mice exhibited a 81% reduction of infiltrating neutrophils (p<0.05) and of proinflammatory genes Gcl2, Gd11b and IL-6 (all p<0.05). This decrease in early inflammation was reflected by an amelioration of liver injury 24h after I/R with an 88% reduction of necrosis area (p<0.01) and 85% reduction of ALT (p<0.05). A similar injury-amplification mechanism existed in the APAP injury model, where hepatic inflammation, injury and necrosis area were >80% reduced in HMGB1 ΔHep mice (all p<0.01) despite normal APAP metabolization and similar injury at early time points.