62–64 RAGE’s interaction with DAMPs also results in activation of p38 SAPK, the transcription factors STAT-3 and AP-1.62,63 Intriguingly, animals treated with extracellular ligand binding domain of RAGE (sRAGE) displayed increased survival after total hepatic IR.62 Moreover, the remnants of sRAGE treated livers revealed diminished activation of JNK, STAT3 and NF-κB.62 Since the author’s 2003

review in the Journal, many advances have been made in elucidating the mechanisms underlying hepatic IR injury.23 These include clarification of interactions between different cell types, a variety of signalling pathways between inflammatory cells, response to oxidative stress, new molecules promoting the release of Selleckchem LBH589 cytokines, expression of chemokines, and

neutrophil recruitment. However, little progress has been made in pinning down the ultra-early events, or critical mediators post-IR that initiate the plethora of late phase responses. Because so many events complicate the later stages of IRI, efforts in the next decade should be focused on designing optimal interventions that will inhibit these very early events, or intercepting the critical mediators that trigger the signalling cascades leading to end-organ damage. “
“Recent data suggest that the chemokine receptor CXCR3 is functionally involved in fibroproliferative disorders, including liver fibrosis. Neoangiogenesis is an important pathophysiological feature of liver scarring, but a functional role of angiostatic CXCR3 chemokines Luminespib mw in this process is unclear. We therefore investigated neoangiogenesis in carbon tetrachloride (CCl4)-induced liver fibrosis in Cxcr3−/− and wildtype mice by histological, molecular, and functional imaging methods. Furthermore, we assessed the direct role of vascular endothelial growth factor (VEGF) overexpression

on liver angiogenesis and the fibroproliferative response using a Tet-inducible bitransgenic mouse model. The feasibility of attenuation of angiogenesis and associated liver fibrosis by therapeutic treatment with the angiostatic chemokine Cxcl9 was systematically analyzed in vitro and in vivo. The results demonstrate that fibrosis progression in Cxcr3−/− mice was strongly linked to enhanced neoangiogenesis and VEGF/VEGFR2 expression compared with wildtype littermates. Systemic VEGF overexpression 上海皓元 led to a fibrogenic response within the liver and was associated with a significantly increased Cxcl9 expression. In vitro, Cxcl9 displayed strong antiproliferative and antimigratory effects on VEGF-stimulated endothelial cells and stellate cells by way of reduced VEGFR2 (KDR), phospholipase Cγ (PLCγ), and extracellular signal-regulated kinase (ERK) phosphorylation, identifying this chemokine as a direct counter-regulatory molecule of VEGF signaling within the liver. Accordingly, systemic administration of Cxcl9 led to a strong attenuation of neoangiogenesis and experimental liver fibrosis in vivo.