Pathways of hepatic stellate cell activation. Features of stellate cell activation can be distinguished between those that stimulate initiation, and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS) and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. (Abbreviations: PDGF – platelet derived growth factor, VEGF – vascular endothelial growth factor; FGF- fibroblast growth factor; ET-1 – endothelin-1; NO – nitric oxide; TGFβ1 – transforming growth factor beta 1; CTGF – connective tissue growth factor; MMP- matrix metalloproteinase; MT-MMP – membrane type matrix metalloproteinase; TIMP – tissue inhibitor of metalloproteinase; TLR- toll like receptor). Reprinted from Ref 1, with permission.