Hepatic

stellate cells play a key role in the initiation of scar by transforming from a quiescent, vitamin A rich state, to an activated state characterized by distinct structural and functional changes. Stimuli for HSC activation and proliferation are derived from neighboring hepatocytes, endothelial and Kupffer cells by way of TGF-β, EGF and platelet-derived growth factor (PDGF).65 The contractility of HSCs is regulated by endothelin (ET), compressing the sinusoids and increasing portal resistance.66 As disease progresses, the balance between ET and nitric oxide (NO), an ET-1 antagonist also produced by HSCs, inclines in favor of ET-1.66 HSCs also release neutrophil and monocyte attractant chemokines, colony stimulating factor (CSF) and monocyte chemotactic Deforolimus protein-1 (MCP-1), that recruit immune cells to the site of injury.67 Other anti-inflammatory cytokines, such as, IL-10, are amplified in early HSC activation and are responsible for an antifibrotic response by reducing collagen 1 and increasing collagenase.68 Another process ATR inhibitor actioned by HSC in liver injury is the production of matrix metalloproteinases (MMPs); these proteolytic enzymes

degrade matrix-forming proteins, such as collagen type 1. As liver injury progresses, this anti-fibrotic reaction is counteracted by tissue inhibitors of metalloproteinases (TIMPs), also produced by HSCs.69 Since activated HSCs are also the main source of TGF-β, they primarily drive fibrogenesis through excessive production of extracellular matrix in ALD.70 Recent high-throughput technologies,

for example microarrays, genomics and proteomics have led to novel concepts in our understanding of several liver pathologies.71–80 Application of these technologies has identified novel pathways selleck chemicals llc that could not have been discovered using traditional approaches and opened up several lines of investigation for understanding the mechanisms of alcohol-mediated tissue injury. Hepatic gene expression profiling using DNA microarrays are reported from animal models of ALD78–80 and human ALD.77,78 The ALD transcriptome profile is dominated by alcohol metabolism and inflammation related molecules, thus differing from other liver diseases.78 Moreover, the transcript response to alcohol in vitro was significantly different from that of other hepatotoxins, such as cancer drugs.81 However, similarities in the hepatic transcriptome profiles of cirrhotic livers from the Lieber DeCarli baboon model of ALD and progressive stages of human ALD, reflect that the effect of alcohol exceeded any confounding factors expected in human ALD.