188,189 In addition to the above, Seth et al. also identified novel molecules (plasminogen, annexinA2, p11, osteopontin) that regulate activation of plasmin and fibrinolysis

in human ALD, in vivo and in vitro cell culture models of alcohol.83,101,186 In the latter models, a moderate dose of alcohol (10 mM; 2 g/kg) caused steatosis with overexpression of pro-fibrinolytic selleck chemicals annexin A2, p11, tPA and plasminogen, associated with plasmin activation and enhanced fibrinolysis. Contrary to this, a high dose of alcohol (100 mM; 6 g/kg) inhibited expression of pro-fibrinolytic genes but sustained an increase in anti-fibrinolytic PAI-1 in vitro and in vivo.186 It is intriguing that a single high dose of alcohol alters the fibrinolytic balance towards the anti-fibrinolytic profile prior to histopathological evidence of cellular injury in this model. These data and other reports187 suggest a role for PAI-1 in the progression of ALD. Indirect evidence of a genetic predisposition to ALD was

addressed earlier. In the past, genetic studies in ALD have focused on genes involved in alcohol metabolism (ADH, ALDH, CYP2E1), oxidative stress (GST, superoxide dismutase [SOD] ), endotoxin (TNF-α, CD14, TLR4), cytokines (IL-10), immune (cytotoxic T-lymphocyte antigen-4) and fibrosis (collagen, MMPs, osteopontin, TGF-β) and are extensively reviewed.190 Due to the differences in the capacity to metabolize alcohol to acetaldehyde, individuals with MCE more active ADH1B*2 and ADH1C*1 alleles are considered to be at PF-02341066 mw increased risk of higher acetaldehyde exposure and development of alcoholic liver injury.191 But results from several studies are inconsistent due to ethnic variability

in the populations studied, with ADH1B*2 being a rare allele in Caucasians. The only large study with a sufficient number of cases and controls failed to detect a significant association between ADH1C variants and alcoholic cirrhosis.192 Further, a meta-analysis of all available studies also failed to show any evidence of an association between ADH or ALDH genotypes and ALD.193 In contrast to ADH and ALDH, CYP2E1 is an inducible enzyme and its activity can increase up to 20-fold following continuous alcohol consumption. There are several polymorphic loci within the human CYP2E1 gene194 with two mutations in linkage disequilibrium giving rise to c1 and c2 alleles. The CYP2E1*5 (c2) allele is associated with approximately 10-fold higher mRNA and protein levels as well as enzyme activity than c1 allele; it could therefore cause a higher exposure of the liver to acetaldehyde and ROS.195 Several studies have looked for an association between a promoter region polymorphism of CYP2E1 and ALD, but no consistent results have emerged in any population. Manganese-dependent superoxide dismutase (SOD2) is a key player in ALD pathogenesis since it is involved in the body’s antioxidant defenses and protects mitochondria from peroxidative damage.