6 The NOX family consists of seven different members (NOX1-5 and the dual oxidases, Duox1 and -2).7 Among the NOX family, both NOX1, NOX2 (also named gp91phox), and NOX4 are expressed on HSCs and may contribute to liver fibrosis.6, 8 Bone marrow (BM) chimeric mice demonstrated that liver fibrosis requires NOX2-generated ROS from both BM-derived

inflammatory cells and endogenous selleck screening library liver cells, including HSCs, whereas NOX1 is required from only endogenous liver cells.6 Furthermore, NOX1 knockout (NOX1KO) HSCs have less ROS generation than NOX2KO HSCs.6 Therefore, we suggest that NOX1 is more crucial than NOX2 in the generation of ROS in HSCs. Upon stimulation with agonists, such Selleckchem PD-L1 inhibitor as angiotensin II (Ang II), the cytosolic subunits, including Rac-GTP, translocate to the membrane-bound cytochrome complex to produce enzymatically active NOX1 and NOX2.9 On the other hand, NOX4 activity is regulated by increased expression of its protein, including during myofibroblast/HSC activation.10-12 In particular,

transforming growth factor beta (TGF-β) signaling increases the protein expression and activity

of NOX through the increase in NOX4 gene transcription, not by agonist-induced complex formation.7 Superoxide dismutase 1 (SOD1) interacts with Ras-related botulinum toxin substrate 1 (Rac1) in the active NOX complex to stimulate NOX activity.13 Mutations in SOD1, such as G93A and G37R, which are associated with familial amyotrophic lateral sclerosis,14 increase NOX activity to produce increased ROS in glial cells in the brain13 and in other organs, including the liver.15 However, the interaction between wild-type (WT) or mutant selleck products SOD1 with NOX in HSCs and in liver fibrosis is unknown. Because of this evidence incriminating NOX1 and NOX4 in the pathogenesis of liver fibrosis, we aimed to assess the effectiveness of treatment with GKT137831, a NOX1/4 inhibitor, on the development of liver fibrosis. Furthermore, We wanted to investigate the role of SOD1 in NOX activity and liver fibrosis. We hypothesized that mice with the SOD1 G37R mutation (SOD1mu) with increased catalytic activity would have increased ROS generation and increased liver fibrosis.