The role of NOX expressed in nonphagocytic AZD1208 datasheet inflammatory cells such as lymphocytes, natural killer cells and natural killer T cells in hepatic fibrogenesis

is unknown. T lymphocytes express a phagocyte-type NOX that functions in T cells to produce ROS in response to stimulation through the T cell receptor.35 When we assessed the expression of M1 and M2 macrophage markers in the fibrotic liver, there was no significant difference between WT and NOX2KO mice, suggesting the less important role of other NOX2-expressing, BM-derived immune cells in hepatic fibrosis. Analysis of expression of NOX components in isolated liver cell fractions from control mice demonstrate that phagocytic NOX components such as NOX2, p40phox, p47phox, and p67phox are mainly expressed in KCs, whereas nonphagocytic NOX components including NOX1, NOXO1, and NOXA1 are expressed in HSCs and SECs. In addition, both NOX1 and NOX2 components are up-regulated in activated HSCs compared with quiescent cells. We confirmed the expression of NOX1 and NOX2 proteins in mouse HSCs as well as in the human activated HSC line LX-2. We demonstrated that Ang II–induced ROS production and fibrogenic responses in NOX1- or NOX2-deficient HSCs are attenuated compared with WT HSCs, indicating

that both NOX1 and NOX2 are important in NOX-mediated ROS generation and fibrogenic responses in HSCs. selleck screening library Taken together, HSCs appear to be the primary cell type for NOX1- and NOX2-mediated hepatic fibrosis. We also found that NOX1 is expressed in the minority of CD31-positive SECs in the fibrotic liver. We suggest that NOX1-mediated low levels of O2.− production in SECs may have some regulatory function in the liver and warrants further study. ROS has diverse effects with respect to different kinds, concentrations, and cell types. H2O2 and superoxide have different physiological characteristics in that H2O2 can easily diffuse across plasma membrane and throughout the cell, whereas superoxide diffuses poorly across cell membranes.36 Although higher concentration of ROS is

cytotoxic, lower concentration of ROS serves Adenosine triphosphate as a second messenger during cellular response to a variety of physiological stimuli. A low dose of H2O2 has mitogenic effects and can mimic the function of growth factors.37 Regarding the effects of ROS on HSCs, the contradictory results have been reported: both mitogenic and cell death–inducing properties. Nontoxic levels of ROS or lipid peroxidation products stimulate the activation, proliferation, and collagen production of HSCs, but high concentration of ROS induce HSC death.4, 5, 38 We speculate that NOX2-mediated robust production of superoxide in KCs acts mainly for the host defense, while NOX1- and NOX2-mediated ROS generation in HSCs may act as an important secondary messenger to activate HSCs in hepatic fibrosis.