NADPH oxidase mediated oxidative stress in hepatic fibrogenesis / 대한간학회지

NADPH oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. ROS is involved as key secondary messengers in numerous signaling pathways, and NADPH oxidases complex has been increasingly recognized as key elements of intracellular signaling of hepatic fibrogenesis. In the liver, NADPH oxidase is functionally expressed both in the phagocytic form and in the non-phagocytic form. The non-phagocytic NADPH oxidase complex is structurally and functionally similar to the phagocytic NADPH, resulting in reduction of molecular oxygen to generate superoxide. There are six homologous NOX proteins in the non-phagocytic forms of NADPH oxidase. An emerging concept is that both phagocytic and nonphagocytic NADPH oxidase components in hepatic stellate cells (HSCs) mediate hepatic fibrosis, suggesting its potential role as a pharmacological target for anti-fibrotic therapy. The molecular components and signaling pathways of various NADPH oxidase homologues that are critical for the fibrotic activity in HSCs need to be more clearly identified.

Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B

Activation of hepatic stellate cells is the earliest step in fibrogeneesis. Alpha-smooth muscle acting [alpha-SMA], expressed by activated hepatic sallate cells, and C-terminal procollagen alpha [III] propeptide [PIIICP] are early markers of fibrogenesis and should precede fibrosis. ASD: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. Paried liver biopsies from patients with hepatitis B before and after therapy with lamivudine [n=47] or placebo [n=33] were studied. Alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression [1.06 +/- 0.23 vs. 0.58 +/- 0.11, pre vs. post, P< 0.05]. Placebo recipients had increased levels of alpha -SMA 0.82 +/- 0.14 vs. 1.32 +/- 0.21, P< 0.05]. PIICP was similarly decreased after lamivudine. Among subjects whose Histological Activity Index fibrosis score was unchanged or worsened, the mean changes in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo. Lamivudine decreased markers of hepatic satellite cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibro-genesis and will be useful in trials of antiviral and antifibrotic agents