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Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo
Author(s) -
Zhan ShanShan,
Jiang Joy X.,
Wu Jian,
Halsted Charles,
Friedman Scott L.,
Zern Mark A.,
Torok Natalie J.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21093
Subject(s) - hepatic stellate cell , phagocytosis , nadph oxidase , microbiology and biotechnology , intracellular , reactive oxygen species , superoxide , apoptosis , biology , chemistry , biochemistry , endocrinology , enzyme
Hepatic stellate cell activation is a main feature of liver fibrogenesis. We have previously shown that phagocytosis of apoptotic bodies by stellate cells induces procollagen α1 (I) and transforming growth factor beta (TGF‐β) expression in vitro . Here we have further investigated the downstream effects of phagocytosis by studying NADPH oxidase activation and its link to procollagen α1 (I) and TGF‐β1 expression in an immortalized human stellate cell line and in several models of liver fibrosis. Phagocytosis of apoptotic bodies in LX‐1 cells significantly increased superoxide production both in the extracellular and intracellular milieus. By confocal microscopy of LX‐1 cells, increased intracellular reactive oxygen species (ROS) were detected in the cells with intracellular apoptotic bodies, and immunohistochemistry documented translocation of the NADPH oxidase p47phox subunit to the membrane. NADPH oxidase activation resulted in upregulation of procollagen α1 (I); in contrast, TGF‐β1 expression was independent of NADPH oxidase activation. This was also confirmed by using siRNA to inhibit TGF‐β1 production. In addition, with EM studies we showed that phagocytosis of apoptotic bodies by stellate cells occurs in vivo . In conclusion, these data provide a mechanistic link between phagocytosis of apoptotic bodies, production of oxidative radicals, and the activation of hepatic stellate cells. (H EPATOLOGY 2006;43:435–443.)