Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo

Shan Shan Zhan, Xiaosong Jiang, Jian Wu, Charles Halsted, Scott L. Friedman, Mark A Zern, Natalia J Torok

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)435-443
Number of pages9
JournalHepatology
Volume43
Issue number3
DOIs
StatePublished - Mar 2006

Fingerprint

Hepatic Stellate Cells
NADPH Oxidase
Phagocytosis
Liver Cirrhosis
Procollagen
Transforming Growth Factor beta1
Transforming Growth Factor beta
Confocal Microscopy
Superoxides
Small Interfering RNA
Reactive Oxygen Species
Up-Regulation
Immunohistochemistry
Extracellular Vesicles
Cell Line
Membranes
Liver

ASJC Scopus subject areas

  • Hepatology

Cite this

Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. / Zhan, Shan Shan; Jiang, Xiaosong; Wu, Jian; Halsted, Charles; Friedman, Scott L.; Zern, Mark A; Torok, Natalia J.

In: Hepatology, Vol. 43, No. 3, 03.2006, p. 435-443.

Research output: Contribution to journalArticle

Zhan, Shan Shan ; Jiang, Xiaosong ; Wu, Jian ; Halsted, Charles ; Friedman, Scott L. ; Zern, Mark A ; Torok, Natalia J. / Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. In: Hepatology. 2006 ; Vol. 43, No. 3. pp. 435-443.
@article{408109d6e31e4f6a94f35a0fce9188e5,
title = "Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo",
abstract = "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.",
author = "Zhan, {Shan Shan} and Xiaosong Jiang and Jian Wu and Charles Halsted and Friedman, {Scott L.} and Zern, {Mark A} and Torok, {Natalia J}",
year = "2006",
month = "3",
doi = "10.1002/hep.21093",
language = "English (US)",
volume = "43",
pages = "435--443",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo

AU - Zhan, Shan Shan

AU - Jiang, Xiaosong

AU - Wu, Jian

AU - Halsted, Charles

AU - Friedman, Scott L.

AU - Zern, Mark A

AU - Torok, Natalia J

PY - 2006/3

Y1 - 2006/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33645243410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645243410&partnerID=8YFLogxK

U2 - 10.1002/hep.21093

DO - 10.1002/hep.21093

M3 - Article

C2 - 16496318

AN - SCOPUS:33645243410

VL - 43

SP - 435

EP - 443

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -