Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo

Joy X. Jiang, Senthil Venugopal, Nobuko Serizawa, Xiangling Chen, Fiona Scott, Yong Li, Roger Adamson, Sridevi Devaraj, Vijay Shah, M. Eric Gershwin, Scott L. Friedman, Natalie J. Török

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Background & Aims Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. Methods An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2-/- mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2-/- mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. Results In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2-/- mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2-/- animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2-/- mice, suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Conclusions Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver fibrogenesis in vivo.

Original languageEnglish (US)
JournalGastroenterology
Volume139
Issue number4
DOIs
StatePublished - Oct 2010

Fingerprint

Hepatic Stellate Cells
NADP
Oxidoreductases
Phagocytosis
Liver
Hepatocytes
Collagen
Bile Ducts
Apoptosis
Fibrosis
Fluorescence
Gadolinium
Smooth Muscle
Actins
Reactive Oxygen Species
Proteins
Tumor Necrosis Factor-alpha
Macrophages
Ligands

Keywords

  • Apoptosis
  • Liver Fibrosis
  • NADPH Oxidase

ASJC Scopus subject areas

  • Gastroenterology
  • Medicine(all)

Cite this

Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo. / Jiang, Joy X.; Venugopal, Senthil; Serizawa, Nobuko; Chen, Xiangling; Scott, Fiona; Li, Yong; Adamson, Roger; Devaraj, Sridevi; Shah, Vijay; Gershwin, M. Eric; Friedman, Scott L.; Török, Natalie J.

In: Gastroenterology, Vol. 139, No. 4, 10.2010.

Research output: Contribution to journalArticle

Jiang, JX, Venugopal, S, Serizawa, N, Chen, X, Scott, F, Li, Y, Adamson, R, Devaraj, S, Shah, V, Gershwin, ME, Friedman, SL & Török, NJ 2010, 'Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo', Gastroenterology, vol. 139, no. 4. https://doi.org/10.1053/j.gastro.2010.05.074
Jiang, Joy X. ; Venugopal, Senthil ; Serizawa, Nobuko ; Chen, Xiangling ; Scott, Fiona ; Li, Yong ; Adamson, Roger ; Devaraj, Sridevi ; Shah, Vijay ; Gershwin, M. Eric ; Friedman, Scott L. ; Török, Natalie J. / Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo. In: Gastroenterology. 2010 ; Vol. 139, No. 4.
@article{802801a62dcc4ce3b8c3af82989257a4,
title = "Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo",
abstract = "Background & Aims Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. Methods An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2-/- mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2-/- mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. Results In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2-/- mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2-/- animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2-/- mice, suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Conclusions Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver fibrogenesis in vivo.",
keywords = "Apoptosis, Liver Fibrosis, NADPH Oxidase",
author = "Jiang, {Joy X.} and Senthil Venugopal and Nobuko Serizawa and Xiangling Chen and Fiona Scott and Yong Li and Roger Adamson and Sridevi Devaraj and Vijay Shah and Gershwin, {M. Eric} and Friedman, {Scott L.} and T{\"o}r{\"o}k, {Natalie J.}",
year = "2010",
month = "10",
doi = "10.1053/j.gastro.2010.05.074",
language = "English (US)",
volume = "139",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in Vivo

AU - Jiang, Joy X.

AU - Venugopal, Senthil

AU - Serizawa, Nobuko

AU - Chen, Xiangling

AU - Scott, Fiona

AU - Li, Yong

AU - Adamson, Roger

AU - Devaraj, Sridevi

AU - Shah, Vijay

AU - Gershwin, M. Eric

AU - Friedman, Scott L.

AU - Török, Natalie J.

PY - 2010/10

Y1 - 2010/10

N2 - Background & Aims Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. Methods An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2-/- mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2-/- mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. Results In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2-/- mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2-/- animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2-/- mice, suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Conclusions Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver fibrogenesis in vivo.

AB - Background & Aims Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. Methods An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2-/- mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2-/- mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. Results In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2-/- mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2-/- animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2-/- mice, suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Conclusions Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver fibrogenesis in vivo.

KW - Apoptosis

KW - Liver Fibrosis

KW - NADPH Oxidase

UR - http://www.scopus.com/inward/record.url?scp=77957342908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957342908&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2010.05.074

DO - 10.1053/j.gastro.2010.05.074

M3 - Article

VL - 139

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -