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J Hepatol. 2014 Feb;60(2):298-305. doi: 10.1016/j.jhep.2013.09.013. Epub 2013 Sep 20.

A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.

Author information

1
Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
2
Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Surgery, University of Cincinnati, Cincinnati, OH, USA; Cincinnati Veterans Administration, Cincinnati, OH, USA.
3
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
5
Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Surgery, University of Cincinnati, Cincinnati, OH, USA; Cincinnati Veterans Administration, Cincinnati, OH, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: gandhicr@ucmail.uc.edu.

Abstract

BACKGROUND & AIMS:

Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver.

METHODS:

We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment.

RESULTS:

CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice.

CONCLUSIONS:

HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.

KEYWORDS:

ALT; Ab; Apoptosis; CCl(4); Depletion; ECM; ET-1; Endotoxemia; GCV; GFAP; H/E; HSC; HSV; Hepatic stellate cells; Hepatocytes; I/R; IL; IP; Injury; Ischemia/reperfusion; KCs; Kupffer cells; LPS; Lipopolysaccharide; Liver; NO; NOS; Necrosis; PBS; ROS; TK; TNF; Tg; WT; alanine aminotransferase; antibody; carbon tetrachloride; endothelin-1; extracellular matrix; ganciclovir; glial fibrillary acidic protein; hematoxylin and eosin; hepatic stellate cell; herpes simplex virus; interleukin; intraperitoneal; ischemia/reperfusion; lipopolysaccharide; nitric oxide; nitric oxide synthase; phosphate-buffered saline; qRT-PCR; quantitative real-time polymerase chain reaction; reactive oxygen species; thymidine kinase; transgenic; tumor necrosis factor; wild type

PMID:
24060854
PMCID:
PMC4195246
DOI:
10.1016/j.jhep.2013.09.013
[Indexed for MEDLINE]
Free PMC Article
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