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

JOURNAL OF HEPATOLOGY

卷:60

Article

Stewart, Rachel K.^1,2  Dangi, Anil^1,2,3,4  Huang, Chao^1,2  Murase, Noriko^1,2  Kimura, Shoko^1,2  Stolz, Donna B.⁵  Wilson, Gregory C.³  Lentsch, Alex B.³  Gandhi, Chandrashekhar R.^1,2,3,4,6 

[1] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA

[3] Univ Cincinnati, Dept Surg, Cincinnati, OH 45267 USA

[4] Cincinnati Vet Adm, Cincinnati, OH USA

[5] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA USA

[6] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

关键词: Hepatic stellate cells;    Depletion;    Ischemia/reperfusion;    Endotoxemia;    Lipopolysaccharide;    Hepatocytes;    Liver;    Injury;    Necrosis;    Apoptosis;   

DOI  :  10.1016/j.jhep.2013.09.013

来源: Elsevier

【 摘 要 】

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 mu l/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 mu g/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-alpha, 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-alpha and endothelin-1 as important mediators of these effects. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

【 授权许可】

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