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Abstract
Discoidin domain receptor 2 (DDR2) is involved in fibrotic disease. However, the exact pathogenic implications of the receptor in early alcoholic liver disease are still controversial. We constructed plasmid vectors encoding short-hairpin RNA against DDR2 to investigate its role in alcoholic liver disease in an immortalized rat hepatic stellate cell line, HSC-T6, and in rats by MTT, RT-PCR and western blot analyses; immunohistochemistry and electron microscopy. Alcohol-induced upregulation of DDR2 was associated with the expression of matrix metalloproteinase 2, the transforming growth factor β1 signaling pathway and tissue inhibitor of metalloproteinase 1; collagen deposition; and extracellular matrix remodeling. Inhibition of DDR2 decreased HSC-T6 cell proliferation and liver injury in rats with 10-week-induced alcoholic liver disease. DDR2 may have an important role in the pathogenesis of early-stage alcoholic liver disease. Silencing DDR2 may be effective in preventing early-stage alcoholic liver disease.
Highlights
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality
The GFP-expressing plasmid p.Discoidin domain receptor 2 (DDR2).short hairpin RNA (shRNA) was transfected into hepatic stellate cells (HSCs)-T6 cells, and the efficiency of transduction was approximately 60% (Fig. 1c)
Immunohistochemistry demonstrated that positive staining of DDR2 in perisinusoidal spaces was less with gene therapy than with ALD treatment (Fig. 2i–k)
Summary
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality. It begins with the fatty liver and proceeds to liver inflammation, necrosis, progressive fibrosis and hepatocellular carcinoma. Sinusoidal capillarization is characterized by loss of differentiation of liver sinusoidal endothelial cells and the formation of basement membrane in the Disse space. It impedes the metabolic exchange of nutrients and waste and precedes the onset of hepatic fibrosis. The formation of basement membrane results from increased sinusoidal deposition of laminin and collagen produced by activated hepatic stellate cells (HSCs) [3]. The ratio of liver to body weight in ALD was increased [6,7,8]
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