Identification of cromolyn sodium as an anti-fibrotic agent targeting both hepatocytes and hepatic stellate cells

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Liver fibrosis and cirrhosis, the late stage of fibrosis, are threatening diseases that lead to liver failure and patient death. Although aberrantly activated hepatic stellate cells (HSCs) are the main cause of disease initiation, the symptoms are primarily related to damaged hepatocytes. Thus, damaged hepatocytes, as well as HSCs, need to be simultaneously considered as therapeutic targets to develop more efficient treatments. Here, we suggest cromolyn sodium as an anti-fibrotic agent to commonly modulate hepatocytes and hepatic stellate cells. The differentially expressed genes from 6 normal and 40 cirrhotic liver tissues which were collected from GEO data were assessed by pharmacokinetic analysis using a connectivity map to identify agents that commonly revert abnormal hepatocytes and HSCs to normal conditions. Based on a series of analyses, a few candidates were selected. Candidates were tested in vitro to determine their anti-fibrotic efficacy on HSCs and hepatocytes. Cromolyn, which was originally developed as a mast cell stabilizer, showed the potential to ameliorate activated HSCs in vitro. The activation and collagen accumulation for HSC cell lines LX2 and HSC-T6 were reduced by 50% after cromolyn treatment at a low concentration without apoptosis. Furthermore, cromolyn treatment compromised the TGF-beta-induced epithelial mesenchyme transition and replicative senescence rate of hepatocytes, which are generally associated with fibrogenesis. Taken together, cromolyn may be the basis for an effective cure for fibrosis and cirrhosis because it targets both HSCs and hepatocytes.
Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Issue Date
2015-12
Language
English
Article Type
Article
Keywords

TISSUE GROWTH-FACTOR; NORMAL HUMAN-LIVER; MAST-CELLS; CARBON-TETRACHLORIDE; FACTOR-BETA; FIBROSIS; EXPRESSION; PROLIFERATION; RATS; FIBROGENESIS

Citation

PHARMACOLOGICAL RESEARCH, v.102, pp.176 - 183

ISSN
1043-6618
DOI
10.1016/j.phrs.2015.10.002
URI
http://hdl.handle.net/10203/207814
Appears in Collection
NT-Journal Papers(저널논문)
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