Lodoxamide Attenuates Hepatic Fibrosis in Mice: Involvement of GPR35?
Mi-Jeong Kim, Soo-Jin Park, So-Yeon Nam and Dong-Soon Im*
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
E-mail: imds@pusan.ac.kr
Tel: +82-51-510-2817, Fax: +82-51-513-6754
Received: November 26, 2018; Revised: May 7, 2019; Accepted: May 21, 2019; Published online: June 13, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

A previous pharmacogenomic analysis identified cromolyn, an anti-allergic drug, as an effective anti-fibrotic agent that acts on hepatocytes and stellate cells. Furthermore, cromolyn was shown to be a G protein-coupled receptor 35 (GPR35) agonist. However, it has not been studied whether anti-fibrotic effects are mediated by GPR35. Therefore, in this study, the role of GPR35 in hepatic fibrosis was investigated through the use of lodoxamide, another anti-allergic drug and a potent GPR35 agonist. Longterm treatment with carbon tetrachloride induced hepatic fibrosis, which was inhibited by treatment with lodoxamide. Furthermore, CID2745687, a specific GPR35 antagonist, reversed lodoxamide-mediated anti-fibrotic effects. In addition, lodoxamide treatment showed significant effects on the mRNA expression of collagen Iα1, collagen Iα2, and TGF-β1 in the extracellular matrix. However, a transforming growth factor α (TGF-α) shedding assay revealed lodoxamide not to be a potent agonist of mouse GPR35 in vitro. Therefore, these results showed anti-fibrotic effects of lodoxamide in mice and raise concerns how lodoxamide protects against liver fibrosis in vivo and whether GPR35 is involved in the action.
Keywords: Fibrosis, Liver, Lodoxamide, CID2745687, Carbon tetrachloride

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