title: Identification of cromolyn sodium as an anti-fibrotic agent targeting both hepatocytes and hepatic stellate cells.
abstract: 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-β-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.
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Republic of Korea.
authors.forename: Joon-Seok
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Biomedical Engineering Center, Asan Institute for Life Sciences, Asan Medical Center and University of Ulsan, College of Medicine, Seoul, 138-736, Republic of Korea.
authors.forename: Jun Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk 570-711, Republic of Korea.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 305-338, Republic of Korea.
authors.forename: Yeseul
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 305-338, Republic of Korea.
authors.forename: Pilhan
authors.initials: P
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Ajou University, Suwon, Gyenggi-do 443-270, Republic of Korea.
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Wonkwang University School of Medicine & Hospital, Iksan, Jeonbuk 570-711, Republic of Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Wonkwang University School of Medicine & Hospital, Iksan, Jeonbuk 570-711, Republic of Korea.
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk 570-711, Republic of Korea; Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do 443-270, Republic of Korea. Electronic address: jinwoo.ch@gmail.com.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004205:Cromolyn Sodium / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D003094:Collagen; D004205:Cromolyn Sodium
keywords: Cirrhosis; Cromolyn; Hepatic stellate cell; Hepatocyte; Liver fibrosis; Pharmacogenomics