title: Combination of sorafenib and gadolinium chloride (GdCl3) attenuates dimethylnitrosamine(DMN)-induced liver fibrosis in rats.
abstract: OBJECTIVE
  Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a potential therapeutic target. The therapeutic effects on liver fibrosis of sorafenib, a multiple tyrosine kinase inhibitor, and gadolinium chloride (GdCl3), which depletes KCs, were evaluated in rats.
  
  
  METHODS
  Liver fibrosis was induced in rats with dimethylnitrosamine, and the effects of sorafenib and/or GdCl3 in these rats were monitored. Interactions among ECs, HSCs and KCs were assessed by laser confocal microscopy.
  
  
  RESULTS
  The combination of sorafenib and GdCl3, but not each agent alone, attenuated liver fibrosis and significantly reduced liver function and hydroxyproline (Hyp). Sorafenib significantly inhibited the expression of angiogenesis-associated cell markers and cytokines, including CD31, von Willebrand factor (vWF), and vascular endothelial growth factor, whereas GdCl3 suppressed macrophage-related cell markers and cytokines, including CD68, tumor necrosis factor-α, interleukin-1β, and CCL2. Laser confocal microscopy showed that sorafenib inhibited vWF expression and GdCl3 reduced CD68 staining. Sorafenib plus GdCl3 suppressed the interactions of HSCs, ECs and KCs.
  
  
  CONCLUSIONS
  Sorafenib plus GdCl3 can suppress collagen accumulation, suggesting that this combination may be a potential therapeutic strategy in the treatment of liver fibrosis.
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. liucheng0082010@163.com.|Laboratory of Molecular Pathology, Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China. liucheng0082010@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. dr_yangzg@aliyun.com.
authors.forename: Zongguo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Hepatology, Affiliated hospital of Shandong University of Trasitional Chinese Medicine, 250014, Jinan, China. wanglei.2006@126.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. luyunfei200@126.com.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. tangbozong@126.com.
authors.forename: Bozong
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. 1144591370@qq.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. xuqingnian68@163.com.
authors.forename: Qingnian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, Shanghai, 201508, China. chenxiaorong@shaphc.org.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Chen
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004128:Dimethylnitrosamine; D004359:Drug Therapy, Combination; D005682:Gadolinium / Q000008:administration & dosage*; D055166:Hepatic Stellate Cells / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D006909:Hydroxyproline / Q000187:drug effects; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D000077157:Sorafenib
chemical_list: D042501:Angiogenic Proteins; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D005682:Gadolinium; D004128:Dimethylnitrosamine; C038958:gadolinium chloride; D006909:Hydroxyproline