title: Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages.
abstract: OBJECTIVE
  Splenectomy in cirrhotic patients has been reported to improve liver function; however the underlying mechanism remains obscure. In the present study, we investigated the mechanism using a murine model, which represents well the compensated liver cirrhosis.
  
  
  METHODS
  C57BL/6 male mice were allowed to drink water including thioacetamide (TAA: 300 mg/L) ad libitum for 32 weeks. After splenectomy at 32 weeks, mice were sacrificed on days one, seven, and 28, respectively, while TAA-administration was continued. Perioperative changes in peripheral blood and liver tissues were analyzed.
  
  
  RESULTS
  TAA treatment of mice for 32 weeks reproducibly achieved advanced liver fibrosis with splenomegaly, thrombocytopenia, and leukocytopenia. After splenectomy, liver fibrosis was attenuated, and macrophages/monocytes were significantly increased in peripheral blood, as well as in the liver. Progenitor-like cells expressing CK-19, EpCAM, or CD-133 appeared in the liver after TAA treatment, and gradually disappeared after splenectomy. Macrophages/monocytes accumulated in the liver, most of which were negative for Ly-6C, were adjacent to the hepatic progenitor-like cells, and quantitative RT-PCR indicated increased canonical Wnt and decreased Notch signals. As a result, a significant amount of β-catenin accumulated in the progenitor-like cells. Moreover, relatively small Ki67-positive hepatic cells were significantly increased. Protein expression of MMP-9, to which Ly-6G-positive neutrophils contributed, was also increased in the liver after splenectomy.
  
  
  CONCLUSIONS
  The hepatic accumulation of macrophages/monocytes, most of which are Ly-6C(lo), the reduction of fibrosis, and the gradual disappearance of hepatic progenitor-like cells possibly play significant roles in the tissue remodeling process in cirrhotic livers after splenectomy.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Yada
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address: siimuro@hyo-med.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iimuro
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Uyama
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Uda
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006971:Hypersplenism / Q000150:complications* / Q000378:metabolism / Q000601:surgery; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000601:surgery*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013156:Splenectomy; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D051153:Wnt Proteins; D012313:RNA; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Liver fibrosis; Monocyte/macrophage; Progenitor cell; Splenectomy