title: Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis.
abstract: Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Noguchi
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: sousuke@med.uoeh-u.ac.jp.
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nabeshima
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kitakyushu, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; Bio-information Research Center, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kitada
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tasaki
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; Department of Emergency Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Takama
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.affiliation: Department of Cell Pathology, Faculty of Medical and Pharmaceutical Sciences, Graduate School of Medical Sciences, Kumamoto University, Kitakyushu, Japan.
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.affiliation: Department of Cell Pathology, Faculty of Medical and Pharmaceutical Sciences, Graduate School of Medical Sciences, Kumamoto University, Kitakyushu, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Department of Occupational Pneumology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and Core Research for Evolutional Science and Technology, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Departments of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000473:pathology; D049109:Cell Proliferation; D002779:Cholestasis / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse