title: Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice.
abstract: OBJECTIVE
  Circulating platelet counts gradually decrease in parallel with progression of chronic liver disease. Thrombocytopenia is a common complication of advanced liver fibrosis and is thought to be a consequence of the destruction of circulating platelets that occurs during secondary portal hypertension or hypersplenism. It is not clear whether thrombocytopenia itself affects liver fibrosis.
  
  
  METHODS
  Thrombocytopenic mice were generated by disruption of Bcl-xL, which regulates platelet life span, specifically in thrombocytes. Liver fibrosis was examined in thrombocytopenic mice upon bile duct ligation. Effect of platelets on hepatic stellate cells (HSCs) was investigated in vitro.
  
  
  RESULTS
  Thrombocytopenic mice developed exacerbated liver fibrosis, with increased expression of type I collagen alpha1 and alpha2, during cholestasis. In vitro experiments revealed that, upon exposure to HSCs, platelets became activated, released hepatocyte growth factor (HGF), and then inhibited HSC expression of the type I collagen genes in a Met signal-dependent manner. In contrast to the wild-type mice, the thrombocytopenic mice did not accumulate hepatic platelets or phosphorylate Met in the liver following bile duct ligation. Administration of recombinant HGF to thrombocytopenic mice reduced liver fibrosis to the levels observed in wild-type mice and attenuated hepatic expression of the type I collagen genes.
  
  
  CONCLUSIONS
  Thrombocytopenia exacerbates liver fibrosis; platelets have a previously unrecognized, antifibrotic role in suppressing type I collagen expression via the HGF-Met signaling pathway.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Seiji
authors.initials: S
authors.lastname: Tadokoro
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000150:complications*; D003094:Collagen / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation; D013921:Thrombocytopenia / Q000150:complications*; D051020:bcl-X Protein / Q000502:physiology
chemical_list: C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D003094:Collagen