title: Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice.
abstract: Osteopontin (OPN) is a chemotactic factor which can be cleaved to the pro-inflammatory form by matrix metalloproteinases (MMPs). To test the hypothesis that OPN can modulate inflammatory liver injury during cholestasis, wild-type (WT) C57BL/6 and OPN knockout (OPN-KO) mice underwent bile duct ligation (BDL). OPN-KO mice showed significant reduction in liver injury (plasma ALT and necrosis) and neutrophil recruitment compared with WT animals at 24h but not 72h after BDL. In WT mice, a 4-fold increase in hepatic MMP-3 mRNA and elevated MMP activities and cleaved OPN levels were observed in bile. WT mice subjected to BDL in the presence of the MMP inhibitor BB-94 showed reduced liver injury, less neutrophil extravasation and diminished levels of cleaved OPN in bile. Thus, during obstructive cholestasis, OPN released from biliary epithelial cells could be cleaved by MMPs in bile. When the biliary system leaks, cleaved OPN enters the parenchyma and attracts neutrophils. In the absence of OPN, other chemoattractants, e.g. chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice.
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Anup
authors.initials: A
authors.lastname: Ramachandran
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Woolbright
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000633:toxicity; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000150:complications*; D007249:Inflammation / Q000209:etiology*; D008026:Ligation; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D053495:Osteopontin / Q000235:genetics / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D013876:Thiophenes; D053495:Osteopontin; D010649:Phenylalanine; C080985:batimastat; D000410:Alanine Transaminase; D019278:Matrix Metalloproteinase 3
keywords: ALT; BDECs; BDL; Bile duct ligation; Cholestasis; H&E; HPF; ICAM-1; Inflammatory liver injury; KO mice; MMP; Neutrophils; OPN; Osteopontin; WT; alanine aminotransferase; bile duct epithelial cells; bile duct ligation; gene knock-out mice; hematoxylin and eosin; high-power fields; intercellular adhesion molecule-1; matrix metalloproteinase; osteopontin; wild type