title: Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis.
abstract: Paracrine signaling between hepatic stellate cells (HSCs) and liver endothelial cells (LECs) modulates fibrogenesis, angiogenesis, and portal hypertension. However, mechanisms regulating these processes are not fully defined. Sorafenib is a receptor tyrosine kinase inhibitor that blocks growth factor signaling in tumor cells but also displays important and not yet fully characterized effects on liver nonparenchymal cells including HSCs and LECs. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSCs and LECs and thereby regulates matrix and vascular changes associated with chronic liver injury. Complementary magnetic resonance elastography, micro-computed tomography, and histochemical analyses indicate that sorafenib attenuates the changes in both matrix and vascular compartments that occur in response to bile duct ligation-induced liver injury in rats. Cell biology studies demonstrate that sorafenib markedly reduces cell-cell apposition and junctional complexes, thus reducing the proximity typically observed between these sinusoidal barrier cells. At the molecular level, sorafenib down-regulates angiopoietin-1 and fibronectin, both released by HSCs in a manner dependent on the transcription factor Kruppel-like factor 6 , suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease.
  
  
  CONCLUSIONS
  Collectively, the results of this study demonstrate that sorafenib inhibits both matrix restructuring and vascular remodeling that accompany chronic liver diseases and characterize cell and molecular mechanisms underlying this effect. These data may help to refine future therapies for advanced gastrointestinal and liver diseases characterized by abundant fibrosis and neovascularization.
authors.affiliation: Gastroenterology Research Unit, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.forename: Chittaranjan
authors.initials: C
authors.lastname: Routray
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.forename: Uday
authors.initials: U
authors.lastname: Shergill
authors.forename: Kevin
authors.initials: K
authors.lastname: Glaser
authors.forename: Robert
authors.initials: R
authors.lastname: Huebert
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.forename: Tetyana
authors.initials: T
authors.lastname: Masyuk
authors.forename: Boris
authors.initials: B
authors.lastname: Blechacz
authors.forename: Andrew
authors.initials: A
authors.lastname: Vercnocke
authors.forename: Erik
authors.initials: E
authors.lastname: Ritman
authors.forename: Richard
authors.initials: R
authors.lastname: Ehman
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Vijay
authors.initials: V
authors.lastname: Shah
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D004730:Endothelium, Vascular; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D019899:Paracrine Communication / Q000187:drug effects*; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib