title: 3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model.
abstract: OBJECTIVE
  Liver biopsy, the gold standard for assessing liver fibrosis, suffers from limitations due to sampling error and invasiveness. There is therefore a critical need for methods to non-invasively quantify fibrosis throughout the entire liver. The goal of this study was to use molecular Magnetic Resonance Imaging (MRI) of Type I collagen to non-invasively image liver fibrosis and assess response to rapamycin therapy.
  
  
  METHODS
  Liver fibrosis was induced in rats by bile duct ligation (BDL). MRI was performed 4, 10, or 18 days following BDL. Some BDL rats were treated daily with rapamycin starting on day 4 and imaged on day 18. A three-dimensional (3D) inversion recovery MRI sequence was used to quantify the change in liver longitudinal relaxation rate (ΔR1) induced by the collagen-targeted probe EP-3533. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for Sirius Red staining and hydroxyproline content.
  
  
  RESULTS
  ΔR1 increased significantly with time following BDL compared to controls in agreement with ex vivo measures of increasing fibrosis. Receiver operating characteristic curve analysis demonstrated the ability of ΔR1 to detect liver fibrosis and distinguish intermediate and late stages of fibrosis. EP-3533 MRI correctly characterized the response to rapamycin in 11 out of 12 treated rats compared to the standard of collagen proportional area (CPA). 3D MRI enabled characterization of disease heterogeneity throughout the whole liver.
  
  
  CONCLUSIONS
  EP-3533 allowed for staging of liver fibrosis, assessment of response to rapamycin therapy, and demonstrated the ability to detect heterogeneity in liver fibrosis.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Farrar
authors.affiliation: Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, WRN 401, 55 Fruit St., Boston, MA 02114, United States.
authors.forename: Danielle K
authors.initials: DK
authors.lastname: DePeralta
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Day
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Rietz
authors.affiliation: Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, WRN 401, 55 Fruit St., Boston, MA 02114, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Pathology, Massachusetts General Hospital and Harvard Medical School, WRN 2, 55 Fruit St., Boston, MA 02114, United States.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Boris
authors.initials: B
authors.lastname: Keil
authors.affiliation: Sanofi Genzyme, 49 New York Ave, Framingham, MA 01701, United States.
authors.forename: Arun
authors.initials: A
authors.lastname: Subramaniam
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sinskey
authors.affiliation: Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, WRN 401, 55 Fruit St., Boston, MA 02114, United States.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.affiliation: Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, WRN 401, 55 Fruit St., Boston, MA 02114, United States. Electronic address: bfuchs@mgh.harvard.edu.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St., Suite 2301, Charlestown, MA 02129, United States. Electronic address: caravan@nmr.mgh.harvard.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
mesh_terms: D000818:Animals; D001652:Bile Ducts; D004195:Disease Models, Animal; D054459:Elasticity Imaging Techniques; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D012372:ROC Curve; D051381:Rats; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D020123:Sirolimus
keywords: Bile duct ligation (BDL); EP-3533; Liver fibrosis; MRI; Molecular imaging; Non-invasive; Type I collagen