Molecular MR imaging of liver fibrosis: a feasibility study using rat and mouse models.
OBJECTIVE
Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment.


METHODS
Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline.


RESULTS
EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control=0.39 ± 0.04, fibrotic=0.55 ± 0.03, p<0.01) and slower signal washout in the fibrotic liver compared to controls (liver t(1/2)=51.3 ± 3.6 vs. 42.0 ± 2.5 min, p<0.05 and 54.5 ± 1.9 vs. 44.1 ± 2.9 min, p<0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r=0.74 (rats), r=0.77 (mice)) and with Ishak scoring (r=0.84 (rats), r=0.79 (mice)).


CONCLUSIONS
Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease.
A 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.
Miloslav
M
Polasek
Bryan C
BC
Fuchs
Ritika
R
Uppal
Daniel T
DT
Schühle
Jamu K
JK
Alford
Galen S
GS
Loving
Suguru
S
Yamada
Lan
L
Wei
Gregory Y
GY
Lauwers
Alexander R
AR
Guimaraes
Kenneth K
KK
Tanabe
Peter
P
Caravan
D000818:Animals; D002251:Carbon Tetrachloride; D024042:Collagen Type I / Q000032:analysis*; D003287:Contrast Media / Q000032:analysis; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D005682:Gadolinium / Q000032:analysis; D006207:Half-Life; D006909:Hydroxyproline / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D015335:Molecular Probes / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D024042:Collagen Type I; D003287:Contrast Media; D015335:Molecular Probes; D004052:Diethylnitrosamine; D005682:Gadolinium; D002251:Carbon Tetrachloride; D006909:Hydroxyproline