TY - JOUR
T1 - Molecular MR imaging of liver fibrosis
T2 - A feasibility study using rat and mouse models
AU - Polasek, Miloslav
AU - Fuchs, Bryan C.
AU - Uppal, Ritika
AU - Schühle, Daniel T.
AU - Alford, Jamu K.
AU - Loving, Galen S.
AU - Yamada, Suguru
AU - Wei, Lan
AU - Lauwers, Gregory Y.
AU - Guimaraes, Alexander R.
AU - Tanabe, Kenneth K.
AU - Caravan, Peter
N1 - Funding Information:
Grant Nos. CA140861 (B.C.F.), CA009502 (G.S.L), CA076183 (K.K.T), and EB009062 (P.C.) from the National Cancer Institute and the National Institute of Biomedical Imaging and Bioengineering , and Tucker Gosnell Research funds (K.K.T.)
Funding Information:
The underlying research reported in the study was funded by the NIH Institutes of Health.
PY - 2012/9
Y1 - 2012/9
N2 - Background & Aims: 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 t1/2 = 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.
AB - Background & Aims: 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 t1/2 = 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.
KW - Carbon tetrachloride
KW - Diethylnitrosamine
KW - Gadolinium
KW - Molecular imaging
KW - Type I collagen
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UR - http://www.scopus.com/inward/citedby.url?scp=84865136247&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2012.04.035
DO - 10.1016/j.jhep.2012.04.035
M3 - Article
C2 - 22634342
AN - SCOPUS:84865136247
SN - 0168-8278
VL - 57
SP - 549
EP - 555
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -