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Noninvasive mapping of the redox status of dimethylnitrosamine-induced hepatic fibrosis using in vivo dynamic nuclear polarization-magnetic resonance imaging.

ABSTRACT: Hepatic fibrosis is a chronic disorder caused by viral infection and/or metabolic, genetic and cholestatic disorders. A noninvasive procedure that enables the detection of liver fibrosis based on redox status would be useful for disease identification and monitoring, and the development of treatments. However, an appropriate technique has not been reported. This study describes a novel method for assessing the redox status of the liver using in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) with the nitroxyl radical carbamoyl-PROXYL as a molecular imaging probe, which was tested in dimethylnitrosamine-treated mice as a model of liver fibrosis. Based on the pharmacokinetics of carbamoyl-PROXYL in control livers, reduction rate mapping was performed in fibrotic livers. Reduction rate maps demonstrated a clear difference between the redox status of control and fibrotic livers according to the expression of antioxidants. These findings indicate that in vivo DNP-MRI with a nitroxyl radical probe enables noninvasive detection of changes in liver redox status.

SUBMITTER: Kawano T

PROVIDER: S-EPMC5009327 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Noninvasive mapping of the redox status of dimethylnitrosamine-induced hepatic fibrosis using in vivo dynamic nuclear polarization-magnetic resonance imaging.

Kawano Takahito T Murata Masaharu M Hyodo Fuminori F Eto Hinako H Kosem Nuttavut N Nakata Ryosuke R Hamano Nobuhito N Piao Jing Shu JS Narahara Sayoko S Akahoshi Tomohiko T Hashizume Makoto M

Scientific reports 20160902

Hepatic fibrosis is a chronic disorder caused by viral infection and/or metabolic, genetic and cholestatic disorders. A noninvasive procedure that enables the detection of liver fibrosis based on redox status would be useful for disease identification and monitoring, and the development of treatments. However, an appropriate technique has not been reported. This study describes a novel method for assessing the redox status of the liver using in vivo dynamic nuclear polarization-magnetic resonanc ...[more]

PMID: 27587186

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Project description:The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4?T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5-2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ?20?min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies.

Project description:BackgroundRenal fibrosis is a key driver of progression in chronic kidney disease (CKD). Recent advances in diagnostic imaging techniques have shown promising results for the noninvasive assessment of renal fibrosis. However, the specificity and accuracy of these techniques are controversial because they indirectly assess renal fibrosis. This limits fibrosis assessment by imaging in CKD for clinical practice. To validate magnetic resonance imaging (MRI) assessment for fibrosis, we derived representative models by mapping histology-proven renal fibrosis and imaging in CKD.MethodsNinety-seven adult Chinese CKD participants with histology were studied. The kidney cortex interstitial extracellular matrix volume was calculated by the Aperio ScanScope system using Masson's trichrome slices. The kidney cortex microcirculation was quantitatively assessed by peritubular capillary density using CD34 staining. The imaging techniques included intravoxel incoherent motion diffusion-weighted imaging and magnetic resonance elastography (MRE) imaging. Relevant analyses were performed to evaluate the correlations between MRI parameters and histology variables. Multiple linear regression models were used to describe the relationships between a response variable and other variables. The best-fit lines, which minimize the sum of squared residuals of the multiple linear regression models, were generated.ResultsMRE values were negatively associated with the interstitial extracellular matrix volume (Rho = -0.397, p < 0.001). The best mapping model of extracellular matrix volume with the MRE value and estimated glomerular filtration rate (eGFR) we obtained was as follows: Interstitial extracellular matrix volume = 218.504 - 14.651 × In(MRE) - 18.499 × In(eGFR). DWI-fraction values were positively associated with peritubular capillary density (Rho = 0.472, p < 0.001). The best mapping model of peritubular capillary density with DWI-fraction value and eGFR was as follows: Peritubular capillaries density = 17.914 + 9.403 × (DWI - fraction) + 0.112 × (eGFR).ConclusionsThe study provides histological evidence to support that MRI can effectively evaluate fibrosis in the kidney. These findings picture the graphs of the mapping model from imaging and eGFR into fibrosis, which has significant value for clinical implementation.

Dataset Information

Noninvasive mapping of the redox status of dimethylnitrosamine-induced hepatic fibrosis using in vivo dynamic nuclear polarization-magnetic resonance imaging.

Publications

Noninvasive mapping of the redox status of dimethylnitrosamine-induced hepatic fibrosis using in vivo dynamic nuclear polarization-magnetic resonance imaging.

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