Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis.

Akiko Hatori,Ming-Rong Zhang,Hidekatsu Wakizaka,Masayuki Fujinaga,Tomoteru Yamasaki,Katsushi Kumata,Lin Xie,Joji Yui,Masanao Ogawa,Feng Wang,Nobuki Nengaki,Kazunori Kawamura

doi:10.1038/srep17327

Abstract

Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4), and liver fibrosis was assessed. Positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]-acetamide ([18F]FEDAC), a radioprobe specific for TSPO, was used for noninvasive visualisation in vivo. PET scanning, immunohistochemical staining, ex vivo autoradiography, and quantitative reverse-transcription polymerase chain reaction were performed to elucidate the relationships among radioactivity uptake, TSPO levels, and cellular sources enriching TSPO expression in damaged livers. PET showed that uptake of radioactivity in livers increased significantly after 2, 4, 6, and 8 weeks of CCl4 treatment. Immunohistochemistry demonstrated that TSPO was mainly expressed in macrophages and hepatic stellate cells (HSCs). TSPO-expressing macrophages and HSCs increased with the progression of liver fibrosis. Interestingly, the distribution of radioactivity from [18F]FEDAC was well correlated with TSPO expression, and TSPO mRNA levels increased with the severity of liver damage. TSPO was a useful molecular imaging biomarker and could be used to track the progression of hepatic fibrosis to cirrhosis with PET.

Highlights

In recent years, various evaluation methods for hepatic fibrosis have been developed, generally involving the use of serum markers and the measurement of liver stiffness
After 2 weeks of treatment, fibrous central venule to central venule (C-C) bridging septa with deposition of thin collagen fibres were observed, and the fibrotic region was increased to 2.68% ± 0.16% of the liver sections compared to 0.36% ± 0.08% of that in the control group
Transient elastography is widely used in Europe to measure liver stiffness; this technology is not sensitive enough to enable accurate assessment of fibrosis progression over time in individual patients[4,6]

Summary

Introduction

Various evaluation methods for hepatic fibrosis have been developed, generally involving the use of serum markers and the measurement of liver stiffness We aimed to evaluate potential utility of TSPO as a molecular imaging biomarker for noninvasive monitoring of the progression of hepatic fibrosis to cirrhosis. To this end, we used a rat model of cirrhosis in which hepatic fibrosis was induced by chronic carbon tetrachloride (CCl4) injection[16,17,18,19]. We measured the uptake of [18F]FEDAC in livers using a PET scanner at various times after CCl4 treatment and evaluated the progression of hepatic fibrosis and the expression of TSPO by histological observation. Our data provide important insights regarding the utility of TSPO as a marker of hepatic fibrosis

Objectives

Methods

Results

Conclusion