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Usefulness of 18F-FPP-RGD2 PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Integrins αv are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αvβ3 imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an 18F-FPP-RGD2 PET probe in a rat model of bleomycin-induced lung fibrosis.

Methods

Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using 18F-FPP-RGD2. Total distribution volume (VT) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan VT and lung pathology was assessed by Spearman’s rank correlation.

Results

Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin αv protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of 18F-FPP-RGD2 rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for 18F-FPP-RGD2 kinetic analysis in the IPF-model lung. Logan VT values for 18F-FPP-RGD2 were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin αv protein expression, and oxygen partial pressure.

Conclusion

Our findings demonstrate that the integrin αvβ3 PET probe 18F-FPP-RGD2 can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin αv of IPF-model rats. These findings support the utility of 18F-FPP-RGD2 PET imaging for the pathophysiological evaluation of pulmonary fibrosis.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We acknowledge Hirotada Murayama and Yumi Asano from Shionogi TechnoAdvance Research Co., Ltd. for preparation of the pathology specimens. We thank members of the Imaging Group at Shionogi & Co., Ltd. for their constructive discussion. We also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This study was funded by Shionogi & Co., Ltd.

Author information

Authors and Affiliations

  1. Biomarker R&D Department, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan

    Shuichi Hiroyama, Miwa Ito & Kohji Abe

  2. Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

    Keiko Matsunaga & Eku Shimosegawa

  3. Research Laboratory for Development, Shionogi & Co., Ltd, Osaka, Japan

    Hitoshi Iimori & Minako Tajiri

  4. Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd, Osaka, Japan

    Yoshiyuki Nakano

Authors
  1. Shuichi Hiroyama
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  2. Keiko Matsunaga
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  3. Miwa Ito
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  4. Hitoshi Iimori
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  5. Minako Tajiri
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  7. Eku Shimosegawa
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  8. Kohji Abe
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Contributions

SH performed the PET experiments, protein analyses, data analysis, and drafted the manuscript. KM performed data analysis and supervised the study. MI performed the PET experiments. HI synthesized the PET probe. MT performed the histological analysis. YN performed the preparation of IPF-model rats. ES supervised the study. KA coordinated and designed the study and drafted the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Shuichi Hiroyama.

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Ethics approval

The experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Shionogi & Co. Ltd. and Osaka University Graduate School of Medicine.

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Not applicable.

Competing interests

The authors declare no competing interests.

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This article is part of the Topical Collection on Preclinical Imaging

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Hiroyama, S., Matsunaga, K., Ito, M. et al. Usefulness of 18F-FPP-RGD2 PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model. Eur J Nucl Med Mol Imaging 49, 4358–4368 (2022). https://doi.org/10.1007/s00259-022-05908-4

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  • DOI: https://doi.org/10.1007/s00259-022-05908-4

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