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Theranostics 2015; 5(11):1175-1186. doi:10.7150/thno.13048 This issue Cite

Research Paper

Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging

Steven Machtaler^1*, Ferdinand Knieling^1*, Richard Luong², Lu Tian³, Jürgen K. Willmann^1✉

1. Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, California, USA
2. Department of Comparative Medicine, Stanford University, Stanford, California, USA
3. Department of Health, Research & Policy, Stanford University, Stanford, California, USA
*Co-first Authors

✉ Corresponding author: Jürgen K. Willmann, M.D., Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, 300 Pasteur Drive, Room H1307, Stanford, CA 94305-5621. P: 650-723-5424; Fax: 650-723-1909; Email: willmannedu More

Abstract

Background: Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background.

Methods: Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology.

Results: Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%).

Conclusions: Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.

Keywords: Targeted ultrasound imaging, P- and E-selectin targeted microbubbles, acute inflammation on chronic colitis background, DCE-US imaging

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