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

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.

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“…7 Additionally, given the clarity of the colon wall images obtained, this technique may prove useful in mouse models of colitis and inflammatory bowel disease. 34,35 …”

Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma

“…Several potential applications of ultrasound molecular imaging exist. Molecular imaging of tumor endothelial markers may help better discriminate between benign and malignant disease [3,4]. After tumor treatment, molecular imaging may provide early indication of tumor response, as molecular changes may precede changes in tumor volume [2,5].…”

US Molecular Imaging of Acute Ileitis: Anti-Inflammatory Treatment Response Monitored with Targeted Microbubbles in a Preclinical Model

“…US molecular imaging combines the advantages of US with those of molecular imaging by using molecularly targeted contrast agent microbubbles and has been recently translated to first-in-human clinical trials in cancer imaging (20,21). By targeting binding ligands to the microbubble shell that recognize inflammation markers that are overexpressed in patients with IBD such as P-selectin and Eselectin (22)(23)(24)(25), US molecular imaging allows quantitative assessment of inflammation in IBD at the molecular level at various anatomic sites after a single injection of molecularly targeted contrast agent (23)(24)(25)(26). Proof-of-principle studies have shown the feasibility of dual P-and E-selectin-targeted US molecular imaging for assessment of inflammation and excellent correlation with other molecular imaging techniques such as PET and histologic examination and immunofluorescence as reference standards in various rodent models of acute and acute-on-chronic IBD (24,25).…”