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

Abstract

Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.25 mg per kilogram of body weight; prednisone, 0.5 mg/kg) and (b) a control group (n = 6; saline). US molecular imaging was performed with a clinical US machine after intravenous injection of clinically translatable dual P- and E-selectin-targeted microbubbles (5 × 10/kg). Three inflamed bowel segments per swine were imaged at baseline, as well as on days 1, 3, and 6 after treatment initiation. At day 6, bowel segments were analyzed ex vivo for selectin expression levels by using quantitative immunofluorescence. Results After induction of inflammation, US molecular imaging signal increased at day 1 in both animal groups (P < .001). At day 3, signal in the treatment group decreased (P < .001 vs day 1), while signal in control animals did not significantly change (P = .18 vs day 1) and was higher (P = .001) compared with that in the treatment group. At day 6, signal in the treatment group further decreased and remained lower (P = .02) compared with that in the control group. Immunofluorescence confirmed significant (P ≤ .04) downregulation of both P- and E-selectin expression levels in treated versus control bowel segments. Conclusion Dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in a large-animal model of acute ileitis. This supports further clinical development of this quantitative and radiation-free technique for monitoring inflammatory bowel disease. © RSNA, 2018 Online supplemental material is available for this article.

Chronic Model of Inflammatory Bowel Disease in IL-10-/- Transgenic Mice: Evaluation with Ultrasound Molecular Imaging

“…Once intravenously injected, MB Selectin remains attached to P- and E-selectin expressed in the inflamed vascular wall for an extended period of time, during which multiple bowel segments can be imaged. Dual-selectin targeted USMI has been validated in murine and swine models of IBD for assessing different degrees of inflammation and monitoring treatment outcomes using histology and immunofluorescence staining as gold standards 15-18. In these small and large animal models of IBD, acute inflammation has been chemically induced using [2,4,6-trinitrobenzenesulfonic acid (TNBS)].…”

Molecular Ultrasound Imaging

“…The experiments in colitis induced mice showed that molecular US assessment of IBD excellently correlated with 18 FDG-PET (positron emission tomography) and histological examination [ 130 ]. Further studies in swine demonstrated that dual-targeted UCA have the potential for clinical translation [ 131 , 132 ]. Wang and co-workers showed that, one hour after inflammation induction by exposing ileum to 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) and ethanol, a significant increase in CEUS signal occurred [ 131 ].…”

“…The US signal changed in line with the increased selectin expression and further increased with the progression of the inflammation. Moreover, P- and E-selectin-targeted MB also proved promising for long-term monitoring of anti-inflammatory IBD treatment in swine [ 132 ]. The combination treatment of prednisone and meloxicam reduced inflammation and downregulated selectin expression in the inflamed vasculature in the bowel.…”

“…Moreover, even better results were achieved using P-selectin glycoprotein ligand-1 analog (PSGL-Ig) instead of sialyl Lewis X [ 80 ]. PSGL-Ig-targeted MB enabled the detection and quantification of inflammation in colitis induced mice [ 130 ] and swine [ 131 , 132 ]. Moreover, post-ischemic myocardium was detected in mice [ 84 ], rats [ 85 ], and even macaques [ 129 ].…”

US Molecular Imaging Sensitively Captures Acute Ileitis Therapy Response

“…The next rational question was whether molecularly targeted US imaging can also be used for therapy monitoring. This question is addressed by Wang et al in this issue of Radiology (7). In this study, acute ileitis was induced in pigs by injecting a mixture of 2,4,6-trinitrobenzene sulfonic acid in ethanol into the distal ileal lumen.…”