Theranostics 2019; 9(21):6031-6046. doi:10.7150/thno.37397

Research Paper

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

Huaijun Wang1, Jose G Vilches-Moure2, Samir Cherkaoui3, Isabelle Tardy3, Charline Alleaume3, Thierry Bettinger3, Amelie Lutz1, Ramasamy Paulmurugan1✉

1. Department of Radiology, Stanford University, School of Medicine, Stanford, California, USA
2. Department of Comparative Medicine, Stanford University, Stanford, California, USA
3. Bracco Suisse SA, Geneva, Switzerland

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Citation:
Wang H, Vilches-Moure JG, Cherkaoui S, Tardy I, Alleaume C, Bettinger T, Lutz A, Paulmurugan R. Chronic Model of Inflammatory Bowel Disease in IL-10-/- Transgenic Mice: Evaluation with Ultrasound Molecular Imaging. Theranostics 2019; 9(21):6031-6046. doi:10.7150/thno.37397. Available from http://www.thno.org/v09p6031.htm

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Abstract

Objective: Acute mouse models of inflammatory bowel disease (IBD) fail to mirror the chronic nature of IBD in patients. We sought to develop a chronic mouse IBD model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI) by using dual P- and E-selectin targeted microbubbles (MBSelectin).

Materials and Methods: Interleukin 10 deficient (IL-10-/- on a C57BL/6 genetic background; n=55) and FVB (n=16) mice were used. In IL-10-/-mice, various experimental regimens including piroxicam, 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS), respectively were used for promoting colitis; colitis was induced with DSS in FVB mice. Using clinical and small animal ultrasound scanners, evolution of inflammation in proximal, middle and distal colon, was monitored with USMI by using MBSelectin at multiple time points. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E staining and for P-selectin expression on immunofluorescence staining.

Results: Sustained colitis was not detected with USMI in IL-10-/- or FVB mice with various experimental regimens. USMI signals either gradually decreased after the colitis enhancing/inducing drug/agents were discontinued, or the mortality rate of mice was high. Inflammation was observed on H&E staining in IL-10-/- mice with piroxicam promotion, while stable overexpression of P-selectin was not found on immunofluorescence staining in the same mice.

Conclusion: Sustained colitis in IL-10-/- mice induced with piroxicam, TNBS or DSS, and in FVB mice induced with DSS, was not detected with USMI using MBSelectin, and this was verified by immunofluorescence staining for inflammation marker P-selectin. Thus, these models may not be appropriate for long-term monitoring of chronic colitis and subsequent treatment response with dual-selectin targeted USMI.

Keywords: inflammatory bowel disease (IBD), ultrasound molecular imaging (USMI), P-selectin, chronic disease, mouse model, Interleukin 10 deficient (IL-10-/-) mice, FVB mice, piroxicam, 2,4,6-trinitrobenzenesulfonic acid (TNBS), dextran sulfate sodium (DSS)