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

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.

IGF-1C hydrogel improves the therapeutic effects of MSCs on colitis in mice through PGE2-mediated M2 macrophage polarization

“…Based on their immunomodulatory and tissue regenerative potential, mesenchymal stem cells (MSCs) have been proposed as promising candidates for the treatment of inflammatory bowel disease (IBD) 1 - 3 . There is increasing evidence that MSCs can regulate the biological activities of a variety of immune cells, such as T cells, B cells, NK cells, neutrophils and macrophages 4 . At present, the immunomodulatory mechanism of MSCs is still not fully elucidated, but it is generally believed that MSCs exert their immunosuppressive function mainly through intercellular contact and secretion of soluble factors, such as transforming growth factor-β1 (TGF-β1), hepatocyte growth factor (HGF), indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), and prostaglandin E 2 (PGE 2 ) 5 , 6 .…”

Toward Point-of-Care Diagnostics to Monitor MMP-9 and TNF-α Levels in Inflammatory Bowel Disease

“…If suitable biomarkers were identified in ex vivo body fluids, it would lead to an increase in research efforts to develop point-of-care diagnostics. Here, we investigated the association between fecal MMP-9 and serum TNF-α level due to inflammation using an established IL10–/– mouse model that has been used to determine the IBD severity. , We found that these two biomolecules could be potentially used to monitor inflammation in IBD. We note that these biomarkers are also elevated in other diseases like rheumatoid arthritis and, therefore, these biomarkers cannot be used to detect IBD.…”

Opportunities and challenges for synthetic biology in the therapy of inflammatory bowel disease

“…Furthermore, associated cytokines such as IL-6, IL-17, IFN-, and TNF- were proved to be modulated which suggested that NZ9000/IL-35 could be a good candidate for preventing IBD development (J. Wang et al, 2019 ). These investigations give an excellent foundation for the potential efficacy of engineered L. lactis as LBP in the treatment of IBD.…”