Quantitative analysis of intravenously administered contrast media reveals changes in vascular barrier functions in a murine colitis model

Abstract

Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract associated with alterations and dysfunction of the intestinal microvasculature. The goal of this work was to develop a preclinical protocol for quantitative functional characterization of the colonic microvasculature in a murine colitis model. Experimental colitis was induced in mice by addition of dextran sodium sulfate to the drinking water. Histopathologic analysis revealed severe multifocal colitis. Dynamics of intravenously injected macromolecular dextran-FITC and biotin-BSA-GdDTPA in the colonic microvasculature were imaged using fluorescent confocal endomicroscopy and MRI (9.4 T), respectively. Both MRI and fluorescent confocal endomicroscopy revealed a substantial increase in the permeability of the colonic microvasculature associated with colitis, resulting in extravascular accumulation of the macromolecular contrast agent in the lumen of the colon. MRI data were validated by immunohistochemical staining of the contrast agent and leakage of fluorescently labeled BSA-FAM coinjected with the MRI contrast agent. Leakage of plasma proteins and deposition of a provisional matrix can support inflammation and stimulate remodeling of the colonic vasculature. Thus, the plasma protein leakage from the colonic microvasculature at the focal inflammatory patches could be quantified by MRI, providing a biomarker for assessment of disease progression.