An entirely automated method to score DSS-induced colitis in mice by digital image analysis of pathology slides

SUMMARY The DSS (dextran sulfate sodium) model of colitis is a mouse model of inflammatory bowel disease. Microscopic symptoms include loss of crypt cells from the gut lining and infiltration of inflammatory cells into the colon. An experienced pathologist requires several hours per study to score histological changes in selected regions of the mouse gut. In order to increase the efficiency of scoring, Definiens Developer software was used to devise an entirely automated method to quantify histological changes in the whole H&E slide. When the algorithm was applied to slides from historical drug-discovery studies, automated scores classified 88% of drug candidates in the same way as pathologists’ scores. In addition, another automated image analysis method was developed to quantify colon-infiltrating macrophages, neutrophils, B cells and T cells in immunohistochemical stains of serial sections of the H&E slides. The timing of neutrophil and macrophage infiltration had the highest correlation to pathological changes, whereas T and B cell infiltration occurred later. Thus, automated image analysis enables quantitative comparisons between tissue morphology changes and cell-infiltration dynamics.

[1]  Johannes Zimmermann,et al.  Automated analysis and detailed quantification of biomedical images using Definiens Cognition Network Technology. , 2009, Combinatorial chemistry & high throughput screening.

[2]  P. Valdez,et al.  IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium , 2011, Nature Immunology.

[3]  Arno Schäpe,et al.  Multiresolution Segmentation : an optimization approach for high quality multi-scale image segmentation , 2000 .

[4]  Bayan S. Sharif,et al.  Fractal analysis in the detection of colonic cancer images , 2002, IEEE Transactions on Information Technology in Biomedicine.

[5]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[6]  J. Lu,et al.  Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity. , 2000, The American journal of pathology.

[7]  R. Xavier,et al.  IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. , 2008, The Journal of clinical investigation.

[8]  S. Sa,et al.  Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens , 2008, Nature Medicine.

[9]  Dolores Diaz,et al.  Phosphorous dysregulation induced by MEK small molecule inhibitors in the rat involves blockade of FGF-23 signaling in the kidney. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[10]  R. Walker,et al.  Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment I , 2006, Histopathology.

[11]  E. Szigethy,et al.  Inflammatory bowel disease. , 2011, Pediatric clinics of North America.

[12]  S. Melgar,et al.  Induction and Activation of Adaptive Immune Populations During Acute and Chronic Phases of a Murine Model of Experimental Colitis , 2010, Digestive Diseases and Sciences.

[13]  Stefan Wirtz,et al.  Chemically induced mouse models of intestinal inflammation , 2007, Nature Protocols.

[14]  R M Levenson,et al.  Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment II , 2006, Histopathology.

[15]  G. Dalmasso,et al.  Temporal and Spatial Analysis of Clinical and Molecular Parameters in Dextran Sodium Sulfate Induced Colitis , 2009, PloS one.

[16]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[17]  E Persohn,et al.  Cell proliferation measurement in cecum and colon of rats using scanned images and fully automated image analysis: validation of method. , 2007, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[18]  M. Washington,et al.  ErbB2 and ErbB3 regulate recovery from dextran sulfate sodium-induced colitis by promoting mouse colon epithelial cell survival , 2011, Laboratory Investigation.

[19]  Deborah B. Thompson,et al.  AUTOMATED LOCATION OF DYSPLASTIC FIELDS IN COLORECTAL HISTOLOGY USING IMAGE TEXTURE ANALYSIS , 1997, The Journal of pathology.

[20]  W. Ouyang,et al.  Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice , 2011, Mucosal Immunology.

[21]  F. Cominelli,et al.  Emerging drugs for the treatment of ulcerative colitis , 2009, Expert opinion on emerging drugs.

[22]  E. Bloemena,et al.  Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines , 1998, Clinical and experimental immunology.

[23]  Lena Holm,et al.  Bacteria Penetrate the Inner Mucus Layer before Inflammation in the Dextran Sulfate Colitis Model , 2010, PloS one.