Unique gene expression and MR T2 relaxometry patterns define chronic murine dextran sodium sulphate colitis as a model for connective tissue changes in human Crohn's disease.
[en] INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. MATERIALS AND METHODS: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T 2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. RESULTS: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn's colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. CONCLUSIONS: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn's disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Breynaert, Christine
Dresselaers, Tom
Perrier, Clementine
Arijs, Ingrid
Cremer, Jonathan
Van Lommel, Leentje
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Unique gene expression and MR T2 relaxometry patterns define chronic murine dextran sodium sulphate colitis as a model for connective tissue changes in human Crohn's disease.
Publication date :
2013
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Abraham C, Cho JH, (2009) Inflammatory bowel disease. N Engl J Med 361: 2066-2078.
Van Assche G, Geboes K, Rutgeerts P, (2004) Medical therapy for Crohn's disease strictures. Inflamm Bowel Dis 10: 55-60.
Graham MF, Diegelmann RF, Elson CO, Lindblad WJ, Gotschalk N, et al. (1988) Collagen content and types in the intestinal strictures of Crohn's disease. Gastroenterology 94: 257-265.
Geboes KP, Cabooter L, Geboes K, (2000) Contribution of morphology for the comprehension of mechanisms of fibrosis in inflammatory enterocolitis. Acta Gastroenterol Belg 63: 371-376.
Geboes K, El-Zine MY, Dalle I, El-Haddad S, Rutgeerts P, et al. (2001) Tenascin and strictures in inflammatory bowel disease: an immunohistochemical study. Int J Surg Pathol 9: 281-286.
Koukoulis G, Ke Y, Henley JD, Cummings OW, (2001) Obliterative muscularization of the small bowel submucosa in Crohn disease: a possible mechanism of small bowel obstruction. Arch Pathol Lab Med 125: 1331-1334.
Shelley-Fraser G, Borley NR, Warren BF, Shepherd NA, (2012) The connective tissue changes of Crohn's disease. Histopathology 60: 1034-1044.
Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A, (2006) IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med 12: 99-106.
Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, et al. (2007) Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56: 1696-1705.
Ding S, Walton KL, Blue RE, Macnaughton K, Magness ST, et al. (2012) Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen alpha1(I)-promoter-GFP reporter mice. PLoS One 7: e42568.
Rieder F, Kessler S, Sans M, Fiocchi C, (2012) Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease. Am J Physiol Gastrointest Liver Physiol 303: G786-801.
Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, et al. (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98: 694-702.
Melgar S, Karlsson A, Michaelsson E, (2005) Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. Am J Physiol Gastrointest Liver Physiol 288: G1328-1338.
Suzuki K, Sun X, Nagata M, Kawase T, Yamaguchi H, et al. (2011) Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium. Pathol Int 61: 228-238.
Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, et al. (2010) The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. J Crohns Colitis 4: 7-27.
Larsson AE, Melgar S, Rehnstrom E, Michaelsson E, Svensson L, et al. (2006) Magnetic resonance imaging of experimental mouse colitis and association with inflammatory activity. Inflamm Bowel Dis 12: 478-485.
Mustafi D, Fan X, Dougherty U, Bissonnette M, Karczmar GS, et al. (2010) High-resolution magnetic resonance colonography and dynamic contrast-enhanced magnetic resonance imaging in a murine model of colitis. Magn Reson Med 63: 922-929.
Quarles CC, Lepage M, Gorden DL, Fingleton B, Yankeelov TE, et al. (2008) Functional colonography of Min mice using dark lumen dynamic contrast-enhanced MRI. Magn Reson Med 60: 718-726.
Young MR, Ileva LV, Bernardo M, Riffle LA, Jones YL, et al. (2009) Monitoring of tumor promotion and progression in a mouse model of inflammation-induced colon cancer with magnetic resonance colonography. Neoplasia 11: 237-246, 231p following 246.
Woessner JF Jr, (1961) The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 93: 440-447.
Perrier C, de Hertogh G, Cremer J, Vermeire S, Rutgeerts P, et al. (2012) Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm Bowel Dis.
Lendrum AC, Fraser DS, Slidders W, Henderson R, (1962) Studies on the character and staining of fibrin. J Clin Pathol 15: 401-413.
Rasband WS (1997-2011) ImageJ. U. S. National Institutes of Health, Bethesda, Maryland, USA.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, et al. (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4: 249-264.
Smyth GK, (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.
Benjamini Y, Hochberg Y. (1995) Controlling the False Discovery Rate: a Powerful Approach to Multiple Testing. J R Stat Soc 289-300.
Prodanov D (2009) MRI Processor, ImageJ Documentation Wiki.
Mahavadi S, Flynn RS, Grider JR, Qiao LY, Murthy KS, et al. (2011) Amelioration of excess collagen IalphaI, fibrosis, and smooth muscle growth in TNBS-induced colitis in IGF-I(+/-) mice. Inflamm Bowel Dis 17: 711-719.
Pinchuk IV, Beswick EJ, Saada JI, Boya G, Schmitt D, et al. (2011) Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells. Gastroenterology 140: 2019-2030.
Mackie EJ, (1994) Tenascin in connective tissue development and pathogenesis. Perspect Dev Neurobiol 2: 125-132.
Barrett R, Zhang X, Koon HW, Vu M, Chang JY, et al. (2012) Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol 180: 636-649.
Baribault H, Penner J, Iozzo RV, Wilson-Heiner M, (1994) Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev 8: 2964-2973.
Tao GZ, Strnad P, Zhou Q, Kamal A, Zhang L, et al. (2007) Analysis of keratin polypeptides 8 and 19 variants in inflammatory bowel disease. Clin Gastroenterol Hepatol 5: 857-864.
Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, et al. (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334: 255-258.
Fiocchi C, Lund PK, (2011) Themes in fibrosis and gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 300: G677-683.