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Dextran Sodium (dextran + sodium)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2006
Takuji Tanaka
Abstract The mouse model for familial adenomatous polyposis, ApcMin/+ mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in ApcMin/+ mice. ApcMin/+ and Apc+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, ,-catenin, p53, and nitrotyrosine, and mutations of ,- catenin and K- ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female ApcMin/+ mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female ApcMin/+ mice but did not develop in Apc+/+ mice. Adenocarcinomas developed in ApcMin/+ mice that received DSS showed loss of heterozygosity of Apc and no mutations in the ,- catenin and K- ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female ApcMin/+ mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of ,-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of ApcMin/+ mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of ApcMin/+ mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development. © 2005 Wiley-Liss, Inc. [source]

CCR6 has a non-redundant role in the development of inflammatory bowel disease

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003
Rosa Varona
Abstract Antigen-loaded tissues such as the intestinal mucosa must simultaneously elicit appropriate immune response to innocuous bacteria and food proteins, and to potentially harmful antigens. Impairment of the mechanisms controlling this response may mediate the excessive immune reaction that can lead to tissue destruction and inflammatory intestinal diseases, including inflammatory bowel disease. The intestinal epithelium influences local immune responses through the expression of adhesion molecules, costimulatory factors, cytokines and chemokines. CCL20, a ,-chemokine expressed in epithelia from colon and other intestinal tissue, plays a role in immune responses of intestinal mucosa, as deduced from the defects in intestinal leukocyte homeostasis shown by mice lacking CCR6, the CCL20 receptor. We studied the response of CCR6-deficient mice in two models of inflammatory bowel disease. The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate. Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain. These results suggest that the CCR6/CCL20 axis has a critical, non-redundant role in the in vivo control of immune responses in the intestine. [source]

Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis

INFLAMMATORY BOWEL DISEASES, Issue 11 2009
Martin A. Storr MD
Abstract Background: Activation of cannabinoid (CB)1 receptors results in attenuation of experimental colitis. Our aim was to examine the role of CB2 receptors in experimental colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB2 receptor-deficient (CB mice. Methods: Mice were treated with TNBS to induce colitis and then given intraperitoneal injections of the CB2 receptor agonists JWH133, AM1241, or the CB2 receptor antagonist AM630. Additionally, CB mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB2 receptor was also performed in animals with TNBS and dextran sodium sulfate colitis. Results: Intracolonic installation of TNBS caused severe colitis. CB2 mRNA expression was significantly increased during the course of experimental colitis. Three-day treatment with JWH133 or AM1241 significantly reduced colitis; AM630 exacerbated colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CB mice. Conclusions: We show that activation of the CB2 receptor protects against experimental colitis in mice. Increased expression of CB2 receptor mRNA and aggravation of colitis by AM630 suggests a role for this receptor in normally limiting the development of colitis. These results support the idea that the CB2 receptor may be a possible novel therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2009) [source]

Suppression of experimental colitis in mice by CD11c+ dendritic cells

INFLAMMATORY BOWEL DISEASES, Issue 2 2009
Joseph E. Qualls PhD
Abstract Background: The innate immune system serves a critical role in homeostasis of the gastrointestinal (GI) tract. Both macrophages (MØs) and dendritic cells (DCs) have been shown to have pathogenic roles in animal models of inflammatory bowel disease. However, studies by several labs have established that resident MØs and DCs within the normal GI tract maintain an immunosuppressive phenotype compared to that seen in other peripheral sites. Recent studies by our lab demonstrated that the depletion of both MØs and DCs before the initiation of dextran sodium sulfate (DSS)-induced colitis resulted in exacerbation of disease, partly caused by increased neutrophil influx. Methods/Results: In this current report, DSS-induced colitis was shown to be significantly more severe when DCs were selectively depleted in mice as indicated by changes in weight loss, stool consistency, rectal bleeding, and histopathology. In contrast to enhanced colitis in MØ/DC-depleted mice, which was associated with increased neutrophil influx, increased colitis in DC-depleted mice was not associated with an increase in neutrophils in the colon, as shown by CXCL1 chemokine levels and myeloperoxidase (MPO) activity. However, increased IL-6 gene and protein expression in colon tissues correlated positively with increased colitis severity in DC-depleted mice compared to colitis in DC-intact mice. Conclusions: This study demonstrates that resident DCs can suppress the severity of acute DSS colitis and that regulation of IL-6 production may contribute to DC-mediated control of intestinal inflammation. (Inflamm Bowel Dis 2008) [source]

A specific inducible nitric oxide inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male ApcMin/+ mice

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2007
Hiroyuki Kohno
Abstract It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the ApcMin/+ mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the ApcMin/+ mouse treated with DSS. Male C57BL/6J ApcMin/+ and Apc+/+ mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-, and interleukin (IL)-1,. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the ApcMin/+ mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNF, and IL-1, of colonic mucosa in the DSS-treated ApcMin/+ mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc+/+ mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the ApcMin/+ mice. © 2007 Wiley-Liss, Inc. [source]

Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms

Osteopontin as two-sided mediator of intestinal inflammation

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6 2009
Katja Heilmann
Abstract Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN,/,) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN,/, mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 , and matrix metalloproteinases was found in acute colitis of OPN,/, mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN,/, mice showed increased serum levels of tumour necrosis factor (TNF)-,, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN,/, mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation. [source]

Functional colonography of Min mice using dark lumen dynamic contrast-enhanced MRI

MAGNETIC RESONANCE IN MEDICINE, Issue 3 2008
C. Chad Quarles
Abstract Dark lumen MRI colonography detects colonic polyps by minimization of the intestinal lumen signal intensity. Here we validate the use of perfluorinated oil as an intestinal-filling agent for dark lumen MRI studies in mice, enabling the physiological characterization of colonic polyps by dynamic contrast-enhanced MRI. In control and Min (multiple intestinal neoplasia) mice with and without pretreatment with oral dextran sodium sulfate (DSS), polyps as small as 0.94 mm diameter were consistently identified using standard 2D gradient echo imaging (voxel size, 0.23 × 0.16 × 0.5 mm). In serial studies, polyp growth rates were heterogeneous with an average ,5% increase in polyp volume per day. In DSS-treated control mice the colon wall contrast agent extravasation rate constant, Ktrans, and extravascular extracellular space volume fraction, ve, values were measured for the first time and found to be 0.10 ± 0.03 min,1 and 0.23 ± 0.09, respectively. In DSS-treated Min mice, polyp Ktrans values (0.09 ± 0.04 min,1) were similar to those in the colon wall but the ve values were substantially lower (0.16 ± 0.03), suggesting increased cellular density. The functional dark-lumen colonography approach described herein provides new opportunities for the noninvasive assessment of gastrointestinal disease pathology and treatment response in mouse models. Magn Reson Med 60:718,726, 2008. © 2008 Wiley-Liss, Inc. [source]

Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice

NEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009
B. De Smet
Abstract, Ghrelin is an important orexigenic peptide that not only exerts gastroprokinetic but also immunoregulatory effects. This study aimed to assess the role of endogenous and exogenous ghrelin in the pathogenesis of colitis and in the disturbances of gastric emptying and colonic contractility during this process. Dextran sodium sulphate colitis was induced for 5 days in (i) ghrelin+/+ and ghrelin,/, mice and clinical and histological parameters were monitored at days 5, 10 and 26 and (ii) in Naval Medical Research Institute non-inbred Swiss (NMRI) mice treated with ghrelin (100 nmol kg,1) twice daily for 5 or 10 days. Neural contractility changes were measured in colonic smooth muscle strips, whereas gastric emptying was measured with the 14C octanoic acid breath test. Inflammation increased ghrelin plasma levels. Body weight loss, histological damage, myeloperoxidase activity and IL-1, levels were attenuated in ghrelin,/, mice. Whereas absence of ghrelin did not affect changes in colonic contractility, gastric emptying in the acute phase was accelerated in ghrelin+/+ but not in ghrelin,/, mice. In agreement with the studies in ghrelin knockout mice, 10 days treatment of NMRI mice with exogenous ghrelin enhanced the clinical disease activity and promoted infiltration of neutrophils and colonic IL-1, levels. Unexpectedly, ghrelin treatment decreased excitatory and inhibitory neural responses in the colon of healthy but not of inflamed NMRI mice. Endogenous ghrelin enhances the course of the inflammatory process and is involved in the disturbances of gastric emptying associated with colitis. Treatment with exogenous ghrelin aggravates colitis, thereby limiting the potential therapeutic properties of ghrelin during intestinal inflammation. [source]

Visceral sensation and colitis: inflammation and hypersensitivity do not always go hand in hand

NEUROGASTROENTEROLOGY & MOTILITY, Issue 2 2006
K. A. Sharkey
Abstract, Visceral sensitivity and inflammation are discussed in relation to novel observations in the current issue of the Journal by Larsson and her colleagues. This paper shows that neither acute nor chronic intestinal inflammation initiated by dextran sodium sulfate is associated with an increase in visceral sensitivity to balloon distension in mice. These findings are discussed in the context of recent work highlighting the role of mast cells, the induction of endogenous antinociceptive pathways and the role of altered bacterial flora in visceral hypersensitivity. [source]

Loss of transgelin in repeated bouts of ulcerative colitis-induced colon carcinogenesis

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2006
Marie Yeo
Abstract Though ulcerative colitis (UC)-associated colon cancer develops from dysplastic lesions caused by chronic inflammation, the specific mechanistic link between chronic inflammation and carcinogenesis in colon has not been integrated into molecular understanding. We therefore established an experimental animal model for colitic cancer, and used proteomic analysis, based on 2-DE and MALDI-TOF,MS, to identify proteins involved in colitic cancer. In our model, 6-week-old C57BL/6J mice were exposed to 15,cycles of dextran sodium sulfate (DSS), with each cycle consisting of 0.7% DSS for 1,week followed by distilled water for 10,days. Colorectal tumors developed in 22 of 24,mice (91.6%), with a tumor multiplicity of 1.727 per tumor-bearing mouse. Comparative 2-DE analysis showed that 38,protein spots were differentially expressed in colon tumors and normal colon. We identified 27 of these proteins, including GRP94, HSC70, enolase, prohibitin, and transgelin. The reduction of transgelin expression in mouse colon tumors was confirmed by Western blotting and immunohistochemistry. We also found that transgelin expression was significantly reduced in human colon tumors compared with adjacent nontumorous tissues. In conclusion, these results suggest that loss of transgelin could be a candidate for biomarker of repeated colitis-associated colon cancer. [source]

Bimodal Oscillation Frequencies of Blood Flow in the Inflammatory Colon Microcirculation

THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 1 2009
Akira Tsuda
Abstract Rhythmic changes in blood flow direction have been described in the mucosal plexus of mice with acute colitis. In this report, we studied mice with acute colitis induced either by dextran sodium sulfate or by trinitrobenzenesulfonic acid. Both forms of colitis were associated with blood flow oscillations as documented by fluorescence intravital videomicroscopy. The complex oscillation patterns suggested more than one mechanism for these changes in blood flow. By tracking fluorescent nanoparticles in the inflamed mucosal plexus, we identified two forms of blood flow oscillations within the inflammatory mouse colon. Stable oscillations were associated with a base frequency of approximately 2 cycles/sec. Velocity measurements in the upstream and downstream vessel segments indicated that stable oscillations were the result of regional flow occlusion within the mucosal plexus. In contrast, metastable oscillations demonstrated a lower frequency (0.2,0.4 cycles/sec) and appeared to be the result of flow dynamics in vessels linked by the bridging mucosal vessels. These blood flow oscillations were not directly associated with cardiopulmonary movement. We conclude that both the stable and metasable oscillating patterns reflect flow adaptations to inflammatory changes in the mucosal plexus. Anat Rec, 2009. © 2008 Wiley-Liss, Inc. [source]

Bridging Mucosal Vessels Associated with Rhythmically Oscillating Blood Flow in Murine Colitis

THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 1 2008
Aslihan Turhan
Abstract Oscillatory blood flow in the microcirculation is generally considered to be the result of cardiopulmonary influences or active vasomotion. In this report, we describe rhythmically oscillating blood flow in the bridging vessels of the mouse colon that appeared to be independent of known biological control mechanisms. Corrosion casting and scanning electron microscopy of the mouse colon demonstrated highly branched bridging vessels that connected the submucosal vessels with the mucosal plexus. Because of similar morphometric characteristics (19 ± 11 ,m vs. 28 ± 16 ,m), bridging arterioles and venules were distinguished by tracking fluorescent nanoparticles through the microcirculation using intravital fluorescence videomicroscopy. In control mice, the blood flow through the bridging vessels was typically continuous and unidirectional. In contrast, two models of chemically induced inflammation (trinitrobenzenesulfonic acid and dextran sodium sulfate) were associated with a twofold reduction in flow velocity and the prominence of rhythmically oscillating blood flow. The blood oscillation was characterized by tracking the bidirectional displacement of fluorescent nanoparticles. Space,time plots and particle tracking of the oscillating segments demonstrated an oscillation frequency between 0.2 and 5.1 cycles per second. Discrete Fourier transforms demonstrated a power spectrum composed of several base frequencies. These observations suggest that inflammation-inducible changes in blood flow patterns in the murine colon resulted in both reduced blood flow velocity and rhythmic oscillations within the bridging vessels of the mouse colon. Anat Rec, 291:74,82, 2007. © 2007 Wiley-Liss, Inc. [source]