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Gene-deficient Mice (gene-deficient + mouse)
Selected AbstractsEpithelial barrier disruption allows nondisease-causing bacteria to initiate and sustain IBD in the IL-10 gene-deficient mouse,INFLAMMATORY BOWEL DISEASES, Issue 8 2007Beate C. Sydora PhD Abstract Background: In the IL-10 gene-deficient mouse model, development of intestinal inflammation is associated with a defect in epithelial barrier integrity that is thought to allow sufficient passage of bacteria or bacterial antigens to initiate a mucosal immune response. Microbial monoassociation experiments into axenic animals have shown that some, but not all, endogenous bacteria will initiate an intestinal inflammatory response. For instance, Bacteroides vulgatus does not initiate intestinal inflammation in axenic IL-10 gene-deficient mice. We investigated whether B. vulgatus requires concomitant disruption of the intestinal epithelial barrier integrity in order to initiate an inflammatory response. Methods: We first identified a dose of the indomethacin that would cause a primary disruption of the epithelial barrier without causing intestinal inflammation. IL-10 axenic mice were then administered this dose of indomethacin in their drinking water for 7 days and concomitantly monoassociated, by oral gavage, with B. vulgatus. Results: Indomethacin treatment (2 ,g/g/d) for 7 days resulted in disruption of epithelial barrier integrity, but it caused neither a systemic inflammatory response nor a mucosal inflammatory response in the colon or cecum. Monoassociation with B. vulgatus alone did not lead to a mucosal inflammatory response, despite a measurable systemic response. In contrast, administration of indomethacin plus B. vulgatus -monoassociation resulted in a marked intestinal inflammatory response in colon and cecum. Conclusions: Our data show that, in a genetically predisposed animal model, the nondisease-causing endogenous bacteria, B. vulgatus, is able to cause an intestinal inflammatory response provided that disruption of the intestinal epithelial barrier has occurred. (Inflamm Bowel Dis 2007) [source] Bacterial antigens alone can influence intestinal barrier integrity, but live bacteria are required for initiation of intestinal inflammation and injuryINFLAMMATORY BOWEL DISEASES, Issue 6 2006Beate C. Sydora PhD Abstract Intestinal flora plays a critical role in the initiation and perpetuation of inflammatory bowel disease. This study examined whether live fecal bacteria were necessary for the initiation of this inflammatory response or whether sterile fecal material would provoke a similar response. Three preparations of fecal material were prepared: (1) a slurry of live fecal bacteria, (2) a sterile lysate of bacterial antigens, and (3) a sterile filtrate of fecal water. Each preparation was introduced via gastric gavage into the intestines of axenic interleukin-10 gene-deficient mice genetically predisposed to develop inflammatory bowel disease. Intestinal barrier integrity and degrees of mucosal and systemic inflammations were determined for each preparation group. Intestinal barrier integrity, as determined by mannitol transmural flux, was altered by both live fecal bacterial and sterile lysates of bacterial antigens, although it was not altered by sterile filtrates of fecal water. However, only live fecal bacteria initiated mucosal inflammation and injury and a systemic immune response. Fecal bacterial antigens in the presence of live bacteria and sterile fecal bacterial antigens have different effects on the initiation and perpetuation of intestinal inflammation. [source] Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitisINFLAMMATORY BOWEL DISEASES, Issue 3 2004Tsunekazu Mizushima MD Abstract Background: FTY720 is a novel reagent that possesses potent immunosuppressive activity. The immunosuppression induced by FTY720 is mediated by completely different mechanisms from those of conventional immunosuppressants, that is, by altering the tissue distribution of lymphocytes rather than inhibiting activation. In this study, we examined the efficacy of FTY720 in the treatment of chronic colitis in an interleukin-10 gene-deficient (IL-10,/,) mouse model. Methods: FTY720 was administered orally for 4 weeks to IL-10,/,mice with clinical signs of colitis. The gross and histologic appearance of the colon and the numbers, phenotype, cytokine production, and apoptosis of lymphocytes were compared with those characteristics in a control group. Results: Single-dose administration of FTY720 resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. Four-week administration resulted in a significant reduction of the CD4+ T lymphocytes subpopulation in the colonic lamina propria and IFN-, production of the colonic lymphocytes, accompanied by a significant decrease in the severity of colitis. Conclusions: Treatment of established colitis in IL-10,/, mice with FTY720 ameliorated the colitis, probably as a result of decreasing the number of lymphocytes in the colonic mucosa and an associated reduction in IFN-, production. [source] Increases in tumor necrosis factor-, following transient global cerebral ischemia do not contribute to neuron death in mouse hippocampusJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Yuki Murakami Abstract The actions of tumor necrosis factor-, (TNF-,) produced by resident brain cells and bone marrow-derived cells in brain following a transient global ischemia were evaluated. In wild-type mice (C57Bl/6J) following 20 min ischemia with bilateral common carotid artery occlusion (BCCAo), TNF-, mRNA expression levels in the hippocampus were significantly increased at 3 h and 36 h and exhibited a biphasic expression pattern. There were no hippocampal TNF-, mRNA expression levels at early time points in either wild-type mice bone marrow transplanted (BMT)-chimeric-TNF-, gene-deficient (T/W) or TNF-, gene-deficient mice BMT-TNF-, gene-deficient mice (T/T), although TNF-, mRNA levels were detectable in T/W BMT mice at 36 h. Histopathological findings showed no intergroup differences between wild-type and TNF-, gene-deficient mice at 4 and 7 days after transient ischemia. In addition, nuclear factor-,B (NF-,B) was activated within 12 h after global cerebral ischemia, but electrophoretic mobility shift assays (EMSA) showed no intergroup differences between wild type and TNF-, gene-deficient mice. In summary, early hippocampal TNF-, mRNA expression may not be related to bone marrow-derived cells, and secondary TNF-, expression as early as 36 h after ischemia probably resulted mainly from endogenous brain cells and possibly a few bone marrow-derived cells. Although we cannot exclude the possibility of the TNF-, contribution to the physiologic changes of hippocampus after transient global ischemia, these results indicate that TNF-, does not influence the morphological changes of the hippocampal neurons under our study condition. [source] Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2007Y. SUZUKI Summary.,Background:,Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. Objectives:,To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. Methods:,Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg,/,), stromelysin-1 (MMP-3,/,), or gelatinase B (MMP-9,/,) and their corresponding wild-type (WT) littermates. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. Results:,ICB induced by t-PA (10 mg kg,1) was significantly less than WT in Plg,/, (P < 0.05) and MMP-3,/, (P < 0.05) but not in MMP-9,/, mice. Furthermore, administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly (P < 0.05) in MMP-3+/+ mice, but had no effect on MMP-3,/, mice. MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was up-regulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. Conclusions:,Our data with gene-deficient mice thus suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke. [source] Epithelial barrier disruption allows nondisease-causing bacteria to initiate and sustain IBD in the IL-10 gene-deficient mouse,INFLAMMATORY BOWEL DISEASES, Issue 8 2007Beate C. Sydora PhD Abstract Background: In the IL-10 gene-deficient mouse model, development of intestinal inflammation is associated with a defect in epithelial barrier integrity that is thought to allow sufficient passage of bacteria or bacterial antigens to initiate a mucosal immune response. Microbial monoassociation experiments into axenic animals have shown that some, but not all, endogenous bacteria will initiate an intestinal inflammatory response. For instance, Bacteroides vulgatus does not initiate intestinal inflammation in axenic IL-10 gene-deficient mice. We investigated whether B. vulgatus requires concomitant disruption of the intestinal epithelial barrier integrity in order to initiate an inflammatory response. Methods: We first identified a dose of the indomethacin that would cause a primary disruption of the epithelial barrier without causing intestinal inflammation. IL-10 axenic mice were then administered this dose of indomethacin in their drinking water for 7 days and concomitantly monoassociated, by oral gavage, with B. vulgatus. Results: Indomethacin treatment (2 ,g/g/d) for 7 days resulted in disruption of epithelial barrier integrity, but it caused neither a systemic inflammatory response nor a mucosal inflammatory response in the colon or cecum. Monoassociation with B. vulgatus alone did not lead to a mucosal inflammatory response, despite a measurable systemic response. In contrast, administration of indomethacin plus B. vulgatus -monoassociation resulted in a marked intestinal inflammatory response in colon and cecum. Conclusions: Our data show that, in a genetically predisposed animal model, the nondisease-causing endogenous bacteria, B. vulgatus, is able to cause an intestinal inflammatory response provided that disruption of the intestinal epithelial barrier has occurred. (Inflamm Bowel Dis 2007) [source] | ||||||||||