Contrasting roles for CXCR2 during experimental colitis.
ABSTRACT Neutrophil recruitment into the colon is believed to play a crucial pathogenic role in the progression of clinical and experimental inflammatory bowel diseases (IBDs). The chemokine receptor CXCR2 is highly expressed on neutrophils, and promotes neutrophil recruitment in several inflammatory diseases. The present study determined the biological role of CXCR2 during trinitrobenzene sulfonic acid (TNBS)-induced colitis in the rat by assessing effects of CXCR2 antibody neutralization on neutrophil accumulation during the early (8 h) and late phase (day 7) of TNBS-induced colitis. CXCR2 expression was elevated (>3-fold above control) within 8 h and remained elevated to day 7 of colitis induction, in parallel with significant increases in neutrophil infiltration. Treatment of colitic rats with a single dose of CXCR2 neutralizing antibody significantly reduced colonic neutrophil accumulation during the early (8 h) phase of TNBS-induced colitis. However, chronic administration of CXCR2 antibody did not reduce colonic neutrophil accumulation during the late phase (day 7) of TNBS-induced colitis. In summary, the present findings suggest a functional role for CXCR2 in initiating neutrophil recruitment during the early phase of TNBS-induced acute colitis, and demonstrate that: early colonic neutrophil accumulation is CXCR2 dependent and the late phase colonic neutrophil accumulation is CXCR2 independent.
Article: cDNA array analysis of cytokines, chemokines, and receptors involved in the development of TNBS-induced colitis: homeostatic role of VIP.[show abstract] [hide abstract]
ABSTRACT: Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.Inflammatory Bowel Diseases 08/2005; 11(7):674-84. · 4.86 Impact Factor
Article: Preventative effects of lactulose in the trinitrobenzenesulphonic acid model of rat colitis.[show abstract] [hide abstract]
ABSTRACT: Lactulose is a drug used as a laxative that has been shown to promote the growth of lactobacilli and bifidobacteria, acting as a prebiotic and with a potential beneficial effect in inflammatory bowel disease. The present study describes the preventive antiinflammatory activity of lactulose in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Rats were rendered colitic by a colonic instillation of 10 mg of TNBS dissolved in 0.25 mL of 50% ethanol. One group of colitic rats received lactulose, which was incorporated in the drinking water (2.5% wt/vol) for 2 weeks before TNBS instillation, and colonic damage was evaluated 1 week after colitis induction. Different biochemical markers of colonic inflammation were assayed: myeloperoxidase activity, glutathione content, tumor necrosis factor alpha, leukotriene B4 levels, and colonic inducible nitric oxide synthase expression. In addition, bacterial counts (for lactobacilli and bifidobacteria) were performed in colonic contents from colitic rats. The results show that lactulose exerted a preventive antiinflammatory effect in this model of rat colitis, as evidenced by a significant reduction of myeloperoxidase activity and by a decrease of both colonic tumor necrosis factor alpha and leukotriene B4 production. This effect was also characterized by an inhibition of colonic inducible nitric oxide synthase expression, which is unregulated as a consequence of the inflammatory status. This beneficial effect was associated with increased levels of lactobacilli and bifidobacteria species in colonic contents in comparison with untreated colitic rats. In conclusion, the intestinal antiinflammatory effect of lactulose could be related to its prebiotic properties, supporting its potential use in human inflammatory bowel disease.Inflammatory Bowel Diseases 04/2005; 11(3):265-71. · 4.86 Impact Factor