IMMUNOMODULATION AND INTESTINAL BARRIER PROTECTION ACTIVITIES OF A NOVEL SYNTHETIC GLUCOSE ANALOGUE IN INFLAMMATORY ANIMAL MODEL OF COLITIS AND ASTHMA.
Creators: name: DUSIO, GIUSEPPINA
Publisher: name: Universit� degli Studi di Milano
Year: 2010

description: The mucosal surfaces of the gastrointestinal and respiratory tracts are the main interfaces between the environment and the host. All two are protected by continuous epithelia that prevents the entry of microbes and integrity loss of these epithelia commonly predispose to infection. On the other hand the epithelial surfaces provide essential absorptive functions for the intake of food and air. SGLT-1 is a co-transporter able to absorb D-glucose, against a concentration gradient, together with Na+. The expression of SGLT-1 on the apical membrane of enterocytes, the cells that line the gut and overlook to the intestinal lumen, is fundamental in order to obtain the maximum D-glucose absorption from the digested alimentary bolo that transits through the gut. Accumulating data support the notion that SGLT1 orchestrates a number of fundamental cellular processes besides its canonical absorptive function. Presented results show a novel role of SGLT-1: this protein if appropriately activated modulates the immune response and protect barrier function.
Our recent findings indicate that the activation of SGLT-1, present at apical membrane of enterocytes inhibits bacteria-induced inflammatory processes and lifesaving treatments, assuming a role as an immunological player. The main drawback of this activation is the high level of glucose that must be administrated (2.5 g/kg) in vivo so to achieve protection. In this contest we have developed a new glucoderivatives, named BLF501, able to ?activate? SGLT-1 in order to achieve the protection against damages induced by LPSs while avoiding the disadvantages caused by high glucose concentration.. Thus our new synthetic molecule BLF501, acting as a potent activator of SGLT-1 at very low dosages, might represent a new pharmacological drug for the treatment of IBD, given the cytoprotective and anti-inflammatory effects linked to SGLT-1 activation. Infact BLF501 stabilizes TJ-protein localization preventing INF-?/TNF-?. or DSS-mediated degradation. BLF501 is very effective at preventing functional (FD-3 flux) and morphological (TJ protein) permeability defects induced by inflammatory or chemically stimuli. In vivo experiments utilizing a chemically-induced mouse model of intestinal inflammation, we found that mice with acute or chronic colitis BLF-501-treated not presents typical mucosal injury, shows a weight recovery and not develops severe clinical symptoms, including bleeding and dehydratation. The TJ protein has been reported to be deregulated in IBD. We have analyzed occludin and ZO-1 localization in colon tissue of different treatments and we have evaluated that intestinal permeability recovery observed with Ussing Chamber analysis is mediated by TJ protein protection. Results suggest that the BLF-501-mediated action involves stabilization of epithelial junction complex also in vivo. Moreover, we observed that activation of pro-inflammatory cytokines, such as TNF-?, and IL-12 in acute and chronic colitis was suppressed by oral administration of BLF-501. We have observed a marked increase of IL-10 levels in mice treated with BLF-501 and acute and chronic cycles of DSS in comparison with DSS alone or with untreated mice. The continuous IL-10 production from immune system components, guaranteeing an endogenous source of this anti-inflammatory cytokine, is able, to down-
The sodium-dependent glucose transporter-1 (SGLT-1) molecule is expressed by intestinal epithelial cells and by pneumocytes. We show here that BLF501, induces protective anti-inflammatory effects in lung of mice exposed to aerosolized lipopolysaccharide (LPS) or to ovalbumin (OVA), as assessed by analysis of serum, brochoalveolar lavage and lung morphology of the mice in both experimental models. Findings in the OVA-induced asthma murine model that aerosol and oral, administration of BLF501 led to a marked decrease of bronchoalveolar cellular infiltrate and of IL-4, IL-5, NO and IgE levels, and increased levels of the anti-inflammatory cytokine IL-10, suggest the promise of SGLT-1 activation by BLF501 as a new approach to improving asthma pathology.
We can conclude thatBLF-501 as ligand of SGLT-1 may be suggested as a new pharmacological approach for the treatment of different inflammatory diseases as IBD and asthma.