EMBO Molecular Medicine | |
Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers | |
Ian Teo1  Steve M. Toms5  Benoit Marteyn2  Teresa S. Barata1  Peter Simpson4  Karen A. Johnston5  Pamela Schnupf2  Andrea Puhar2  Tracey Bell5  Chris Tang3  Mire Zloh6  Steve Matthews4  Phillip M. Rendle5  Philippe J. Sansonetti2  | |
[1] Departments of Medicine, Infectious Diseases & Immunity, Imperial College London, Hammersmith Hospital, Ducane Road, London, UK;Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire & Unité INSERM 786, Paris, France;Sir William Dunn School of Pathology, South Parks Road, Oxford, UK;Cross-Faculty NMR Centre & Department of Life Sciences, Imperial College London, South Kensington, London, UK;Industrial Research (IRL), Lower Hutt, New Zealand;UCL School of Pharmacy, University College London, London, UK | |
关键词: dendrimer; diarrhoea; infection; interleukin‐6; nanobiotechnology; | |
DOI : 10.1002/emmm.201201290 | |
来源: Wiley | |
【 摘 要 】
Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases. –>See accompanying article http://dx.doi.org/10.1002/emmm.201201668Abstract
【 授权许可】
CC BY
Copyright © 2012 EMBO Molecular Medicine
Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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