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Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers
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2012 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 4, no 9, p. 866-881Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2012. Vol. 4, no 9, p. 866-881
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Immunology in the medical area Microbiology in the medical area
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URN: urn:nbn:se:umu:diva-156944DOI: 10.1002/emmm.201201290PubMedID: 22887873OAI: oai:DiVA.org:umu-156944DiVA, id: diva2:1293121
Available from: 2019-03-03 Created: 2019-03-03 Last updated: 2019-03-08Bibliographically approved

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Puhar, Andrea

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