Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Abstract

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.201201668

Keeping it small: towards a molecular definition of nanotoxicology

“…Teo et al sought to develop a non-antibiotic approach to prevent acute gut wall damage in infectious diarrhoeas (54). Molecular modelling studies suggested that the glycosylated surface of dendrimers confers physicochemical properties that enable electrostatic interactions with lymphocyte antigen 96 or MD2 in the TLR4-MD2-LPS complex (55).…”

“…Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In a rabbit model of shigellosis, PETIM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion (54). The authors suggested that orally delivered dendrimer molecules could be useful for preventing gut wall tissue damage in a wide spectrum of diseases.…”

Dendrimers: Breaking the paradigm of current musculoskeletal autoimmune therapies

“…The flexibility in the design of dendrimers also allows tailoring the specific requirements for achieving certain biological features such as immunomodulation (Blattes et al, ; Chauhan et al, ; Kannan et al, ; Portevin et al, ; Rolland et al, ; Tang et al, ; Teo et al, ) or specific cell targeting (Thomas, Shukla, Kotlyar, Kukowska‐Latallo, & Baker, ; Yang, Cheng, Xu, Wang, & Wen, ).…”

“…Dendrimers are well established nanocarriers for drug delivery (Ballerini, Baldi, Aldinucci, & Maggi, ; Gouveia, Lima, Nunes, & Reis, ; Sk & Kojima, ; H. Wang, Huang, Chang, Xiao, Cheng, ). However, recent studies have proposed the potential anti‐inflammatory properties of these nanoparticles (Blattes et al, ; Kannan et al, ; Tang et al, ; Teo et al, ). These act by modulating inflammatory/immune cells activity, cytokine release, and cell costimulation (Avti & Kakkar, ).…”

“…That would benefit RA patients as TLR4 has been shown to be increased in peripheral blood mononuclear cells (PBMCs) from those patients (Roelofs et al, ). Similar glycosylated PAMAM dendrimers proved capable of preventing epithelial gut wall damage and intestinal villous destruction in a rabbit model of shigellosis by reducing IL‐6 and IL‐8 expression, as well as, minimizing bacterial invasion by altering the balance between cytokine‐mediated tissue injury and T‐cell‐mediated tolerance in the gut, maintaining the integrity of the epithelial gut wall (Teo et al, ).…”