Potential of PEGylated toll-like receptor 7 ligands for controlling inflammation and functional changes in mouse models of asthma and silicosis
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Teixeira Ferreira, Tatiana Paula
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Lacerda Mariano, Lívia
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Ghilosso-Bortolini, Roberta
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Santos de Arantes, Ana Carolina
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Fernandes, Andrey Junior
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Berni, Michelle
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Cecchinato, Valentina
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Uguccioni, Mariagrazia
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Maj, Roberto
Telormedix SA, Bioggio, Switzerland
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Barberis, Alcide
Telormedix SA, Bioggio, Switzerland
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Machado Rodrigues Silva, Patricia
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Martins, Marco Aurélio
Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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Published in:
- Frontiers in immunology. - 2016, vol. 7, p. 95
English
Prior investigations show that signaling activation through pattern recognition receptors can directly impact a number of inflammatory lung diseases. While toll-like receptor (TLR) 7 agonists have raised interest for their ability to inhibit allergen-induced pathological changes in experimental asthma conditions, the putative benefit of this treatment is limited by adverse effects. Our aim was to evaluate the therapeutic potential of two PEGylated purine-like compounds, TMX-302 and TMX-306, characterized by TLR7 partial agonistic activity; therefore, the compounds are expected to induce lower local and systemic adverse reactions. In vitro approaches and translation to murine models of obstructive and restrictive lung diseases were explored. In vitro studies with human PBMCs showed that both TMX-302 and TMX-306 marginally affects cytokine production as compared with equivalent concentrations of the TLR7 full agonist, TMX-202. The PEGylated compounds did not induce monocyte-derived DC maturation or B cell proliferation, differently from what observed after stimulation with TMX-202. Impact of PEGylated ligands on lung function and inflammatory changes was studied in animal models of acute lung injury, asthma, and silicosis following Lipopolysaccharide (LPS), allergen (ovalbumin), and silica inhalation, respectively. Subcutaneous injection of TMX- 302 prevented LPS- and allergen-induced airway hyper-reactivity (AHR), leukocyte infiltration, and production of pro-inflammatory cytokines in the lung. However, intranasal instillation of TMX-302 led to neutrophil infiltration and failed to prevent allergen-induced AHR, despite inhibiting leukocyte counts in the BAL. Aerosolized TMX-306 given prophylactically, but not therapeutically, inhibited pivotal asthma features. Interventional treatment with intranasal instillation of TMX-306 significantly reduced the pulmonary fibrogranulomatous response and the number of silica particles in lung interstitial space in silicotic mice. These findings highlight the potential of TMX-306, emphasizing its value in drug development for lung diseases, and particularly silicosis.
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Medicine
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https://n2t.net/ark:/12658/srd1319117
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