title: Potential of PEGylated Toll-Like Receptor 7 Ligands for Controlling Inflammation and Functional Changes in Mouse Models of Asthma and Silicosis.
abstract: 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.
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Tatiana Paula Teixeira
authors.initials: TP
authors.lastname: Ferreira
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Lívia Lacerda
authors.initials: LL
authors.lastname: Mariano
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghilosso-Bortolini
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Ana Carolina Santos
authors.initials: AC
authors.lastname: de Arantes
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Andrey Junior
authors.initials: AJ
authors.lastname: Fernandes
authors.affiliation: Institute for Research in Biomedicine, Universitá della Svizzera Italiana , Bellinzona , Switzerland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Berni
authors.affiliation: Institute for Research in Biomedicine, Universitá della Svizzera Italiana , Bellinzona , Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecchinato
authors.affiliation: Institute for Research in Biomedicine, Universitá della Svizzera Italiana , Bellinzona , Switzerland.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
authors.affiliation: Telormedix SA , Bioggio , Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maj
authors.affiliation: Telormedix SA , Bioggio , Switzerland.
authors.forename: Alcide
authors.initials: A
authors.lastname: Barberis
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Patricia Machado Rodrigues E
authors.initials: PM
authors.lastname: Silva
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro , Brazil.
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Martins
keywords: ALI; PEGylated ligands; TLR7; asthma; silicosis