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.
Highlights
Inhalation of environmental airborne substances in the form of aeroallergens and particulate matter can result in allergic respiratory dysfunctions and pneumoconiosis, such as asthma and silicosis, respectively [1,2,3,4]
None of the PEGylated compounds resulted to be toxic on PBMCs; with no relevant apoptosis induced after over night exposure to TMX-302 or TMX-306 (10 μM, data not shown)
Cytofluorimetric analysis on human PBMCs labeled with carboxyfluorescein succinimidyl ester (CFSE) and incubated with the different compounds showed that the PEGylated partial agonists do not induce B cell proliferation (Figure 3C)
Summary
Inhalation of environmental airborne substances in the form of aeroallergens and particulate matter can result in allergic respiratory dysfunctions and pneumoconiosis, such as asthma and silicosis, respectively [1,2,3,4]. Air pollutants may impact on allergic airway-related morbidity and mortality [5, 6]. While asthma is among those diseases with an obstructive pulmonary function pattern [7], silicosis is pathologically characterized as a fibrogranulomatous disease with a restrictive pulmonary function profile [8]. Both asthma and silicosis are highly prevalent worldwide, cause elevated socioeconomic costs, and can be fatal [3]. The situation is even more alarming in case of silicosis, since no proper therapy is available [9]
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