A Novel Quinoline With Airway Relaxant Effects and Anti-Inflammatory Properties

Abstract

Background In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Here, we investigated the relaxant and anti-inflammatory properties in the airways of a novel quinoline (RCD405). Methods The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate immune cell influx and goblet cell hyperplasia of the airways. The inflammatory response, as reflected by the production of cytokines and chemokines, was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. Results RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated. The OVA- specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation. In vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. Conclusions RCD405 has airway relaxant effects and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.