Abstract
Background Quinoline-3-carboxamides have been used to treat autoimmune/inflammatory diseases in humans because they inhibit the functions of S100 calcium-binding protein A9 (S100A9), which participates in the development of neutrophilic inflammation in asthmatics and in an animal model of neutrophilic asthma. However, the therapeutic effects of these chemicals have not been evaluated in asthma. The purpose of this study was to evaluate the effect of paquinimod, one of the quinoline-3-carboxamides, on a murine model of neutrophilic asthma. Methods Paquinimod was orally administered to 6-week-old C57BL/6 mice sensitized and challenged with ovalbumin (OVA)/complete Freund's adjuvant (CFA) and OVA. Lung inflammation and remodeling were evaluated using bronchoalveolar lavage (BAL) and histologic findings including goblet cell count. S100A9, caspase-1, IL-1β, MPO, IL-17, IFN-γ, and TNF-α were measured in lung lysates using western blotting. Results Paquinimod restored the enhancement of airway resistance and the increases in numbers of neutrophils and macrophages of BAL fluids and those of goblet cells in OVA/CFA mice toward the levels of sham-treated mice in a dose-dependent manner (0.1, 1, 10, and 25 mg/kg/day, p.o.). Concomitantly, p20 activated caspase-1, IL-1β, IL-17, TNF-α, and IFN-γ levels were markedly attenuated. Conclusion These data indicate that paquinimod effectively inhibits neutrophilic inflammation and remodeling in the murine model of neutrophilic asthma, possibly via downregulation of IL-17, IFN-γ, and IL-1β.
Highlights
Quinoline-3-carboxamides have been used to treat autoimmune/inflammatory diseases in humans because they inhibit the functions of S100 calcium-binding protein A9 (S100A9), which participates in the development of neutrophilic inflammation in asthmatics and in an animal model of neutrophilic asthma
IL-8, TNF-α, interferon-c (INF-c), and IL-17 are assumed to be responsible for neutrophilic inflammation [8], therapies to protect against these molecules have not yet resulted in a good clinical response in severe asthmatic patients [9]. us, other molecular mediators should be regarded as therapeutic candidates for the treatment of neutrophilic inflammation
To the best of our knowledge, this is the first report for the therapeutic effect of paquinimod against animal model of neutrophilic asthma. e S100A9 protein binds to the proinflammatory receptors involving receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) [13], both of which are involved in the pathogenesis of asthma [15]. e binding of S100A9 to TLR4 induces NF-κB activation and cytokine secretion in myeloid cells [28, 29]
Summary
Quinoline-3-carboxamides have been used to treat autoimmune/inflammatory diseases in humans because they inhibit the functions of S100 calcium-binding protein A9 (S100A9), which participates in the development of neutrophilic inflammation in asthmatics and in an animal model of neutrophilic asthma. E purpose of this study was to evaluate the effect of paquinimod, one of the quinoline-3-carboxamides, on a murine model of neutrophilic asthma. Paquinimod restored the enhancement of airway resistance and the increases in numbers of neutrophils and macrophages of BAL fluids and those of goblet cells in OVA/CFA mice toward the levels of sham-treated mice in a dose-dependent manner (0.1, 1, 10, and 25 mg/kg/day, p.o.). Ese data indicate that paquinimod effectively inhibits neutrophilic inflammation and remodeling in the murine model of neutrophilic asthma, possibly via downregulation of IL-17, IFN-c, and IL-1β. IL-8, TNF-α, interferon-c (INF-c), and IL-17 are assumed to be responsible for neutrophilic inflammation [8], therapies to protect against these molecules have not yet resulted in a good clinical response in severe asthmatic patients [9]. IL-8, TNF-α, interferon-c (INF-c), and IL-17 are assumed to be responsible for neutrophilic inflammation [8], therapies to protect against these molecules have not yet resulted in a good clinical response in severe asthmatic patients [9]. us, other molecular mediators should be regarded as therapeutic candidates for the treatment of neutrophilic inflammation.
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