1. The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease.
- Author
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Han B, Poppinga WJ, Zuo H, Zuidhof AB, Bos IS, Smit M, Vogelaar P, Krenning G, Henning RH, Maarsingh H, Halayko AJ, van Vliet B, Stienstra S, Graaf AC, Meurs H, and Schmidt M
- Subjects
- Animals, Cell Line, Transformed, Chromans chemistry, Complex Mixtures antagonists & inhibitors, Complex Mixtures pharmacology, Disease Models, Animal, Gene Expression Regulation, Guinea Pigs, Humans, Hydrogen Sulfide agonists, Hydrogen Sulfide blood, Hypersensitivity etiology, Hypersensitivity immunology, Hypersensitivity metabolism, Inflammation, Interleukin-8 antagonists & inhibitors, Interleukin-8 genetics, Interleukin-8 immunology, Lipopolysaccharides administration & dosage, Lung, Male, Malondialdehyde antagonists & inhibitors, Malondialdehyde metabolism, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle immunology, Myocytes, Smooth Muscle pathology, NF-E2-Related Factor 2 antagonists & inhibitors, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 immunology, Neutrophils drug effects, Neutrophils immunology, Neutrophils pathology, Oxidative Stress, Piperazines chemistry, Pulmonary Disease, Chronic Obstructive immunology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive physiopathology, Reactive Oxygen Species metabolism, Tars chemistry, Tars toxicity, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA genetics, Transcription Factor RelA immunology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antioxidants pharmacology, Chromans pharmacology, Hypersensitivity prevention & control, Piperazines pharmacology, Pulmonary Disease, Chronic Obstructive drug therapy, Reactive Oxygen Species antagonists & inhibitors
- Abstract
COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress.
- Published
- 2016
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