The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease

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.

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

“…Previously, we demonstrated that 6-chromanol derived SUL-compounds are protective in models of type 2 diabetes 7 , long-term hypothermic storage 5 and chronic obstructive pulmonary disease 8 . Further, the molecular mechanisms of SUL-compounds were studied in detail in adipose-tissue-derived stem cells demonstrating that compound SUL-109 activated mitochondrial membrane complexes I and IV thereby alleviating mitochondrial ROS production and preserving ATP production 5 .…”

“…In type 2 diabetes, treatment with SUL-121 halted the progression of kidney damage and prevented endothelial dysfunction through a mechanism involving lowered ROS production 7 . Further, in chronic obstructive pulmonary disease, SUL-121 also reduced ROS production, resulting in reduced LPS-induced airway hyper reactivity and neutrophil influx and increased hydrogen sulfide (H 2 S) production 8 .…”

Impaired Hemorheology in Exacerbations of COPD

“…Nowadays, COPD treatment options include quitting smoking, pharmacological treatment (short-acting anticholinergic, short-acting beta 2 -agonist, long-acting anticholinergic, long-acting beta 2 -agonist, and inhaled corticosteroids), and nonpharmacological treatment (pulmonary rehabilitation) [ 7 – 9 ]. Aim of pharmacological treatment is to improve the quality of life and exercise tolerance beside achieving the reduction of symptoms and attacks [ 7 , 8 ]. Inhaled corticosteroids specifically reduce the number of COPD exacerbations [ 10 ].…”

“…These properties are influenced by pathophysiological processes, including a variety of pulmonary diseases, thereby increasing the clinical relevance of blood rheology information [ 13 , 15 – 17 ]. In COPD patients, RBC were shown to alter morphologically, like cytoskeleton changes, ultrastructural modifications, and reductions of glycophorin A, band 3, and RBC thiols [ 7 , 18 , 19 ]. Rheological blood properties were demonstrated to progressively deteriorate as pulmonary insufficiency increases in patients with chronic bronchitis [ 18 ].…”

Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease

“…Inhibition of NOX4 expression was markedly slowing COPD progress by modulating ROS production in ASM [ 9 ]. Sul-121 is a novel compound with anti-oxidative capacity and can effectively inhibit airway inflammation and airway hyperresponsiveness in COPD models by reducing intracellular reactive oxygen species production in ASM [ 55 ]. Leptin receptor increased expressed on ASM of COPD and has be found inhibited ASM proliferation, migration and eotaxin production through stimulating ASM to secrete prostaglandin E2 [ 56 ].…”