title: 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.
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.|GRIAC research institute, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.|GRIAC research institute, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Wilfred J
authors.initials: WJ
authors.lastname: Poppinga
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.|GRIAC research institute, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Haoxiao
authors.initials: H
authors.lastname: Zuo
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.
authors.forename: Annet B
authors.initials: AB
authors.lastname: Zuidhof
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.
authors.forename: I Sophie T
authors.initials: IS
authors.lastname: Bos
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Smit
authors.affiliation: Sulfateq B.V. Groningen, the Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vogelaar
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept. Pathology and Medical Biology, Laboratory for Cardiovascular Regenerative Medicine, Groningen, the Netherlands.
authors.forename: Guido
authors.initials: G
authors.lastname: Krenning
authors.affiliation: University of Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.affiliation: Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, Department of Pharmaceutical Sciences, West Palm Beach, FL, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Sulfateq B.V. Groningen, the Netherlands.
authors.forename: Bernard
authors.initials: B
authors.lastname: van Vliet
authors.affiliation: Sulfateq B.V. Groningen, the Netherlands.
authors.forename: Stef
authors.initials: S
authors.lastname: Stienstra
authors.affiliation: Sulfateq B.V. Groningen, the Netherlands.
authors.forename: Adrianus Cornelis van der
authors.initials: AC
authors.lastname: Graaf
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.|GRIAC research institute, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.affiliation: University of Groningen, Department of Molecular Pharmacology, Groningen, the Netherlands.|GRIAC research institute, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D045424:Complex Mixtures / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006801:Humans; D006862:Hydrogen Sulfide / Q000819:agonists / Q000097:blood; D006967:Hypersensitivity / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007249:Inflammation; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung; D008297:Male; D008315:Malondialdehyde / Q000037:antagonists & inhibitors / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013638:Tars / Q000737:chemistry / Q000633:toxicity; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D002839:Chromans; D045424:Complex Mixtures; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010879:Piperazines; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; C000627052:Sul-121; D013638:Tars; D051996:Transcription Factor RelA; C024746:tobacco tar; D008315:Malondialdehyde; D006862:Hydrogen Sulfide