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

Sci Rep. 2016 May 27;6:26928. doi: 10.1038/srep26928.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antioxidants / pharmacology*
  • Cell Line, Transformed
  • Chromans / chemistry
  • Chromans / pharmacology*
  • 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
  • Hypersensitivity / prevention & control*
  • 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
  • Piperazines / pharmacology*
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / immunology
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Reactive Oxygen Species / antagonists & inhibitors*
  • Reactive Oxygen Species / metabolism
  • Tars / chemistry
  • Tars / toxicity
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / immunology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Chromans
  • Complex Mixtures
  • Interleukin-8
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Piperazines
  • Reactive Oxygen Species
  • Rela protein, mouse
  • Sul-121
  • Tars
  • Transcription Factor RelA
  • tobacco tar
  • Malondialdehyde
  • Hydrogen Sulfide