Effects of intranasal treatment with slow (GYY4137) and rapid (NaHS) donors of hydrogen sulfide in lipopolysaccharide-induced airway inflammation in mice

Pulm Pharmacol Ther. 2017 Aug;45:170-180. doi: 10.1016/j.pupt.2017.06.006. Epub 2017 Jun 20.

Abstract

We have investigated the effects of slow (GYY4137) and rapid (NaHS) hydrogen sulfide (H2S) releasing donors in lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS (0.1 mg/ml) in 60 μl PBS was administered by the intranasal (i.n.) route and control group received vehicle, whereas the subgroups of mice were treated with i.n. GYY4137 or NaHS. The tracheal reactivity, inflammatory cell count in bronchoalveolar lavage (BAL) fluid and lung histopathology were evaluated in all groups 48 h after LPS/PBS applications. 5-Hydroxytryptamine (5-HT)-induced contraction response in isolated tracheas was enhanced after LPS treatment but carbachol response was not altered. Incubation with atropine (10-6 M), 5-HT2A receptor antagonist ketanserin (10-9-10-7 M) and 5-HT3 receptor antagonist alosetron (10-8 and 10-7 M) prevented 5-HT-induced hyperreactivity whereas 5-HT4 receptor antagonist GR113808 (10-7 M, 10-6 M) did not have any effect in LPS-treated group. Electrical field stimulation (EFS) of isolated tracheas elicited frequency-dependent contractile response, which was not altered by LPS treatment alone but was enhanced in the presence of 5-HT (10-9-10-4 M). This data indicated that 5-HT2A and 5-HT3 receptors, and acetylcholine released from cholinergic nerves were contributing to 5-HT-induced hyperreactivity in the present experiments. The increase in neutrophil count along with cytokine (IL-1β, TNF-α) levels in bronchoalveolar lavage (BAL) fluid and histopathological changes like paranchymal inflammation and interalveolar thickening were determined in LPS-treated mice. H2S production in lung homogenates were determined by the methylene blue assay, and found to be similar in both LPS and control groups. The experiments conducted after i.n. treatment with H2S donors has shown that only GYY4137 (1 mg/kg) inhibited 5-HT-induced hyperreactivity, and both GYY4137 and NaHS (1 mg/kg) prevented the neutrophil increase in BAL fluid in LPS-induced airway inflammation. IL-1β increase in BAL fluid was abolished by both GYY4137 and NaHS treatments whereas TNF-α levels remained unchanged. Furthermore, GYY4137 treatment did not have any effect in LPS-induced changes of lung pathology whereas NaHS prevented the paranchymal inflammation. The different H2S releasing pattern of these donors may explain the difference of their effects in this model. Compounds that provide stable H2S levels via local application may be a new therapeutic approach in airway inflammation.

Keywords: Airway hyperreactivity; Airway inflammation; GYY4137; Hydrogen sulfide; Mice.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Bronchial Hyperreactivity / prevention & control
  • Bronchoalveolar Lavage Fluid
  • Cytokines / metabolism
  • Female
  • Hydrogen Sulfide / pharmacology*
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / toxicity
  • Lung / pathology
  • Mice
  • Morpholines / administration & dosage*
  • Morpholines / pharmacology
  • Neutrophils / metabolism
  • Organothiophosphorus Compounds / administration & dosage*
  • Organothiophosphorus Compounds / pharmacology
  • Serotonin / administration & dosage
  • Serotonin / metabolism
  • Sulfides / administration & dosage*
  • Sulfides / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • GYY 4137
  • Interleukin-1beta
  • Lipopolysaccharides
  • Morpholines
  • Organothiophosphorus Compounds
  • Sulfides
  • Tumor Necrosis Factor-alpha
  • Serotonin
  • sodium bisulfide
  • Hydrogen Sulfide