A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase

So Ri Kim, Kyung Sun Lee, Seoung Ju Park, Kyung Hoon Min, Min Hee Lee, Kyung Ae Lee, Orit Bartov, Daphne Atlas, Yong Chul Lee

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Rationale: Cellular redox homeostasis altered by excessive production of reactive oxygen species (ROS) and weakening of the antioxidant defense leads to oxidative stress. Oxidative stress is characterized as a decrease in glutathione/glutathione disulfide (GSH/GSSG) and the triggering of a number of the redox-sensitive signaling cascades. Recent studieshave demonstrated that ROS play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Objectives: Here we characterized for the first time the protective properties of a new hydrophobic thiol compound, N-acetyl cysteine proline cysteine amide (CB3), in allergic airway diseases. Methods: We used ovalbumin (OVA)-inhaled mice to evaluate the role of CB3 as an antiinflammatory reagent and to determine its molecular signaling activity in allergic airways. Measurements and Main Results: The administration of CB3 (1-50 mg/kg) to OVA-inhaled mice restored the decreased GSH levels, enhanced IL-10 expression, and significantly reduced the increase of Th2 cytokines and OVA-specific IgE. CB3 decreased the number of inflammatory cells and airway hyperresponsiveness in the lungs. We also found that the administration of CB3 dramatically decreased the nuclear translocation of the nuclear factor-κB (NF-κB) and the phosphorylation of p38 mitogen-activated protein kinases (MAPKs) in lungs after OVA inhalation. In addition, allergen-induced airway inflammation and hyperresponsiveness were substantially reduced by the administration of inhibitors of NF-κB and p38 MAPK, BAY 11-7085, and SB 239063, respectively. Conclusions: These results suggest that CB3 attenuates allergic airway disease by up-regulation of GSH levels as well as inhibition of NF-κB and p38 MAPK activity..

Original languageEnglish
Pages (from-to)1015-1024
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15

Keywords

  • Asthma
  • Glutathione
  • N-acetyl cysteine proline cysteine amide
  • Nuclear factor-κb
  • Oxidative stress
  • P38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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