Exp Mol Med.  2007 Dec;39(6):756-768.

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha

• Lee KS
• Kim SR
• Park HS
• Park SJ
• Min KH
• Lee KY
• Choe YH
• Hong SH
• Han HJ
• Lee YR
• Kim JS
• Atlas D
• Lee YC

Abstract

Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

Keyword

hypoxia-inducible factor-1, alpha subunit; lung inflammation; N-acetylcysteinamide; NF-kappaB; oxidative stress; respiratory hypersensitivity

MeSH Terms

Acetylcysteine/*analogs & derivatives/therapeutic use
Animals
Asthma/drug therapy/*immunology/pathology
Bronchial Hyperreactivity/*drug therapy/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
Mice
NF-kappa B/*metabolism
Ovalbumin/immunology
Reactive Oxygen Species/*metabolism
Vascular Endothelial Growth Factor A/metabolism