Exp Mol Med.  2006 Jun;38(3):217-229.

An antioxidant modulates expression of receptor activator of NF-kappaB in asthma

• Lee KS
• Park HS
• Park SJ
• Kim SR
• Min KH
• Jin SM
• Li L
• Lee YC

Abstract

Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-kappaB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.

Keyword

capillary permeability; eosinophilia; oxidative stress; signal transduction; vascular endothelial growth factor

MeSH Terms

Vascular Endothelial Growth Factor A/analysis/antagonists & inhibitors/metabolism
Thiazolidines
Thiazoles/*pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
Receptors, Tumor Necrosis Factor/genetics/*metabolism
Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
Reactive Oxygen Species/metabolism
RNA, Messenger/genetics/metabolism
Pyrrolidonecarboxylic Acid
Proto-Oncogene Proteins c-akt/metabolism
Protein Kinase Inhibitors/pharmacology
Prodrugs/pharmacology
Phosphorylation/drug effects
Ovalbumin/immunology
Osteoprotegerin
Mice, Inbred C57BL
Mice
Immunohistochemistry
Glycoproteins/genetics/*metabolism
Gene Expression/drug effects
Female
Capillary Permeability/drug effects
Bronchoalveolar Lavage Fluid/chemistry/cytology
Blotting, Western
Asthma/*drug therapy/immunology/metabolism
Antioxidants/*pharmacology
Animals