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

Kyung Sun Lee,Liangchang Li,Sun Mi Jin,Hee Sun Park,Yong Chul Lee,So Ri Kim,Kyung Hoon Min,Seoung Ju Park

doi:10.1038/emm.2006.27

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.

Highlights

Bronchial asthma is a chronic inflammatory disease of the airways characterized by airway eosinophilia, goblet cell hyperplasia with mucus hypersecretion, and hyperresponsiveness to inhaled allergens and nonspecific stimuli, which usually induce increased vascular permeability, resulting in plasma exudation (Kay, 1991; Bousquet et al, 2000)
RT-PCR and real-time RT-PCR analyses showed that receptor activator of NF- B (RANK) mRNA expression in lung tissues was increased at 72 h after OVA inhalation compared with the levels after saline inhalation (Figure 2A and B)
Bronchial asthma is characterized by inflammation of the airways which is usually accompanied by increased vascular permeability, resulting in plasma exudation

Summary

Introduction

Bronchial asthma is a chronic inflammatory disease of the airways characterized by airway eosinophilia, goblet cell hyperplasia with mucus hypersecretion, and hyperresponsiveness to inhaled allergens and nonspecific stimuli, which usually induce increased vascular permeability, resulting in plasma exudation (Kay, 1991; Bousquet et al, 2000). The inflammatory cells recruited to the asthmatic airways have a capability of producing ROS. Evidence for increase oxidative stress in asthma is further provided by the finding of defective endogenous antioxidant capacity in asthmatic patients (Dworski, 2000). L-2-Oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, works as an antioxidant by increasing intracellular glutathione level (Asti et al, 1995; Blesa et al, 2002). OTC raises the plasma concentrations of cysteine, which is the rate-limiting amino acid for intracellular GSH synthesis (Porta et al, 1991; Vita et al, 1998; Oiry et al, 1999). GSH is synthesized from cysteine and is a vital intra- and extracellular

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Conclusion