ovalbumin and 2-oxothiazolidine-4-carboxylic-acid

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.

Topics: Animals; Antioxidants; Asthma; Blotting, Western; Bronchoalveolar Lavage Fluid; Capillary Permeability; Female; Gene Expression; Glycoproteins; Immunohistochemistry; Mice; Mice, Inbred C57BL; Osteoprotegerin; Ovalbumin; Phosphorylation; Prodrugs; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrrolidonecarboxylic Acid; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Receptors, Vascular Endothelial Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazoles; Thiazolidines; Vascular Endothelial Growth Factor A

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Oxidative stress plays critical roles in airway inflammation. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce increased vascular permeability are not clearly understood. We have used a murine model of asthma to evaluate the effect of l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine that acts as an antioxidant, more specifically in the increase of vascular permeability. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of vascular endothelial growth factor (VEGF). Administration of OTC markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that at 72 h after ovalbumin inhalation, increased levels of hypoxia-inducible factor-1alpha (a transcriptional activator of VEGF) in nuclear protein extracts of lung tissues were decreased by the administration of OTC. These results indicate that OTC modulates vascular permeability by lowering VEGF expression.

Topics: Animals; Asthma; Capillary Permeability; Female; Mice; Mice, Inbred BALB C; Ovalbumin; Phosphatidylinositol 3-Kinases; Phosphorylation; Prodrugs; Pyrrolidonecarboxylic Acid; Reactive Oxygen Species; Thiazoles; Thiazolidines; Thioctic Acid; Vascular Endothelial Growth Factor A

Oxidative stress plays an important role in the pathogenesis of bronchial asthma. An excess production of reactive oxygen species (ROS) and defective endogenous antioxidant defense mechanisms may be present in asthma. Reduced glutathione (GSH) is one of the most important reducing agents against oxidant free radicals. A reducing agent, L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, increases intracellular GSH. We have used a mouse model for asthma to determine effects of OTC on allergen-induced bronchial inflammation and airway hyper-responsiveness. The administration of OTC reduced bronchial inflammation and airway hyper-responsiveness. ROS generation in bronchoalveolar lavage fluids was increased by ovalbumin (OVA) inhalation, but this increase was diminished by administration of OTC. The increased IL-4, IL-5, IL-13, and eosinophil cationic protein levels in lungs after OVA inhalation were significantly reduced by the administration of OTC. In addition, the increased expression of ICAM-1, VCAM-1, RANTES, and eotaxin in lungs after OVA inhalation was significantly reduced by the administration of OTC. We also showed that the increased NF-kappaB levels in nuclear protein extracts of lung tissues at 72 h after OVA inhalation were decreased by the administration of OTC. These findings suggest that OTC may reduce airway inflammation and hyper-responsiveness through regulation of NF-kappaB activity.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchitis; Cell Adhesion Molecules; Chemokines; Disease Models, Animal; Eosinophil Cationic Protein; Interleukins; Lung; Mice; NF-kappa B; Ovalbumin; Prodrugs; Pyrrolidonecarboxylic Acid; Reactive Oxygen Species; Thiazoles; Thiazolidines