osteoprotegerin and Asthma

To clarify the detailed molecular mechanisms underlying the development of asthma, we assessed the potential immune effects of prenatal osteoprotegerin (OPG) inhibition in the pathogenesis of asthma. The effects of OPG deficiency on the development of asthma were evaluated using an ovalbumin-induced asthma model in OPG knockout mice. Histological analysis demonstrated that OPG was mainly detected in airway epithelial cells in wild type mice. After ovalbumin sensitization and challenge, accumulation of inflammatory cells, gene expression of T helper 2-related cytokines and mucus hypersecretion in lung tissues were inhibited by OPG deficiency. Importantly, the serum level of IgE was not increased in OPG KO mice after ovalbumin sensitization and challenge. Based on these findings, OPG knockout mice were protected against methacholine-induced airway hyperresponsiveness. OPG expression is thought to be essential for induction of the allergic immune response in asthma.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Hypersensitivity; Lung; Mice; Mice, Inbred BALB C; Mice, Knockout; Osteoprotegerin; Ovalbumin

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