guanosine-triphosphate and Asthma

Asthma, a disease that affects nearly 15% of the world's population, is characterised by lung inflammation and reversible airway obstruction, which leads to wheezing and dyspnoea. Asthma is a prototype for allergic processes initiated by tissue inflammatory leukocytes, such as mast cells, whose secreted mediators recruit lymphocytes and eosinophils to the lung parenchyma. Signals transmitted through G-protein-coupled receptors (GPCRs) contribute to both the development and perpetuation of allergic processes, and pharmacological agents that block or stimulate GPCR action have been a mainstay of allergic disease therapy. Despite the widespread use of GPCR-targeted agents, little is understood about intracellular regulation of G protein pathways in immune cells. Regulators of G protein signalling (RGS proteins) enhance G protein deactivation and may contribute to the specificity and precision characteristic of GPCR signalling pathways. This review discusses the emerging functions of RGS proteins in immune processes and inflammatory states such as asthma, and their potential value as therapeutic targets for the treatment of allergic disease.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Drug Design; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine Triphosphate; Heterotrimeric GTP-Binding Proteins; Humans; Inflammation; Mice; Mice, Transgenic; Multigene Family; Receptors, G-Protein-Coupled; RGS Proteins; Signal Transduction

NO synthase was studied in intact rats and in rats with bronchial asthma epitheliocytes after inhalation of phenotherol, propranolol, guanosine triphosphate (GTP) and combined inhalation of GTP with phenotherol. NO synthase mediator action on bronchial patency during adrenoagonists and GTP inhalation was demonstrated.

Topics: Administration, Inhalation; Adrenergic Agonists; Adrenergic Antagonists; Animals; Asthma; Bronchi; Bronchodilator Agents; Drug Interactions; Epithelial Cells; Fenoterol; Guanosine Triphosphate; Nitric Oxide Synthase; Propranolol; Rats

It has been proposed that reduced beta-adrenergic responsiveness plays an important role in the increased airway reactivity of asthmatic patients. This hypothesis has been supported by studies showing reduced beta-adrenergic responsiveness in lymphocytes of asthmatic patients, predominantly during the occurrence of active and severe symptoms. Little is known about the mechanism underlying this relationship and its clinical relevance with respect to bronchial hyperreactivity. Therefore, in this study we assessed the status of the beta-adrenergic receptor-adenylate cyclase system in lymphocytes of allergic asthmatic patients in relation to parameters of bronchial hyperreactivity. This was performed before and after challenge with house-dust mite allergen, as a possible modulating factor of beta-adrenergic responsiveness. It was shown that lymphocytes of 'stable' allergic asthmatic patients with increased airway reactivity may have normal beta-adrenergic responsiveness and a normal beta-adrenergic receptor number. After allergen challenge, however, a group of 12 patients developed reduced beta-adrenergic responsiveness, which could be partially attributed to changes in the beta-adrenergic receptor number, while changes distal to the receptor also occurred. The results indicate that reduced beta-adrenergic responsiveness in lymphocytes of allergic asthmatic patients is a consequence of an active disease state rather than the reflection of a primary aetiological factor. A number of the patients concomitantly developed enhanced bronchial reactivity to propranolol after allergen challenge, which might indicate that reduced beta-adrenergic receptor function also occurs at the level of the bronchial tree. In five of the patients it was shown that beta-adrenergic hyporesponsiveness could be restored after environmental control in combination with drug treatment, thus indicating the dynamic character of the lymphocyte beta-adrenergic receptor system in asthmatic patients.

Topics: Adenylyl Cyclases; Adolescent; Adult; Asthma; Bronchial Provocation Tests; Cell Membrane; Dihydroalprenolol; Female; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Isoproterenol; Lymphocytes; Male; Propranolol; Receptors, Adrenergic, beta; Respiratory Hypersensitivity