Therapy Analysis - Asthma
The pathology of asthma
Asthma is a chronic airway disease characterized by degranulated mast cells, infiltration of eosinophils and increased number of activated T-helper 2 cells, which give rise to the clinical symptoms of breathlessness, coughing, tightness of the chest and wheezing. These clinical manifestations are attributed to a multiple array of inflammatory mediators including chemokines, cytokines, growth factors, inflammatory peptides and lipid mediators.
Current pharmacological management of asthma as advised by the British Thoracic Society ranges from the use of shortacting ß2 bronchodilators to long-term oral steroid use. In cases where ß2 agonists are used more than once-daily, these guidelines recommend inhaled steroids as regular prevention therapy. Inhaled steroids are the most effective controllers of the underlying inflammatory processes. Evidence also suggests that at appropriate doses, they may also be safe in infants and young children.
The expression of inflammatory mediators in asthmatics is regulated by pro-inflammatory transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kB). Structural changes in the airways, for example epithelial and smooth muscle cell hyperplasia, are a major source of these mediators. Upon activation, pro-inflammatory transcription factors translocate into the nucleus, and bind to specific regions of DNA and interact with large co-activator molecules that have intrinsic histone acetyltransferase (HAT) activity. Acetylation of histone, fundamental to gene transcription, unwinds DNA to allow RNA polymerase II and basal transcription complexes to initiate transcription. The reversal of this process is mediated by histone deacetylases (HDAC) and corepressors, which suppress gene transcription.
Corticosteroids suppress the production of chemotactic mediators and adhesion molecules, and inhibit the survival of eosinophils, mast cells and T-lymphocytes in the airways. At the protein level, corticosteroids bind to glucocorticoid receptors (GR) in the cytoplasm, which are bound to molecular chaperones, such as heat-shock protein-90, in theirinactive state. Upon activation via corticosteroid binding, GRs dissociate from their molecular chaperones and translocate into the nucleus whereupon they dimerize and bind to glucocorticoid-response elements in the promoter region of steroid-sensitive genes. GR homodimers may bind to promoter regions of genes that encode pro-inflammatory proteins or negative glucocorticoid-response elements. This broad spectrum of anti-inflammatory effects is what led steroids to become the primary choice for chronic asthma.
