THE AIRWAY ANTIINFLAMMATORY EFFECTS OF FLUTICASONE PROPIONATE

Studies over the last decade have elucidated the pathogenetic mechanis ms involved in the inflammatory processes that occur in the respirator y tract in asthma and allergic rhinitis. These diseases are accompanie d by an increase in inflammatory cell populations in the epithelium an d submucosa. Mast cells degranulate in response to allergen, leading t o release of inflammatory mediators and an immediate inflammatory resp onse. The late response to allergen challenge, occurring 8-24 h later, can be linked to presentation of allergen by Langerhans' dendritic ce lls to T-lymphocytes and the generation by sensitized T-cells of cytok ines with a TH2 profile (interleukins 4, 5 and 13). These cytokines, a long with GM-CSF, lead to eosinophil infiltration and stimulate B-cell IgE production. Cytokine production from mast cells (TNF alpha; IL-4, IL-5, IL-13) as well as T-lymphocytes, contributes to the activation of structural cells - mainly epithelium and endothelium - which expres s adhesion molecules and chemokines leading to further inflammatory ce ll infiltration. These processes also underly chronic inflammation in naturally occurring clinical disease. Glucocorticoids, and fluticasone propionate in particular, have been found to modify this inflammatory process, largely through their potential to inhibit transcription fac tor activity. Transcription factors such as NF-kappa B and AP-1, when upregulated, are responsible for the induced activity of many pro-infl ammatory genes involved in allergic inflammation. Studies in vitro hav e shown that T-cells are extremely sensitive to glucocorticoids, with fluticasone propionate inhibiting both their proliferation and cytokin e production. Although mast cell degranulation and release of preforme d mediators is not steroid-sensitive, cytokine synthesis by this cell population is sensitive to inhibition by fluticasone propionate. The c ytokine, chemokine and adhesion molecule synthesis by structural cells (especially TNF alpha production and E selectin expression) is also i nhibited by fluticasone propionate. This activity in reducing cytokine and chemokine synthesis modifies the cell infiltration and cell activ ation of other cells such as eosinophils. In addition, glucocorticoids directly promote eosinophil apoptosis thereby decreasing their tissue survival. In vivo studies in humans and animal models, involving the upper and lower airways, have verified many of the in vitro findings, both in studies using acute allergen challenge and in those investigat ing the chronic inflammatory state. Fluticasone propionate has been fo und to reduce airway epithelial dendritic cell, mast cell, eosinophil and T-lymphocyte infiltration, submucosal eosinophil accumulation and to decrease epithelial and endothelial cell activation. These airway a nti-inflammatory effects are associated with a reduction in mediator r ecovery from the airways. These profound effects on airway inflammatio n relate to the fundamental effect of glucocorticoids in modifying gen e transcription and underlie the clinical benefits of this inhaled the rapy in improving lung function, reducing the level of bronchial hyper -responsiveness, reducing bronchodilator requirements and reducing sym ptom expression. This global effect has been recognized in the primary positioning of inhaled glucocorticoid therapy, such as fluticasone pr opionate, in national and international guidelines for the management of patients with asthma and rhinitis.