The pharmaceutical component of asthma therapy involves the use of various medications, delivery systems, and doses of bronchodilator and anti-inflammatory agents depending on the age of the patient and their disease severity. Despite the availability of multiple medications which have demonstrable efficacy in selected patients, the overall trends indicate that asthma is still not well controlled, and in many parts of the world actually is increasing in prevalence and severity. The inflammatory nature of asthma, potentially related to both genetic (atopy, lung size) and environmental factors (allergen exposure, viral infections, smoke exposure), has recently come under intense study. Unfortunately, despite aggressive basic and clinical research efforts, the precise biologic, immunologic and physiologic factors relevant to the initiation and the propagation of this inflammatory response are still not established. Moreover, despite the availability of drugs that are considered to be anti-inflammatory (cromolyn, nedocromil sodium, corticosteroids), many asthma patients' symptoms are inadequately controlled and a """"""""cure"""""""" has not been remotely possible. However, using knowledge available from the investigation of the pathogenesis of immunoinflammatory responses in a number of other disease states, we feel it is now possible to use this information and directly apply it to the asthmatic patient. In this regard, the participation of various cytokine networks, as well as adhesion molecules interacting with specific cell surface ligands, has been demonstrated to be critical in the development of tissue inflammation. The presence of cytokines in asthmatic bronchoalveolar lavage fluid, and the relevance of adhesion molecule expression to the development of airway eosinophilia and hyper- responsiveness in primates, has underscored the potential relevance of these inflammatory networks in asthma. With the development of specific cytokine and adhesion molecule antagonists, the relative importance of these biologic interactions can now be more specifically addressed with regard to both the pathogenesis and treatment of asthma. Therefore, we propose to develop strategies by which some of these new treatment alternatives can be evaluated using two distinct asthmatic populations that, by inference, may differ in their ongoing airway inflammatory response either quantitatively or qualitatively. The two protocols are as follows: first, in mild to moderate asthmatic patients, a protocol analyzing the effectiveness of a cytokine antagonist (rhu IL-1R) and second, in corticosteroid-dependent asthmatic patients, a protocol using an immunosuppressive agent which may affect adhesion molecule expression (mycophenolic acid).
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