Airway inflammation is thought to play a critical role in the pathogenesis of chronic asthma. Glucocorticoids form the mainstay of anti-inflammatory therapy in this disease. Several studies have demonstrated that not all asthmatics have improvement in pulmonary function following glucocorticoid therapy. These patients are subjected to the unwanted side effects of prolonged systemic glucocorticoid therapy, often in situations where there is no evidence that it is exerting any appreciable benefit. The clinical characteristics and mechanisms of steroid resistance in these patients are poorly understood. The present proposal will examine the role of steroid pharmacokinetics and immune mechanisms in the pathogenesis of steroid resistance in asthma. We expect to find 2 subsets of asthmatics with poor response to steroid therapy: one subset will have abnormal glucocorticoid pharmacokinetics such that glucocorticoids are not reaching the target tissue sites as therapeutically active concentrations. The second subset will have abnormal glucocorticoid receptor (GR) number or function in their macrophages or a critical regulatory T cell involved in the termination of immune responses in the airway. The failure to terminate ongoing airway inflammation may result in airway fibrosis and the failure to improve pulmonary function despite steroid therapy.
Our specific aims will include characterization of the phenotype and cytokine production by T cells from peripheral blood and bronchoaveolar lavage (BAL) of patients with steroid resistant asthma and steroid responsive asthma prior to and/or following a course of steroid therapy. The basis for their steroid resistance will be studied by examining the mechanism for steroid mediated enhancement of their PHA induced lymphocyte responses, and evaluating GR number and function of freshly isolated subpopulations of peripheral blood mononuclear cells (PBMC) as well as T cell lines and T cell clones derived from these patients. Bronchial biopsies will be obtained to assess the degree of inflammation and fibrosis of their airways. The elucidation of mechanisms underlying steroid resistance will undoubtedly have important consequences for more objective criteria to diagnose this condition, and the development of alternative therapeutic modalities in the treatment of this disease as well as other inflammatory conditions where similar pathologic mechanisms may exist.
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