Circadian changes in airway function are an important aspect of asthma, as more than 70% of deaths and 80% of respiratory arrests occur during sleep related hours. This alteration in airway function has been linked to eosinophils, which have been shown to be increased at night in the airways of asthmatic patients. However, little is known about the mechanisms of nocturnal worsening of asthma, nocturnal asthma (NA). The global hypothesis of this proposal is that NA is due to production of specific cytokines by activated T lymphocytes in response to a low serum cortisol. These activated T cell products induce a reduction of glucocorticoid receptor (GR) binding affinity and result in increased eosinophil influx into the lung, thus decreasing lung function at night. After initially determining the GR binding affinity of peripheral blood lymphocytes in subjects with NA, non-nocturnal asthma (NNA) and control subjects, the proposal will evaluate if this alteration is inducible in-vitro by the activated T cell products interleukin (IL)-2 and IL-4. These cytokines have been shown to reduce GR binding affinity in steroid resistant asthmatics. If our hypothesis is correct, then T cell IL-2, IL-4, IL-5 and granulocyte-macrophage colony stimulating factor (GMCSF) MRNA expression and product in lung tissue and bronchoalveolar lavage fluid at four time points will be evaluated. IL-5 and GMCSF are involved in eosinophil differentiation and survival, thus their presence is important in evaluation of the kinetics of eosinophil influx into the lung. To determine the effect of decreasing endogenous corticosteroids at night on T lymphocyte function and eosinophil influx, physiologic doses of hydrocortisone to block the nocturnal nadir of cortisol will be infused. To further clarify this relationship, metyrapone will be used to block cortisol output by the adrenal gland. If the hypothesis is correct, hydrocortisone infusion will alter T cell production of the above described cytokines and thereby increasing GR binding affinity. Conversely, metyrapone will result in the opposite effect. The end result will be either an improvement (hydrocortisone infusion) or decrement (metyrapone administration) in lung function. The information gained from this proposal will determine the mechanisms and timing of nocturnal eosinophil influx produced by reduced glucocorticoid receptor binding affinity in the face of low serum cortisol. This information has mechanistic and therapeutic importance for nocturnal asthma, and asthma in general.
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