The nocturnal worsening of asthma has a profound effect on patients in regard to daily activities, morbidity and mortality. Investigation into the nocturnal aspect of asthma has enlightened us about the alterations that take place in regard to pathophysiology. Hence, better treatment programs have been developed based upon a chronotherapeutic approach. It appears that a major underlying factor in nocturnal asthma is the inflammatory response which occurs on a circadian basis. The mechanism which initiates this inflammatory cascade is not well understood. This proposal will attempt to establish the sequence of events which occur during the night that trigger the inflammatory response. Our general hypothesis is that in patients with nocturnal asthma, the feedback mechanism to decrease the inflammatory process, i.e., corticotropin releasing hormone and cortisol, is altered and thus leads to the overnight increase in airways inflammation and decrements in lung function. This increase in inflammation includes the production of cytokines IL-2 and IL-4 which cause a reduction in glucocorticoid receptor binding affinity overnight. Thus, we will determine the circadian alterations in CRH in relation to lung function and inflammation. We will then separate the direct effect of CRH by infusion from its effect via increased cortisol output by blockade of adrenal function with metyrapone. Additionally, since we have shown interleukin-1beta(IL-1beta) to be increased at night in bronchoalveolar lavage fluid and IL-1beta is involved in feedback mechanisms of CRH release, its relationship to the inflammatory process will be investigated. Finally, since a reduction in corticosteroid receptor binding affinity occurs with increased inflammation, this aspect will be evaluated in regard to CRH and cortisol control. By establishing the mechanisms which initiate the inflammatory response at night, a better understanding of inflammation in asthma during both day and night will be developed. This will then lead to potentially better therapeutic interventions for all asthma patients.
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