Mechanisms of Steroid Resistance in Severe Asthma

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Severe asthma [SA] is characterized by inadequate control of asthma symptoms and airway physiology despite good therapy, and therefore is associated with impaired response to the most effective agents for asthma management, namely inhaled corticosteroids [ICS]. Dysfunction of the glucocorticoid receptor [GR] is associated with SA, and is in part a consequence of high levels of cytokines associated with Th2 lymphocyte activation, including IL-4. Recent evidence suggests that nitric oxide [NO] may amplify production of IL-4 in the absence of a key anti-inflammatory cytokine, IL-10. We have shown that IL-10 is deficient in asthma, suggesting that NO may be a critical factor in regulating IL-4. Further, the nuclear transcription factor GATA-3 is essential for Th2 lymphocyte differentiation, and its binding to DNA is inhibited by normal GR. To define the mechanisms of SA, we propose (1) to characterize markers of inflammation and remodeling in SA, and compare to mild-moderate asthma [MMA] which is controlled in ICS, (2) to establish the function of the GR in SA and MMA with two complementary techniques, (3) to characterize GATA-3 expression in SA and MMA, (4) to determine the functional consequences of GR dysfunction on cytokine production and co-stimulatory molecule expression, and (5) to establish the mechanisms by which GR dysfunction occurs, with focus on Th2 cytokines, IL-10, and NO. The PI has an established track record of mechanistic investigations in asthma. Twenty patients with SA are already identified, and links to a minority clinic and managed care with >270,000 covered lives will add to our recruitment capabilities. We offer to the collaborative program (1) an established program of clinical, translational, and basic research in asthma, (2) mechanistic studies to evaluate the development of GR dysfunction in SA, and (3) an innovative question of GATA-3 expression in SA.