Nocturnal worsening of asthma, hereby referred to as nocturnal asthma, affects up to 75% of chronic stable asthmatics. It is characterized by decreased lung function at night in associated with increased inflammatory cell influx into the airways and alveolar tissue. Because it is a naturally occurring, unchallenged model of asthma in humans, unique mechanistic information about the inflammatory response can be obtained. In this proposal, mechanisms governing the inducing of steroid resistance by increased inflammation at night and how these mechanisms governing the induction of steroid resistance by increased inflammation at night and how this process modulates the airway remodeling process will be determined. The global hypothesis of this proposal is that cytokines, interleukin (IL)-4 and IL-13, are increased at night and induce a state of reduced steroid responsiveness. This state further enhances the production of other inflammatory mediators, such as tumor necrosis factor-alpha) by the alveolar macrophage. This increased inflammation culminates in enhanced necrosis factor-alpha (TNF-alpha) by the alveolar macrophage. This increased inflammation culminates in enhanced airway fibroblast leading to airway structural changes or remodeling. To confirm or refute this hypothesis, the first specific aim will determine if glucocorticoid receptor-beta (GR-beta), a form of the glucocorticoid receptor that is not transcriptionally active, is increased at night in nocturnal asthma, and whether its expression is associated with reduced steroid responsiveness at night in nocturnal asthma, and whether its expression is modulated by the cytokines IL-4 and IL-13. The third and fourth specific aims will determine whether these cytokine salter airway fibroblast function and enhance the remodeling process. Specifically, specific aim 3 will determine whether receptors for GR-beta, IL-4 and IL- 13 are present on the airway fibroblast, and whether these cytokines modulate GR-beta expression in the fibroblast. The fourth specific aim will determine whether IL-4 and IL-13 promote airway remodeling by directly altering fibroblast function, or by inducing a functional state of corticosteroid resistance. We will also determine if the effects of IL-4 and IL-13 on fibroblasts are enhance by production of TNF-alpha, as it is increased at night in nocturnal asthma, and exerts fibrogenic properties. The significance of this proposal is that it will add important information regarding the pathophysiology of airway inflammation and the airway structural changes we refer to as airway remodeling. Through understanding of the effects of IL-4 and IL-13 on GR-beta regulation in airway inflammatory cells and fibroblasts, and the functional consequences of reduced steroid responsiveness, direct therapeutic strategies can be designed to decreased inflammation, alter the remodeling process and ultimately improve asthmatic symptoms and lung function.
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