Grant: Project Grant

Glucocorticoids (GCs) are essential steroid hormones that play key roles in stress and injury. GCs dampen inflammation and promote healing following damage, infection or other inflammatory trauma. In the context of inflammatory diseases, it is the ability to reduce inflammation that makes synthetic GCs (often called "steroids") highly effective and widely used anti-inflammatory drugs. However, resistance to the beneficial effects of GCs is observed in many patients with inflammatory disease. This represents a major and unresolved clinical need. In the current application, we use severe asthma as a model GC resistant disease to explore this problem. Aside from anti-inflammatory actions, endogenous GCs promote a variety of metabolic and other effects, which in the context of high-dose GC therapy produce serious and unwanted complications. Patients with severe asthma in whom inhaled GCs do not provide effective therapy require high-dose, often oral, GCs as therapy. However, even high-dose GC therapy may not control their disease. Nevertheless, while asthma in these individuals is resistant to the anti-inflammatory effects of GC, the GR-dependent side-effects still occur. We therefore investigate molecular mechanisms by which inflammatory genes fail to be repressed by GCs. To gain an understanding of GC-resistance, gene expression in the airways and GC responses in airway epithelial cells is compared between normal individuals, mild/moderate asthma and severe asthma. Understanding GC-resistance will promote new approaches to improve therapy. Importantly, knowing when patients are truly resistant to GC therapy will allow them to be more rapidly transitioned from GC-based interventions to more effective therapies. The current application uses severe asthma to address these issues and the results have the potential to ultimately improve clinical practice.