Grant: Operating Grant

In asthma there is inflammation of the lung and which, if left uncontrolled, leads to worsening of symptoms, increasing discomfort and disability. If unchecked this results in irreversible airway damage (airways remodelling) and ultimately, in the context of a severe asthma attack, possibly death. Clinically, the most effective drugs to combat lung inflammation are inhaled synthetic glucocorticoids (corticosteroids). By reducing the production of inflammatory mediators that are released by cells in the lung, these drugs resolve lung inflammation to improve asthma symptoms. In this proposal, the molecular mechanisms by which glucocorticoids act to reduce inflammation are examined. Glucocorticoids bind to a specific protein, the glucocorticoid receptor, which represses the synthesis (expression) of multiple inflammatory proteins. While glucocorticoids work in the majority of asthmatics, many individuals could benefit considerably from an improved effectiveness. In this proposal, I critically examine mechanisms by which glucocorticoids may dampen inflammation in the lung. By understanding these processes, we will be better placed to improve the clinical effectiveness of these drugs. Finally, it is possible that not all the effects of glucocorticoids, in respect of modulating inflammation, are anti-inflammatory. By identifying potentially unhelpful aspects of glucocorticoid action, we can again take steps to improve therapies for those asthmatics who do not respond well to existing glucocorticoids.