Citation | Flower discovered one of the major mechanisms by which anti-inflammatory glucocorticoids act. The prevalent view was that these drugs "stabilised membranes". Flower showed instead that activation of an intracellular glucocorticoid receptor and ongoing RNA and protein synthesis was essential and identified a glucocorticoid-stimulated protein that blocked the generation of pro-inflammatory lipid mediators by restricting the release of substrate fatty acids. He isolated and purified this protein (now called lipocortin 1 or annexin 1) and in collaboration, it was cloned and sequenced. Flower demonstrated that human recombinant lipocortin 1 had potent glucocorticoid-like actions, reducing inflammation and inhibiting pituitary hormone release. Removal of lipocortin 1 using immunoneutralisation or anti-sense strategies blocked glucocorticoid actions in many biological models confirming that this was the main mediator of their action. Flower's concepts of glucocorticoid pharmacology have great explanatory force and his research has been a major step forward in our understanding of how these drugs act. |