Epac as a novel regulator of airway smooth muscle phenotype and function. Potential implications in asthma and COPD

PhD ceremony: Ms. S.S. Roscioni, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Epac as a novel regulator of airway smooth muscle phenotype and function. Potential implications in asthma and COPD

Promotor(s): prof. M. Schmidt, prof. H. Meurs

Faculty: Mathematics and Natural Sciences

Sara Roscioni has studied the cAMP effector enzyme exchange protein directly activated by cAMP (Epac) as a promising inhibiting mediator of various pathophysiological processes in the airways, such as inflammation and ASM contraction and remodeling.

Astma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases characterized by increased airway smooth muscle (ASM) contractile responsiveness and airway remodeling. Changes in ASM phenotype play an important role in disease pathogenesis as they underpin the abilities of ASM to contract, proliferate and synthetize inflammatory mediators. Cyclic AMP (cAMP)-elevating β2-adrenoceptor agonists are potent bronchodilators, but their effectiveness to inhibit inflammation and subsequent development of airway hyperresponsiveness and remodeling is limited by receptor desensitization. Therefore, post-receptor mechanisms may help to define a more targeted therapeutic intervention. Roscioni demonstrated that Epac induces ASM relaxation and therefore may have an impact on the treatment of airway obstruction in asthma and COPD. In addition, Epac inhibited ASM proliferation induced by growth factors, which may reveal novel promising properties of Epac in the treatment of airway remodeling. Notably, she showed that Epac prevents phenotypic alterations of ASM induced by growth factors, resulting in the maintenance of a normo-contractile, normo-proliferative phenotype. Her data also showed that in ASM cells Epac inhibits cytokine release induced by cigarette smoke, which is a main risk factor in COPD. Remarkably, Roscioni found that chronic exposure to cigarette smoke may reduce Epac expression, which might account for the variable anti-inflammatory potential of current cAMP-directed medications. The results described in her thesis indicate that selective targeting of Epac-regulated signaling in the airways represents a promising approach to exploit the beneficial effects of cAMP in the treatment of airway diseases.