New avenues for Epac in inflammation and tissue remodeling in COPD

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lung mainly caused by cigarette smoke. The main characteristic of COPD is a progressive loss of lung function due to inflammation and tissue remodeling, including airway fibrosis and emphysema. Little is known about the molecular mechanisms that cause the development and progression of COPD. This thesis aims to acquire more knowledge about these processes, to be able to make steps forward to improve current therapy for COPD.
In this thesis the main focus is on the effector protein of the signaling molecule cyclic AMP, “exchange protein directly activated by cyclic AMP” (Epac), which has two isoforms, Epac1 and Epac2. In airway smooth muscle cells we show that Epac inhibits cigarette smoke extract (CSE)-induced inflammation. Interestingly, Epac1 protein expression is downregulated in lung tissue from COPD patients, which may result from increased expression of miRNA-7. In epithelial cells CSE reduces the expression of the adhesion molecule E-cadherin and the protein AKAP9, leading to reduction of the epithelial barrier that protects the airways against detrimental stimuli. AKAPs form complexes to localize proteins, including Epac, to specific cell compartments, thereby regulating cellular functions. In vivo studies demonstrated that Epac1 and Epac2 are indeed involved in inflammatory and remodeling processes induced by cigarette smoke that are also seen in COPD patients.
The experiments described and discussed in this thesis reveal potential new drug targets that may lead to improved therapy of COPD.