Epac2 and PLCε contribute to the inflammatory response to cigarette smoke in vivo

Abstract

β2‐Agonists increase cellular cAMP by binding to Gs‐coupled receptors, leading to activation of PKA as well as the cAMP‐regulated exchange factors Epac1 and ‐2, the latter known to signal to PLCε. We showed recently that Epac activation reduces cigarette smoke (CS) extract‐induced IL‐8 release from airway smooth muscle cells by inhibiting Nf‐κB. We now studied the role of the Epac signalosome in CS‐induced airway inflammation in vivo. Mice were pretreated with vehicle, the β2‐agonist fenoterol or the Epac1 and ‐2 activator 8‐pCPT and exposed to CS or filtered air for 5 days. In bronchoalveolar lavage fluid of CS exposed wild‐type mice, total inflammatory cells, macrophages and neutrophils were all increased. Treatment with fenoterol or 8‐pCPT did not alter the inflammatory response induced by CS, although fenoterol slightly increased total inflammatory cells in air exposed mice. Compared to wild‐types, the CS‐induced increase in total inflammatory cells, macrophages and neutrophils were reduced in Epac2−/− mice, whereas specifically the neutrophils were reduced in PLCε−/− mice. In conclusion, Epac2 enhances CS‐induced airway inflammation in vivo presumably by activating PLCε. (NAF grant 3.2.09.034)