Interaction between cigarette smoke and cyclic AMP signaling in human bronchial epithelial function

COPD is a chronic inflammatory disease characterized by infiltration of inflammatory cells. Airway smooth muscle and epithelial cells contribute to inflammatory cytokine release and airway remodeling. Notably, cAMP‐elevating drugs such as β 2 ‐agonists and phosphodiesterase inhibitors diminish COPD symptoms. Compartimentalization of cAMP and its effectors by A‐kinase anchoring proteins (AKAPs) may explain distinct cellular responses to cAMP. We studied the impact of the β 2 ‐agonist fenoterol, Epac‐specific 8‐pCPT‐2′‐ O ‐Me‐cAMP and PKA‐specific 6‐Bnz‐cAMP on cigarette smoke extract (CSE)‐induced interleukin‐8 (IL‐8) release from human bronchial epithelial (HBE) cells. To interfere with AKAP functions, binding of PKA to all AKAPs was blocked by HT31. Barrier functions were monitored by ECIS and ZO‐1 or E‐cadherin staining. Expression of AKAPs was assessed by qPCR and western blots. Exposure of HBE cells to CSE enhanced IL‐8 release, reduced barrier function, and redistributed E‐cadherin from cell‐cell contacts. Such processes were sensitive to cAMP, its effectors and to HT31. CSE reduced AKAP250 in HBE cells but increased AKAP450 leaving AKAP79 nearly unaffected. We conclude that CSE‐induced changes in human bronchial epithelial functions are profoundly regulated by cAMP and its effectors PKA, Epac and AKAPs. (Supported by the Dutch Asthma Foundation and a Rosalind Franklin Fellowship to M. Schmidt).