Extracellular cAMP-Adenosine Pathway Signaling: A Potential Therapeutic Target in Chronic Inflammatory Airway Diseases.

Adenosine is a purine nucleoside that, via activation of distinct G protein-coupled receptors, modulates inflammation and immune responses. Under pathological conditions and in response to inflammatory stimuli, extracellular ATP is released from damaged cells and is metabolized to extracellular adenosine. However, studies over the past 30 years provide strong evidence for another source of extracellular adenosine, namely the "cAMP-adenosine pathway." The cAMP-adenosine pathway is a biochemical mechanism mediated by ATP-binding cassette transporters that facilitate cAMP efflux and by specific ectoenzymes that convert cAMP to AMP (ecto-PDEs) and AMP to adenosine (ecto-nucleotidases such as CD73). Importantly, the cAMP-adenosine pathway is operative in many cell types, including those of the airways. In airways, ß2-adrenoceptor agonists, which are used as bronchodilators for treatment of asthma and chronic respiratory diseases, stimulate cAMP efflux and thus trigger the extracellular cAMP-adenosine pathway leading to increased concentrations of extracellular adenosine in airways. In the airways, extracellular adenosine exerts pro-inflammatory effects and induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary diseases. These considerations lead to the hypothesis that the cAMP-adenosine pathway attenuates the efficacy of ß2-adrenoceptor agonists. Indeed, our recent findings support this view. In this mini-review, we will highlight the potential role of the extracellular cAMP-adenosine pathway in chronic respiratory inflammatory disorders, and we will explore how extracellular cAMP could interfere with the regulatory effects of intracellular cAMP on airway smooth muscle and innate immune cell function. Finally, we will discuss therapeutic possibilities targeting the extracellular cAMP-adenosine pathway for treatment of these respiratory diseases.

Extracellular metabolism of 3',5'-cyclic AMP as a source of interstitial adenosine in the rat airways.

In the respiratory tract, intracellular 3',5'-cAMP mediates smooth muscle relaxation triggered by the ß2-adrenoceptor/Gs protein/adenylyl cyclase axis. More recently, we have shown that ß2-adrenoceptor agonists also increase extracellular 3',5'-cAMP levels in isolated rat trachea, which leads to contraction of airway smooth muscle. In many other tissues, extracellular 3',5'-cAMP is metabolized by ectoenzymes to extracellular adenosine, a catabolic pathway that has never been addressed in airways. In order to evaluate the possible extracellular degradation of 3',5'-cAMP into 5'-AMP and adenosine in the airways, isolated rat tracheas were incubated with exogenous 3',5'-cAMP and the amount of 5'-AMP, adenosine and inosine (adenosine metabolite) produced was evaluated using ultraperformance liquid chromatography-tandem mass spectrometry. Incubation of tracheal tissue with 3',5'-cAMP induced a time- and concentration-dependent increase in 5'-AMP, adenosine and inosine in the medium. Importantly, IBMX (non-selective phosphodiesterase (PDE) inhibitor) and DPSPX (selective ecto-PDE inhibitor) reduced the extracellular conversion of 3',5'-cAMP to 5'-AMP. In addition, incubation of 3',5'-cAMP in the presence of AMPCP (inhibitor of ecto-5'-nucleotidase) increased extracellular levels of 5'-AMP while drastically reducing extracellular levels of adenosine and inosine. These results indicate that airways express an extracellular enzymatic system (ecto-phosphodiesterase, ecto-5'-nucleotidase and adenosine deaminase) that sequentially converts 3',5'-cAMP into 5'-AMP, adenosine and inosine. The observation that extracellular 3',5'-cAMP is a source of interstitial adenosine supports the idea that the extrusion and extracellular metabolism of 3',5'-cAMP has a role in respiratory physiology and pathophysiology.