Oxidative/nitrosative stress selectively altered A2B adenosine receptors in chronic obstructive pulmonary disease

The primary aim of this study was to investigate adenosine receptors (ARs) in bronchoalveolar lavage (BAL) macrophages from patients with chronic obstructive pulmonary disease (COPD) and age‐matched healthy smokers. A2BARs were significantly decreased in BAL macrophages from patients with COPD when compared with healthy smokers. The effect of proinflammatory cytokines and oxidative/ nitrosative stress on AR expression and function in U937 cells before and after PMA treatment was evaluated. IL‐1 β and TNF‐α treatment up‐regulated A2A‐ and A3ARs but not A1‐ or A2BARs, whereas IL‐6 did not modify AR expression. In contrast, oxidative/nitrosative stress selectively decreased A2BAR expression, which was associated with a reduction in the potency of the adenosine agonist 5′‐N‐ethylcarboxamideadenosine (NECA) to induce cAMP. Further, the ability of NECA to enhance cell proliferation was increased after oxidative/nitrosative stress. The specific involvement of A2BARs was investigated by using potent and selective A2BAR antagonist and by A2BAR knockdown using siRNA and demonstrated responses similar to those obtained with oxidative/nitrosative stress. N‐acetylcysteine (NAC), an antioxidant agent, counteracted the decrease in A2BAR expression, as well as the altered NECA effects on cAMP and cell proliferation. These findings highlight the central role of A2BARs in alveolar macrophages, suggesting that their modulation could represent an innovative pharmacological strategy to manage COPD.—Varani, K., Caramori, G., Vincenzi, F., Tosi, A., Barczyk, A., Contoli, M., Casolari, P., Triggiani, M., Hansel, T., Leung, E., MacLennan, S., Barnes, P. J., Fan Chung, K., Adcock, I., Papi, A., Borea, P. A. Oxidative/nitrosative stress selectively altered A2B adenosine receptors in chronic obstructive pulmonary disease. FASEB J. 24, 1192–1204 (2010). www.fasebj.org