Oxidative/nitrosative stress selectively altered A(2B) 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. A(2B)ARs 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-1beta and TNF-alpha treatment up-regulated A(2A)- and A(3)ARs but not A(1)- or A(2B)ARs, whereas IL-6 did not modify AR expression. In contrast, oxidative/nitrosative stress selectively decreased A(2B)AR 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 A(2B)ARs was investigated by using potent and selective A(2B)AR antagonist and by A(2B)AR knockdown using siRNA and demonstrated responses similar to those obtained with oxidative/nitrosative stress. N-acetylcysteine (NAC), an antioxidant agent, counteracted the decrease in A(2B)AR expression, as well as the altered NECA effects on cAMP and cell proliferation. These findings highlight the central role of A(2B)ARs 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 A(2B) adenosine receptors in chronic obstructive pulmonary disease.
Varani
Katia
K
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Caramori
Gaetano
G
Vincenzi
Fabrizio
F
Tosi
Alice
A
Barczyk
Adam
A
Contoli
Marco
M
Casolari
Paolo
P
Triggiani
Massimo
M
Hansel
Trevor
T
Leung
Edward
E
Maclennan
Stephen
S
Barnes
Peter J
PJ
Chung
Kian Fan
KF
Adcock
Ian
I
Papi
Alberto
A
Borea
Pier Andrea
PA
D000111:Acetylcysteine / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000368:Aged; D018893:Bronchoalveolar Lavage; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000096:biosynthesis* / Q000235:genetics; D012907:Smoking / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells; D014665:Vasodilator Agents / Q000494:pharmacology
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D016207:Cytokines; D016166:Free Radical Scavengers; D034741:RNA, Small Interfering; D043704:Receptor, Adenosine A2B; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; D000111:Acetylcysteine