Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury.
Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883-treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy.
Sun
Chun-Xiao
CX
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston 77030, USA.
Zhong
Hongyan
H
Mohsenin
Amir
A
Morschl
Eva
E
Chunn
Janci L
JL
Molina
Jose G
JG
Belardinelli
Luiz
L
Zeng
Dewan
D
Blackburn
Michael R
MR
D000241:Adenosine / Q000009:adverse effects*; D000818:Animals; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology*; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
C430917:CVT 3033; D011687:Purines; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; D000241:Adenosine