Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia.

Kathryn E Barletta, R Elaine Cagnina, Marie D Burdick, Joel Linden, Borna Mehrad

American journal of respiratory and critical care medicine 2012 Nov 15

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Activation of the adenosine A(2B) receptor (A(2B)R) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance. To test the hypothesis that absence of adenosine A(2B) receptor signaling promotes host defense against bacterial pneumonia. We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A(2B)R. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro. A(2B)R(-/-) mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow-derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A(2B)R(-/-) and wild-type mice, but A(2B)R(-/-) neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A(2B)R(-/-) mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia. These data suggest that the absence of A(2B)R signaling enhances antimicrobial activity in gram-negative bacterial pneumonia.

Citation

Kathryn E Barletta, R Elaine Cagnina, Marie D Burdick, Joel Linden, Borna Mehrad. Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia. American journal of respiratory and critical care medicine. 2012 Nov 15;186(10):1044-50