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The Adenosine A2a Receptor Inhibits Matrix-Induced Inflammation in a Novel Fashion

¹ Department of Medicine, Division of Pulmonary and Critical Care Medicine, and ² The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Maureen R. Horton, M.D., 1830 E. Monument Street, 5th floor, Baltimore, MD 21205. E-mail: mhorton2{at}jhmi.edu

Endogenous mediators within the inflammatory milieu play a critical role in directing the scope, duration, and resolution of inflammation. High-molecular-weight extracellular matrix hyaluronan (HA) helps to maintain homeostasis. During inflammation, hyaluronan is broken down into fragments that induce chemokines and cytokines, thereby augmenting the inflammatory response. Tissue-derived adenosine, released during inflammation, inhibits inflammation via the anti-inflammatory A2 adenosine receptor (A2aR). We demonstrate that adenosine modulates HA-induced gene expression via the A2aR. A2aR stimulation inhibits HA fragment–induced pro-fibrotic genes TNF-, keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-2, and MIP-1 while simultaneously synergizing with hyaluronan fragments to up-regulate the TH1 cytokine IL-12. Interestingly, A2aR stimulation mediates these affects via the novel cAMP-activated guanine nucleotide exchange factor EPAC. In addition, A2aR-null mice are more susceptible to bleomycin-induced lung injury, consistent with a role for endogenous adenosine in inhibiting the inflammation that may lead to fibrosis. Indeed, the bleomycin treated A2aR-null mice demonstrate increased lung inflammation, HA accumulation, and histologic damage. Overall, our data elucidate the opposing roles of tissue-derived HA fragments and adenosine in regulating noninfectious lung inflammation and support the pursuit of A2aR agonists as a means of pharmacologically inhibiting inflammation that may lead to fibrosis.

Key Words: adenosine • hyaluronan • chemokines • lung fibrosis

CLINICAL RELEVANCE Endogenous mediators are critical in the scope, duration, and resolution of inflammation. We show that adenosine modulates hyaluronan-induced genes via the A2a receptor, and thus elucidate the roles of hyaluronan fragments and adenosine in lung inflammation.

 

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